FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	JOINT MEETING OF THE
	NONPRESCRIPTION DRUGS ADVISORY COMMITTEE
	AND THE
	ARTHRITIS ADVISORY COMMITTEE

	Tuesday,
	July 20, 1999

	The Ballrooms
	Holiday Inn Gaithersburg
	2 Montgomery Village Avenue
	Gaithersburg, Maryland

IN ATTENDANCE:

Nonprescription Drugs Advisory Committee

ERIC P. BRASS, M.D., Ph.D., Chairman
Chair, Department of Medicine
Harbor-UCLA Medical Center
1000 West Carson Street
Torrance, California  90509

SANDRA TITUS, Ph.D., Executive Secretary
Advisors and Consultants Staff (HFD-21)
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland  20857

GEORGE A. BLEWITT, M.D., Non-Voting Industry Representative
Nonprescription Drug Manufacturers Association
c/o Dr. Lorna Totman
1150 Connecticut Avenue, N.W.
Washington, D.C.  20036

EDWIN E. GILLIAM, Ph.D.
Family Nurse Practitioner
Bone Marrow Transplantation Program
University Physician, Inc.
3695 West Sunbright Drive
Tucson, Arizona  85742-1138

KAREN HAMILTON, Consumer Representative
Director, Department of Consumer Affairs
400 R Street, Suite 3000
Sacramento, California  95814-6200

MARY ANNE KODA-KIMBLE, Pharm.D.
Professor of Clinical Pharmacy
Dean, School of Pharmacy
University of California at San Francisco
513 Parnassus, Room S926
San Francisco, California  94143-0446

EDWARD P. KRENZELOK, Pharm.D.
Director, Pittsburgh Poison Center
Children's Hospital of Pittsburgh
3705 Fifth Avenue

Pittsburgh, Pennsylvania  15213

IN ATTENDANCE:

Nonprescription Drugs Advisory Committee (Continued)

RICHARD A. NEILL, M.D.
Assistant Professor
Department of Family Practice and Community Medicine
University of Pennsylvania College of Medicine
39th and Market Streets, 615 Mutch Building
Philadelphia, Pennsylvania  19104

HARI C. SACHS, M.D.
Coleman, Coleman, and Sachs
11119 Rockville Pike, Suite 310
Rockville, Maryland  20852

Nonprescription Drugs Advisory Committee Consultants

JENNIFER ANDERSON, Ph.D.
Boston University School of Medicine
CHQOER VA Medical Center (152)
200 Springs Road
Bedford, Massachusetts  01730

REBAT HALDER, M.D.
Chairman, Department of Dermatology
Howard University College of Medicine
2041 Georgia Avenue, N.W.
Washington, D.C.  20060

CAROL McNEELY, M.D., Ph.D.
1120 19th Street, Suite 250
Washington, D.C.  20036

Guest Expert

LYNN GERBER, M.D.
Rehab Medicine Department
National Institutes of Health
Building 10, GS 235
9000 Rockville Pike
Bethesda, Maryland  20892

IN ATTENDANCE:

Arthritis Advisory Committee

STEVEN B. ABRAMSON, M.D., Chairman
Chairman of Rheumatology and Medicine
Hospital for Joint Diseases
301 East 17th Street
New York, New York  10003

KATHLEEN REEDY, Executive Secretary
Advisors and Consultants Staff (HFD-21)
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland  20857

JANET D. ELASHOFF, Ph.D.
Director, Division of Biostatistics
Cedars-Sinai Medical Center
8700 Beverly Boulevard
Los Angeles, California  90048

E. NIGEL HARRIS, M.D.
Dean, Department of Internal Medicine
Office of the Dean
Morehouse School of Medicine
720 Westview Drive S.W.
Atlanta, Georgia  30310-1495

DANIEL J. LOVELL, M.D., M.P.H.
Associate Director
Division of Pediatric Rheumatology
Department of Pediatrics
Children's Hospital Medical Center
Pavilion Building, Room 1-29
3333 Burnet Avenue
Cincinnati, Ohio  45229-3039

LEONA M. MALONE, M.S.W., Consumer Representative
8D Lexington Lane East
Palm Beach Gardens, Florida  33418

IN ATTENDANCE: (Continued)

FRANK PUCINO, JR., Pharm.D.
Clinical Care Specialist
Pharmacy Department
National Institutes of Health
Building 10, Room 1N-257
9000 Rockville Pike
Bethesda, Maryland  20892

YVONNE S. SHERRER, M.D.
Assistant Professor of Medicine
Medical Director, Center for Rheumatology,
 Immunology, and Arthritis
University of Miami School of Medicine
5333 North Dixie Highway, Suite 110
Fort Lauderdale, Florida  33334

DAVID E. YOCUM, M.D.
Professor of Medicine
Division of Rheumatology
Department of Medicine
University of Arizona
UMC Building, Room 6409
1501 North Campbell Avenue
Tucson, Arizona  85724

	C O N T E N T S

	PAGE

Call to Order and Introductions

Eric P. Brass, M.D., Ph.D.
NDAC Chair and Joint Meeting Chair	9

Conflict of Interest Statement

Sandra Titus, Ph.D.
Executive Secretary, NDAC	11

Welcome

John E. Hyde, M.D., Ph.D.
Acting Deputy Director
Division of Anti-Inflammatory, Analgesic,
and Ophthalmic Drug Products	13

FDA Presentations on NDA 21-070,
Flexeril 5mg (Cyclobenzaprine HCL)

Background and Efficacy

James P. Witter, M.D., Ph.D.
Medical Officer, DAAO		15

Pharmacokinetics

Sue-Chih Lee, Ph.D.
Pharmacokinetics Reviewer
Division of Pharmaceutical Evaluation III	24

Abuse Potential

Michael Klein, Ph.D.
Senior Interdisciplinary Scientist
Division of Anesthetic, Critical Care,
 and Addiction Drug Products	31

	C O N T E N T S

	PAGE

FDA Presentations (Continued)

Safety

Rosemarie Neuner, M.D., M.P.H.
Medical Officer, Division of Over-the-
 Counter Drug Products	41

Label Comprehension

Kathryn Aikin, Ph.D.
Social Science Analyst, Division of Drug
 Marketing, Advertising, and Communications	50

Neurologic Impact

Linda Katz, M.D., M.P.H.
Deputy Director of OTC	58

Presentations by the Sponsor,
Merck & Company

Introduction

Edwin Hemwall, Ph.D.
Regulatory Affairs	65

Review of Flexeril OTC Development Program

Scott Korn, M.D.
Clinical Research	72

Conclusion

Edwin Hemwall, Ph.D.	114

Questions from Advisory Committees
to FDA Staff and the Sponsor	117

	C O N T E N T S

	PAGE

Open Public Hearing

Larry D. Sasich, Pharm.D.
Public Citizen	146

Questions from Advisory Committees
to FDA Staff and the Sponsor	151

Charge to the Committee

Linda Katz, M.D., M.P.H.	171

Discussion of Questions by
Advisory Committees	172

	P R O C E E D I N G S	(8:30 a.m.)
DR. BRASS:  Good morning.  I'm told this is working.  I'm Eric Brass, chair of the Department of Medicine at Harbor-UCLA Medical Center, and chair of the Nonprescription Drugs Advisory Committee.  I'd like to welcome everybody to this joint meeting of the Nonprescription Drugs Advisory Committee with the Arthritis Advisory Committee to discuss an NDA for 5-milligram Flexeril OTC.
We have a very large group, and so I would like to begin by going around the table and asking everybody to introduce themselves.  That will also allow them to familiarize themselves with this high-tech microphone where you actually have to press the on button before you talk, and then please remember to press the off button because nobody else will be able to talk by pressing the on button.
So if we can start at the far end of the table, please, and if you can introduce yourself?
DR. HALDER:  Rebat Halder, Department of Dermatology, Howard University.
DR. SHERRER:  Yvonne Sherrer, rheumatologist, Fort Lauderdale, Florida.
DR. ANDERSON:  Jennifer Anderson, statistician from Boston, Massachusetts.

DR. KRENZELOK:  Ed Krenzelok, Pittsburgh Poison Center and University of Pittsburgh.
DR. GERBER:  Lynn Gerber, physiatrist-rheumatologist, Clinical Center, NIH.
DR. PUCINO:  Frank Pucino, Pharmacy Department, Clinical Center, NIH.
DR. McNEELY:  Carol McNeely, dermatologist, Washington, D.C.
DR. HARRIS:  Nigel Harris, rheumatologist, Dean, Morehouse School of Medicine.
DR. BLEWITT:  George Blewitt, industry liaison representative to the Nonprescription Drugs Advisory Committee.
DR. YOCUM:  Dave Yocum, University of Arizona, rheumatologist.
DR. SACHS:  Hari Sachs, pediatrics, Rockville, Maryland.
DR. TITUS:  Sandy Titus, the administrator for Nonprescription Drugs Advisory Committee.
DR. NEILL:  Richard Neill, family physician at the University of Pennsylvania.
MS. MALONE:  Leona Malone, consumer rep for the Arthritis Committee, West Palm Beach.

MS. HAMILTON:  Kathleen Hamilton, consumer rep to the Nonprescription Drugs Advisory Committee, and director of the California Department of Consumer Affairs.
DR. ELASHOFF:  Janet Elashoff, biostatistics, Cedar-Sinai and UCLA.
DR. GILLIAM:  Eddie Gilliam, family nurse practitioner, Tucson, Arizona.
DR. LOVELL:  Dan Lovell, pediatric rheumatologist, University of Cincinnati.
DR. HYDE:  John Hyde, Acting Deputy, Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products, FDA.
DR. MIDTHUN:  Karen Midthun, Acting Division Director, Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products, FDA.
DR. KATZ:  Linda Katz, Deputy Director, Division of Over-the-Counter Drug Products.
DR. GANLEY:  Charlie Ganley, Director, Division of Over-the-Counter Drug Products, FDA.
DR. DeLAP:  Robert DeLap, Director, Office of Drug Evaluation V, FDA.
DR. BRASS:  Thank you all.
I'll now ask Dr. Titus to read the conflict of interest statement.

DR. TITUS:  The following announcement addresses conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
Based on the submitted agenda for the meeting and all financial interests reported by the participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research which have been reported by the participants present no potential for a conflict of interest at this meeting, with the following exceptions.  In accordance with 18 U.S.C. 208(b), full waivers have been granted to Dr. Mary Anne Koda-Kimble and Dr. David Yocum.  A copy of these waiver statements may be obtained by submitting a written request to the agency's Freedom of Information office, Room 12A-30, in the Parklawn Building.

In addition, we would like to disclose for the record that Dr. Steven Abramson has an interest in Merck.  Dr. Kenneth Brandt has an interest in Merck, and Johnson & Johnson, the parent company of Ortho-McNeil.  Dr. David Yocum's employer, the University of Arizona, has interests in Novartis.  These unrelated interests do not constitute a financial interest in the particular matter within the meaning of 18 U.S.C. 208.  Notwithstanding these interests, it has been determined that it is in the agency's best interest to have Dr. Abramson, Dr. Brandt, and Dr. Yocum participate fully in all matters concerning Flexeril.
In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.
DR. BRASS:  Thank you.
I'll ask Dr. Hyde now to make some opening remarks.
DR. HYDE:  Good morning and welcome to the members of the Nonprescription Drugs and the Arthritis Advisory Committees, the representatives of Merck, and to the audience.

The purpose of today's meeting is to seek advisory committee input on the application to market the muscle relaxant Flexeril over the counter.  Flexeril is an approved prescription product, but currently there is no muscle relaxant approved for OTC use.  Thus, this application under consideration represents an introduction of a new class of agents into the OTC market.
As Dr. Witter will describe shortly, the topic of muscle relaxants for over-the-counter use has been the focus of a process extending back over a decade.  The activities involved previous advisory committee meetings, several FDA divisions, including the Neuropharmacologic Drug Products, Analgesic and Inflammatory Division, OTC Division, as well as drug companies and members of the public.
A great deal of effort has gone into defining the questions raised by OTC muscle relaxant use and to trying to determine ways in which those questions might best be answered.  Today's meeting is a major milestone in that process.  Previous public meetings have been general or rather theoretical.  Today we have a specific application before us.  Today we have actual study results to consider.  This promises to be a rich advisory committee experience, so in the interest of getting into today's business, I'll yield to the first speaker.
DR. BRASS:  Thank you, Dr. Hyde.

Just a word about the format this morning.  We will begin with the presentations from the FDA, followed by the presentations by sponsor.  Because of the likelihood of many issues being addressed by both sets of presentations, I'm going to ask the committee to hold all questions for the FDA until after the sponsor's presentation, with the only exceptions being very brief questions of clarification.  Otherwise, we will probably be here through tomorrow's meeting discussing this.
So, with that background, I'd like to ask Dr. Witter from the FDA to begin the FDA's presentations.
DR. WITTER:  Can you hear me okay?  Yes.
Good morning and welcome to today's combined meeting of the Nonprescription Drugs Advisory Committee and Arthritis Advisory Committee to consider Flexeril for over-the-counter use.  This should be an interesting discussion, so please do as our friend is doing here and pay close attention.
Next slide.

Besides myself discussing briefly some of the background and efficacy with Flexeril, the other speakers today will be Dr. Lee discussing PK issues, Dr. Paul Andreason discussing the neurologic impact of Flexeril, Dr. Michael Klein discussing the abuse potential, Dr. Rosemarie Neuner discussing safety aspects, and Dr. Kathryn Aikin discussing label comprehension.  I know that our speakers are excited and ready to go, so I'll try and move along here.
Next slide.
As Dr. Hyde has indicated, we have been discussing muscle relaxants in general or consideration for their use over-the-counter for a while now.  This slide attempts to kind of get you some sense of history here.  As you can see, I've broken this up into two groups, one discussing muscle relaxants as a group of drugs and the other as single agents.  The first meeting that I'm aware of was in 1982 when these compounds were in a different division.  There were two subsequent meetings, the most recent being in March of 1995, which was also a combined meeting, as is today.
As single agents, there was a meeting in February of 1997 to discuss whether Soma should be a scheduled compound, and then, of course, we have today's meeting, which is the first to consider use of muscle relaxants over-the-counter in the U.S.
Next slide.

Now, in terms of what's gone on previously, there's been a lot of interesting discussion, as I'm sure there will be today, and I'd like to just present that for a bit here.  In March of 1995, the following five questions were posed to the advisory committee meeting.  I think it's fair to say that we didn't get much beyond the first question, which is:  "Should muscle relaxants be considered for over-the-counter use?"  I think part of the problem was trying to decide things in the absence of data, which is not the problem today.
Next slide.
Some of the discussion at these prior meetings involved the realization, for example, that muscle relaxants are a diverse group of compounds, ranging from compounds such as Parafon Forte to Robaxin to Soma, and, of course, Flexeril.  It was also appreciated that because most of these are old compounds, they were actually DESI'd into use because of the Kefauver-Harris amendment in 1962.  But that was not the case with Flexeril.  Flexeril, as we know, was submitted in December of 1975 and was approved in August of 1997.
Next slide.

The muscle relaxants, other issues were whether there was efficacy, and probably the best way to summarize both the DESI review and the 1994 clinical practice guidelines, which I believe is in your package, is that muscle relaxants as a group are probably more effective than placebo but not NSAIDs, and that contributes to why the labeling says "as an adjunct to" things like rest and physical therapy for the prescription muscle relaxants.
The mechanism of action was discussed and it was generally appreciated that these were not direct peripheral muscle relaxants, and there was a question as to whether, in fact, efficacy was because of their sedative properties.
Next slide.
The other discussion focused on who the target population is and is there a societal benefit for muscle relaxants, especially over-the-counter?  What is the frequency of spasm and pain in areas such as the back, legs, shoulders and neck?  What is the nature of the prescribed use of muscle relaxants?  Is the condition of back pain from muscle spasm self-recognizable?  There was a lot of discussion about that issue, and I think we'll be discussing that again today.  And would delay in diagnosis lead to serious consequences?
Next.

As I mentioned, these are, for the most part, old drugs, and there was also a concern that there's a large PK/PD knowledge gap as assessed by current standards.  There was also discussion as to whether the prescription doses were too unsafe for OTC use, and if that was the case, then effectiveness and safety of the OTC dose must be established as we're discussing today.
There were discussions about whether general guidelines were possible, and, in fact, I'll describe something that was issued in 1986, but it was pretty much decided that each drug would really have to stand on its own merits.
Next.
Also at this meeting was described the proposed World Health Organization core set of outcome criteria for lower back pain, which included such endpoints as patient global, time to and duration of improvement, forward flexion, quality of life index, disability index, and medication use.
Next slide.
Now, what I had mentioned as a letter in 1986 from the agency described some of the types of studies that should be considered for muscle relaxants over-the-counter.  These were, for example, cognitive impairment and/or sedation in the elderly, usage trials to mimic over-the-counter conditions, PK trials in healthy volunteers, the elderly, with renal impairment, and cirrhotic patients, and then other types of trials to assess, for example, abuse potential, market/mall studies, et cetera.
Next.

So hopefully that sets some kind of a perspective on why we have the kinds of studies that we have today for Flexeril.  There were in fact 13 studies submitted for this NDA.  Four protocols dealt with clinical pharmacology PK, six protocols discussed psychomotor aspects, and three protocols were designated as Phase III clinical studies.  Those were broken up into two types.  There were placebo-controlled, which is Study 6 and 8, and there was a use trial, which was Study 9, which was an open-label study.
Next.
Just in the interest of time, I'll just briefly describe some of the results of these Phase III trials.  In terms of looking at the patients in Studies 6 and 8 ‑‑ by the way, these were basically one-week studies ‑‑ there were, as you can see here, four groups, Flex 2.5, Flex 5, Flex 10, and placebo.  The reason that there are more in the Flex 5 group, for example, is that this was a common dose between the two Studies 6 and 8.

The patients in Studies 6 and 8 had a physician rated moderate or moderately severe painful muscle spasm of the lumbar and/or cervical spine region.  The spasm was at either less than or equal to 7 or 14 days, depending on the study, as is in front of you; whereas in Study 9, patients had self-diagnosed back pain.
Next.
Concomitant therapies.  In Studies 6 and 8, analgesics, psychomotor agents, and muscle relaxants were not allowed.  Yet there were a few patients in Study 6 who took NSAIDs in the Flex 5 group, and the four patients in Study 6 took aspirin.  Just so we're on the same page, Flex 5 refers to 5 milligrams three times a day.  Study 9, on the other hand, did allow analgesics, and, in fact, 16 percent of the patients took ibuprofen, and 11 percent of patients took acetaminophen during this study.  Heat therapy was allowed, and anywhere from 27 to 38 percent of patients used this modality.
Next.

In terms of looking at Studies 6 and 8, overall the completion rate was 86 to 93 percent.  The discontinuations were really primarily for two reasons, either clinical adverse events or ineffective therapy.  As you can see here, for example, in Study 6, Flexeril 10 was significantly different than placebo in terms of withdrawal for clinical adverse events, whereas for ineffective therapy, the Flex 2.5 in Study 8 was different than Flex 5.  This generally depicts, although I'm not showing all the data today, the tendency that at the higher doses of Flex 5 and Flex 10, patients tended to withdraw because of clinical adverse events, whereas with Flex 2.5 and placebo they tended to withdraw from the trials because the therapy was ineffective.
Next slide.
Primary endpoints in Studies 6 and 8 in the placebo-controlled trials were basically all patient-derived 5-point categorical scales.  For example, a global impression of change, medication helpfulness, and the diary card, relief from starting backache.  The global impression was also the variables studied in Study 9.
Next slide.
Again, in the interest of time, I'm just going to show some of the results here.  This is patient global at Visit 3, which is essentially at the one-week time point.  The results are consistent, so this is really representative.  You can see here is depicted the mean and standard deviations in both Studies 6 and 8.  As you can see, Flexeril 5 and Flexeril 10 in Study 6 were significantly different than placebo, although the effect sizes appear modest.  In Study 8, Flexeril 5 again does distinguish itself statistically from placebo, whereas Flex 2.5 does not.  Again, the results appear to be clinically modest.

Next slide.
Now, I'm not describing the other primary endpoints of medication helpfulness and the diary.  They were, again, basically the same type of results.  I'd just like to describe briefly the secondary results of physician rating of muscle spasm.  This was again on a 5-point categorical scale ranging from zero/none to 4/severe board-like muscles.
Next slide.
Looking at the results for this secondary variable, again at Visit 3, here I've depicted the mean change from baseline, and as you can see, in Study 6, Flexeril 5 and Flex 10 again do separate from placebo, but again the results appear to be clinically modest, and the same applies for Study 8 in that Flex 5 does separate from placebo but Flex 2.5 does not.
Next slide.

Now, in terms of discussing and thinking about whether Flexeril works, one could argue that it is useful to focus on the distinction between efficacy and effectiveness.  It is widely accepted that in a randomized clinical trial, like Studies 6 and 8, efficacy means that the treatment produces a reduction in the probability of experiencing the adverse outcome in the study group being investigated.  Efficacy, however, needs to be distinguished from effectiveness.  Effectiveness implies that the treatment works under usual conditions of use as opposed to conditions of investigation.  It is possible to perform trials to assess effectiveness.
So it could be argued, for example, that efficacy and the question of whether efficacy was established in Studies 6 and 8, the problem is that, for example, there were not a lot of elderly patients, and so efficacy cannot be necessarily true in all the subgroups.  Effectiveness in Study 9 was probably not demonstrated for several reasons, because of a lack of a control group, either active or especially a placebo-control group, because of lack of physician verification of the muscle spasm as the cause of the pain, because of the use of concomitant analgesics and NSAIDs which confounded the results in the trial, and really because also of a lack of endpoints.  In this case you'll recall that there was only a patient global being studied in Study 9.
Next slide.

So some of the issues that we will probably be discussing today are:  Has, in fact, the effectiveness for OTC use been established?  This will probably come down to a discussion of statistically significant results but are they clinically meaningful?  I'm sure there will be a discussion again as to whether back spasm as a source of back pain is, in fact, self-recognizable, and were the appropriate endpoints studied?
Thank you.
DR. BRASS:  Any clarification questions for Dr. Witter?
(No response.)
DR. BRASS:  Do you want to go ahead and just introduce your next speaker?
DR. WITTER:  Our next speaker is Dr. Lee.
DR. LEE:  Good morning.  My name is Sue-Chih Lee.  I'm the pharmacokinetics reviewer for the Flexeril NDA.  I will talk about pharmacokinetic issues of this drug.
Next, please.

To support this NDA, the sponsor conducted four pharmacokinetic studies, one study to determine single and multiple dose pharmacokinetics and dose proportionality, one study in elderly subjects, and one in hepatic impairment patients.  A study to determine bioavailability/bioequivalence was conducted to determine the performance of a new formulation, also provided literature articles and study reports.  Of those, the ones related to drug metabolism and drug-drug interactions are considered most relevant.
Next, please.
I will go through briefly the pharmacokinetic characteristics of cyclobenzaprine and then talk about issues.  First, absorption and bioavailability.  After a single dose administration, peak plasma concentrations occurred at four to five hours after dose.  The absolute bioavailability is about 0.55.
Next, please.
This slide shows the plasma concentration time profiles.  The left-hand side shows profiles after a single dose administration, and the right-hand side is for after multiple dose administration.  Three doses were studied, 2.5 milligrams, 5 milligrams, and 10 milligrams.  As you know, the prescription dose was 10 milligrams TID, while the proposed OTC use is 5 milligrams TID.  Those proportionalities were established for the three doses studied.  It's apparent that plasma concentrations increased substantially after multiple dose, as you can see from here.  This is after multiple dose, and this is after single dose.  The accumulation ratio is about four-fold.
Next, please.

Plasma protein binding, based on a literature article, is about 93 percent for cyclobenzaprine, over a concentration range of 0.1 to 1 microgram per mil.  We do not have information on binding in the therapeutic concentration range, which is close to 0.01 micrograms per mil.  However, it's expected that protein binding will be 93 percent or greater than the therapeutic concentration range, depending on whether the binding is linear or non-linear.
Next, please.
Elimination of cyclobenzaprine is primarily through metabolism, while biliary excretion and renal excretion played only minor role or even negligible role.  The effective half-life of cyclobenzaprine is about 18 hours in healthy young subjects.
Next, please.
This slide shows the proposed metabolic pathway for cyclobenzaprine.  As you can see, several metabolites were found.  Glucuronide to N-demethylated products were considered the major metabolites.  However, this scheme may not represent the total picture, as the reflection of the dose was not accounted for.

The sponsor conducted in vitro studies to identify what cytochrome P450 enzymes were responsible for the metabolism of cyclobenzaprine.  The individual studies show that N-demethylation reaction was mediated primarily through CYP 3A4 and 1A2, while CYP 2D6 played a minor role.  The sponsor concluded that genetic polymorphism is not a major concern because CYP 2D6 plays only a minor role, and also there is a low potential for inhibition of cyclobenzaprine metabolism by other concurrent medications due to multiple metabolic pathways and cytochrome P450 involved.  However, we do not consider the study as definitive because the studies were conducted at a much higher cyclobenzaprine concentrations than the therapeutic levels.
Next, please.

I will talk about pharmacokinetics in special populations, including elderly and hepatic impairment patients.  First, a study was conducted in elderly subjects.  Historical data in young subjects were used as comparison.  In elderly subjects, longer effective half-life was found, which was about 33 hours as compared to 18 hours in young volunteers.  The AUC in elderly was 85 to 95 percent higher than in young subjects.  Steady-state concentrations in elderly subjects after 5 milligram TID dosing was similar to that observed in young volunteers after 10 milligram TID dosing.  Because of this elevated plasma concentration in elderly patients, we consider that dose adjustment should be considered for elderly patients.
Next, please.
This is just to illustrate the plasma concentrations at steady state.  This is for healthy elderly, while this is for healthy young subjects.  When I say healthy, it just means that there is no, say, liver disease or heart disease.  As you can see, the plasma concentration in the elderly is about twice as high as in the young subjects.
Next, please.
This is about hepatic impairment patients.  The study was conducted in 16 mild to moderate hepatic impairment patients, and also there were 8 healthy control subjects who were age matched.  However, we found out that there was only one patient that had moderate hepatic impairment based on the Child-Pugh classification.  Therefore, we consider this basically a study in mild hepatic impairment patients.
Next, please.

Again, the effective half-life in hepatic impairment patients were found to be higher than in control subjects, resulting in elevated plasma concentrations.  It was also observed that many patients had not reached steady state at the end of the study, and therefore plasma concentration and a degree of accumulation will be even higher than what was observed in this study.
Next, please.
This is just to show again the plasma concentrations.  The upper curve is for the hepatic patients, and the lower curve for healthy controls.  This is just to show that the concentration in hepatic patients are elevated.
Next, please.
I will go to PK considerations in OTC switch.  First of all, for special populations, as I have mentioned, in elderly and mild hepatic impairment patients, there were elevated plasma concentrations, and we would recommend dosage adjustment in these patients.  For moderate or severe hepatic impairment patients, there are no information in these patients, and therefore we consider cyclobenzaprine should not be used in these patients.
Another consideration is for pediatric population.  There is no PK studies, and therefore we consider it necessary for the sponsor to conduct studies in pediatrics so that dosage determination will be based on scientific data.  Of course, these are for the committee to consider.
Next, please.

Another consideration in OTC switch is drug-drug interactions.  There are pharmacokinetic interactions with several drugs which are already in the label, and I will mainly focus on the pharmacokinetic interactions.  Although there are no clear signals from the prescription products about drug-drug interaction potentials, however, based on the data we have, we cannot rule out the potential at this time.
The sponsor did conduct studies to determine whether the metabolism of cyclobenzaprine can be inhibited by other concomitant medications.  However, as I mentioned before, the study to identify primary cytochrome P450 enzymes was not definitive, and further research is needed.  Another aspect is whether cyclobenzaprine can act as an inhibitor of the cytochrome P450 enzymes and therefore inhibit the metabolism of other concomitant drugs.  An in vitro study was conducted for this purpose.  However, the study did not include cytochrome P450 2C19 substrate, and the study in 2D6 was high 2D6 substrate concentrations.  Therefore, we considered in vitro study with these two isozyme substrates are necessary.  Again, these are for the committee to consider.
Next, please.

With slowly evolving information, another implication is about the prescription label.  The prescription product was approved in 1977, and there was limited pharmacokinetic information.  With the new information that we have, we think that the future work should also include revision of the prescription label and mostly with the information related to drug metabolism and information in special populations, and possibly also dosage adjustment.
Thank you.  This concludes my presentation.
DR. BRASS:  Dr. Yocum?
DR. YOCUM:  With the effects in the P450 system, does grapefruit juice affect metabolism at all, or is that known?
DR. LEE:  I do not know, especially at this point.  I don't know exactly what is the cytochrome P450 responsible for the metabolism of cyclobenzaprine.
DR. BRASS:  Thank you.
We're going to shift order again and ask Dr. Klein to discuss the abuse potential.

DR. KLEIN:  Good morning.  With this NDA the sponsor had submitted data related to drug abuse and drug misuse of the product.  The sort of data that was submitted is what we usually use within our division for a review of drugs for scheduling under the Controlled Substances Act.  This is largely epidemiological data.  It's data that's related to usage problems, to problems that occur with actual use of the drug.  We never use it as stand-alone.  We use it to complement pharmacological data, the way that a drug is used in treatment, as well as interactions of the drug with other likely concomitant medications.
Could I have the next slide, please?
The three data systems which were addressed in the sponsor's NDA were data from the Drug Abuse Warning Network, or DAWN, Poison Control Center reports from the American Association of Poison Control Center's Toxic Exposure Surveillance System, and adverse events reports.  In addition to review of the sponsor's submissions, we independently went into the separate databases and looked at the information ourselves.
Could I have the next slide, please?

Briefly, DAWN identifies substances that are associated with drug-induced or drug-related emergency department visits, and medical examiner or coroner deaths.  It's used to track increases or decreases in abuse or misuse of a drug.  The emergency department data on the next slide, please, is from a selected sample of approximately 500 hospital emergency departments in 21 major metropolitan areas across the United States, and it's used to product estimates of drug abuse visits to emergency departments in the U.S.  The medical examiners data comes from approximately 175 jurisdictions and collects information on drug-related and drug-induced deaths involving both legal and illegal substances.  Death has to be directly caused by the drugs, such as a fatal overdose or possibly an accident or a homicide that's related to drug use in order for it to enter into the system.
Next slide.
Now, the emergency department visits are included in DAWN if the drug is illegal or legal and used inappropriately or displays evidence of dependence or is used intentionally for psychic effects or for suicide attempts.  Accidental ingestions or inhalations of the drug are not included if there's no intent to abuse or if the adverse affect developed when the drug was used as prescribed.  Also, accidental overdoses of OTC or Rx drugs taken as directed, unless used in combination with an illicit drug, are not included in the DAWN system.  Also, alcohol is reportable only when used in combination with another drug.

We usually look at the number of emergency department mentions in this selected sample from DAWN.  We look at prescription data, actual usage data, and we calculate a very simple frequency of use by the emergency department over the number of prescriptions used in a certain time period.  We chose for cyclobenzaprine two comparators of carisoprodol and diazepam because all three are centrally acting, they're available by prescription, they have sedating effects, and they also had the same therapeutic indication.
We see that the relative frequencies of reporting into DAWN for diazepam and carisoprodol are in the 10 to 11 range, and cyclobenzaprine close to 4.  In the case of diphenhydramine, it's not a good comparator because of its availability being OTC, but we threw in a number of emergency department mentions just so that you see how diphenhydramine stacked up in emergency department submissions in this data set compared to the three muscle relaxants.  I urge you to notice that we can't calculate the frequency of use because it being an OTC drug, we don't have actual usage data.  But you see that diphenhydramine falls into the range between carisoprodol and diazepam in emergency department mentions.
Could I have the next slide, please?

Now, bearing that in mind, I thought that you might want to see how diphenhydramine stacked up back in our archival data, so I went back to some old DAWN data, also covering the same number of years, 1977 to 1982, so that you could get a perspective of how these three drugs ranked back when diphenhydramine was available by prescription only.  The emergency department mentions for diphenhydramine were one-tenth what they have been for the last six years of reporting.  Diazepam is roughly the same, has roughly the same emergency department mentions, and carisoprodol was much lower at that time.
Could I have the next slide, please?
DAWN can be broken down by age, and you see that the 6 to 17 age range constituted 8 percent of these emergency department mentions, and by gender, 58 percent.  Actually, that comes out to more than 100 percent, but it was 58 percent female and 42 percent male.
Next slide, please.
The reason for the emergency department visits were largely overdose, three-quarters of which were attempted suicides.  The "Others" category, which came up to about 17.5 percent, included a whole gamut of reasons, including recreational abuse, accident, other psychic effects, and so on.
Next slide, please.

As you can see from this slide, most of the emergency department mentions resulted from cyclobenzaprine use in combination with other drugs.  That's approximately 80 percent were in combination with other drugs, the majority of which the major drug in combination or the substance in combination was alcohol.  We show that there were other drugs of abuse that were also associated with cyclobenzaprine, and those are much smaller numbers that are on the slide.
Next slide, please.
For the medical examiner reports, we can see that the single drug episodes occur with a very low frequency.  There were 146 total reports, of which only seven involved cyclobenzaprine used by itself, and the remainder in combination.  Other drugs of abuse that were used in combination included alcohol, and other drugs of abuse are listed.  They're also low level, but they included cocaine, marijuana, heroin and other opiates as well.
Next slide, please.
The Poison Control Center data provides data that can be used in addressing drug abuse that relates to exposure duration.  Information is also provided for the reason for use, and it's broken down by age, the medical outcome, as well as a description of the clinical reasons for the Poison Control Center data.

Next slide, please.
In between 1986 and 1997, there were 31,000 Poison Control Center reports for cyclobenzaprine, of which approximately 17,000 were for use of the drug by itself.  More than 90 percent of these reports resulted from a single exposure over a short time period.  So these were one-time events, as opposed to a drug such as heroin, which, if you have a report that involves heroin, you expect more chronic use on a regular basis.  Intentional abuse and misuse combined was approximately 5 percent of these reports.
Next slide.
Suicide attempt was the most frequently reported reason for toxic exposure to cyclobenzaprine.  Thirty-eight percent of the reports involved the drug in the suicide attempt as a single agent, and 53 percent were in combination with all other substances.
Next slide.
Eight percent of these suspected suicides involved minors, who were primarily teenagers, and that's for cyclobenzaprine in combination, and for cyclobenzaprine use alone, it was approximately 6 percent that involved minors.
Next slide.

The most serious medical outcomes for the drug alone.  In this case, I'm just addressing the moderate effects and major effects because those are the ones that really required some sort of medical attention to varying degrees.  The major effects may have had more long lasting adverse consequences, and of course death.  These comprised approximately 14 percent of the toxic exposures, and 3 percent of those involved minors.  For all the reports, 21 percent of the toxic exposures were rated with the most serious medical outcomes, and 4 percent of these involved minors.
Next slide.
Again, the most serious medical outcomes involved combinations with alcohol and other drugs.  So it was hypnotics, opiates, antidepressants, other skeletal muscle relaxants, and drugs of abuse.  There were 39 deaths of all ages, total of all ages, and these were reported primarily for the drug and alcohol combinations again.
Next slide.

The primary clinical effects were neurologic, of which 68 percent were of the adverse effects reported were neurologic, the major one being drowsiness or lethargy, 44 percent.  But these also included confusion, hallucinations, and the cardiovascular effects were about 16 percent of the reports, of which 13 percent were tachycardia.
Next slide, please.
AERS is the spontaneous reporting system of adverse effects.  It comes in directly to FDA.  This area is going to be discussed much more thoroughly in the following talk by Dr. Neuner.  We just looked at reports of drug abuse, drug dependence, and drug withdrawal as COSTART terms that would be reported to the system.  There were approximately 9 reports of withdrawal and/or dependence.  A couple of the reports were associated with depression.  These may have been related to pre-existing conditions of the patients, and that sort of information on depression when it's pre-existing is hard to tease out from this sort of data system.
Next slide.
In conclusion, there is a signal of abuse and dependence from these systems.  The major contributor to the signal is related to overdoses from suicide attempts, and approximately 8 percent of the suicide attempts occurred in minors.  The relevance of these signals, the significance of them has to be taken in the context of the drug's safety features, its pharmacology, how it's going to be used in treatment, and other concomitant medications.

Thank you.
DR. BRASS:  Dr. Yocum?
DR. YOCUM:  In your ED department stuff, do you have any data on relationship to accidents such as motor vehicle accidents, fractured hip in the elderly, any sort of data that relates to some of the side effects that we're seeing?
DR. KLEIN:  No.  No, I'm afraid I don't, but we could go back over the system.  In a case like that, that sort of information isn't tabulated individually, but the reports could be retrieved, with some difficulty.
DR. BRASS:  Could you just clarify in the 39 deaths in the Poison Control data, were any of those with cyclobenzaprine alone?
DR. KLEIN:  Three were.
DR. BRASS:  Thank you.
Yes?
DR. LOVELL:  You presented data on diphenhydramine when it went from prescription to OTC and it resulted in ‑‑ I think I heard you say a 10-fold increase in reports to your ‑‑

DR. KLEIN:  Yes.  I have to be very careful not to say that this event caused that 10-fold increase, because in the intervening time, there are a lot of changes, a lot of changes to the whole drug abuse scene, a lot of changes to the way people are taking drugs, and a lot of differences in the way a drug is recognized.  So what I'm saying at this point is that to compare diphenhydramine now to those three muscle relaxants is not a very clean comparison because they're both available to different extents.  But this is just to show you the perspective, that from that time period, that's what it was.
I mean, we also see that carisoprodol is also much lower, and in the intervening years abuse reports of carisoprodol have increased.  But that data is there.  There's a 10-fold change in these number of reports, but to make the direct link as to what the cause was, I can't pull that out from the data.
DR. BRASS:  Thank you.
Dr. Neuner?
DR. NEUNER:  Good morning.  My name is Rosemarie Neuner and I'm a medical reviewer from the Division of Over-the-Counter Drugs.  For the next few minutes I will be discussing the findings of the Flexeril MR actual use trial and the safety review for this NDA.
Next slide, please.

My talk is comprised of data from the following sources:  the results from the actual use trial and a safety review of the clinical study safety database, and postmarketing surveillance data from postmarketing studies, spontaneous adverse event reports, a search of the literature, and overdose data.  I will not be discussing the latter since it has already been presented by my colleague, Dr. Klein.
Next slide, please.
I would like to begin my talk with the results from the actual use study.
Next.
First I would like to start with some general background information about actual use studies.  These studies simulate OTC use and usually have few exclusion criteria.  Study objectives depend on the specific product and concerns related to that product such as compliance, dosing, duration of use, off-label use, safety and efficacy.
Next slide, please.

For Flexeril MR, there were two compliance issues that were studied in the actual use trial.  They were:  Are consumers able to follow labeling directions for appropriate dosing and duration of use for this product?  Are consumers able to follow the warning statements regarding driving and the operation of heavy machinery while using this product?
Next slide, please.
The study itself was a multi-center, open-label, non-randomized, uncontrolled 7-day study in 468 adults with self-diagnosed painful muscle spasm, tightness or soreness of the back or neck.  Recruitment for this study was done by a variety of public advertisements.  Fifty-six percent of the participants entered in this study were recruited by newspaper ads.
Next slide, please.
Unlike other actual use studies, the Flexeril MR actual use trial excluded patients if they had a history of heart or thyroid disease, psychosis, substance abuse, concomitant treatment with sedatives, tranquilizers or anti-depressants, or if they had pending litigation or workmen's compensation for back or neck injury.
Next slide, please.

In this study, a 10-day supply of the drug was dispensed and used without physician intervention according to the listed directions, which read:  "Take one tablet every six to eight hours.  Do not exceed three tablets in 24 hours continuously for more than seven days."  The study materials were collected from the participants on days 8 through 10.
Next slide, please.
The methods of evaluation used to assess patterns of use and participants' compliance with label directions were pill counts and the recordings from the participants' diary cards.  The criteria used for determining non-compliance with the label instructions were as follows:  If a participant took more than three tablets in at least one day; if a participant took more than one tablet per dose at least once, or if they medicated three times a day for eight, nine, or ten consecutive days.
Next.
Eighty-eight percent of the 468 participants entered completed the study.  Twelve percent discontinued for a variety of reasons, such as adverse events, loss to follow-up, ineffective therapy, protocol deviations, never took therapy, or for other reasons.  Ninety-six percent actually returned their diary cards and were included in the final study analysis.
Next slide.

The table on this slide shows that the overall compliance rate for the study was 73 percent.  The sponsor also looked at the compliance rates of two other subgroups of participants, those who reported somnolence and those who had used the prescription drug previously.  Individuals who had taken the drug previously tended to be more non-compliant, which means that they actually took more medication than directed.
Next slide, please.
This slide shows that the breakdown by reason for non-compliance for the three groups that were looked at in this study, as I have mentioned previously, this breakdown by reason for non-compliance shows that those who used the drug previously tended to be more non-compliant.
Next slide, please.
Analysis of the usage data revealed that 56 percent continued to take at least one pill for an additional three days, 13 percent took more than four pills per day.
Next slide.
After the study was under way, the sponsor added questions to assess the participants' adherence to the warning statements regarding not to drive or operate machinery.  Thus, only 235 of the 449 participants were queried.  This table shows that 60 percent of those questioned drove while taking this medication despite the warning not to drive.
Next slide.

The table on this slide shows that although only 29 percent of those queried operated machinery, 10 percent of them did not avoid doing so in face of the warning statements.
Next, please.
In conclusion, the actual use study's limited length makes it difficult to determine if there is a risk for potential misuse or drug abuse.  The failure to heed the warnings regarding driving and operating heavy machinery is worrisome due to the drug's potential for sedation.
Next slide.
I will next discuss the clinical trial safety database.
Next, please.
A total of 2,106 subjects were enrolled in the 13 trials.  One thousand six hundred and thirty-two subjects actually took cyclobenzaprine.  The duration of these trials ranged from 1 to 14 days.  The majority of these studies were single-dose trials.
Next, please.

Demographically, the Phase III trials were predominantly Caucasian, female, age 30 to 39 years old.  There were very few minority subjects enrolled in these studies.  Only 5.3 percent of those who were treated with cyclobenzaprine were over 65 years of age.
Next, please.
Forty-eight percent of the cyclobenzaprine subjects reported one or more drug adverse events, as compared to 26 percent of the placebo subjects in these studies.
Next, please.
There was one reported death in the cyclobenzaprine group due to an acute MI.  This occurred in a 33-year-old diabetic obese female after five days of treatment with cyclobenzaprine 5 milligrams three times a day, who developed shortness of breath and widened QRS complexes on EKG, which progressed to ventricular fibrillation, cardiac arrest, and death.  Autopsy revealed severe heart disease and measurable blood levels of a cocaine metabolite.  Thus, this individual's death, due to an MI in the face of at least three known risk factors for heart disease, was confounded by the use of cocaine, which is a known arrhythmogenic agent.
Next slide, please.

The most commonly reported adverse events in the double-blind studies were somnolence, dry mouth, headache, asthenia/fatigue, nausea and dizziness.  The incidences of somnolence, dry mouth, asthenia/fatigue and dizziness were found to be dose related compared to placebo.
Next, please.
It is important to note that the clinical trials submitted in support of this application were not designed to demonstrate possible adverse events due to drug-disease interactions such as glaucoma, thyroid or heart disease, prostatic hypertrophy, seizures, or drug-drug interactions.
Next slide.
Thus, no conclusions can be drawn from the safety database regarding subgroup analysis for risk of adverse events due to age and race.  The risk for potentially developing drug-drug and drug-disease interactions cannot be adequately assessed either.
Next.
The next part of my talk concerns postmarketing surveillance data associated with the use of prescription cyclobenzaprine.
Next slide, please.

The sponsor has resubmitted the data from two postmarketing studies with over 7,600 subjects, which has been previously reviewed by the agency.  Overall, the safety profiles from these two studies were similar to that of the safety review database generated from the 13 clinical studies.
Next slide, please.
The sponsor has also submitted 968 postmarketing case reports of adverse events due to prescription cyclobenzaprine that they had collected up to August of 1998.  Sixty-six of the 968 cases were due to drug overdoses.  One hundred and eighty-six of the remaining 902 cases were classified as serious in nature.  Fifty-one were death reports due to a variety of causes.  There were an additional 35 deaths in the FDA's SRS database associated with the use of cyclobenzaprine that are currently under review.
Next slide, please.
The most frequently reported postmarketing adverse events collected by the sponsor were mental disorder, hallucination, rash, somnolence, nausea, dizziness, confusion, and seizures.
Next, please.

Due to the limitations in time, I will only be discussing a few of these reports as related to drug-drug interactions.  There were a total of 24 case reports of drug-drug interactions with cyclobenzaprine.  Eight cases involved the use of alcohol, four cases involved the use of monoamineoxidase inhibitors, three cases involved the use of fluoxetine, an SSRI.  The nine remaining cases involved a mixture of agents from various drug classes.
Next, please.
This NDA also contained the results of a worldwide literature search on cyclobenzaprine.  One hundred and twenty-six publications from peer and non-peer-reviewed journals were submitted for a review, which included 25 case reports of a variety of adverse events such as neuroleptic malignant syndrome, torsades de pointes, seizures, drug-induced delirium, and tinnitus.  There were also four articles expressing concern regarding the poor risk-benefit ratio of this drug in the elderly, who are at risk for developing adverse events due to the drug's anticholinergic effects.
Next slide, please.
Conclusions from the review of the postmarketing data are that risk does exist for drug-induced confusion, disorientation, hallucinations, and psychosis associated with the use of cyclobenzaprine.  The risk for drug-induced adverse events cannot be assessed since drug interaction studies were not done.
Next slide, please.

Finally, the literature suggests individuals over 65 years of age may be at an increased risk for developing psychiatric disorders and CNS adverse events due to the drug's anticholinergic side effects.
Thank you.
DR. BRASS:  Any questions for Dr. Neuner?
(No response.)
DR. BRASS:  Thank you.
We will go on to Dr. Aikin.
DR. AIKIN:  Good morning.  My name is Kathryn Aikin.  I am a social science analyst in the Division of Drug Marketing, Advertising and Communications.  I'd like to talk to you today about the label comprehension study done as part of the application package for Flexeril.
Next slide, please.

Unlike prescription drugs, which are designed to be administered under the supervision of an alert intermediary, such as a doctor or other health professional, consumers should be able to safely and effectively use over-the-counter drugs based solely on the package labeling.  It is for this reason that the Code of Federal Regulations states that for OTC labeling to be clear and truthful, it must contain information on intended uses, directions, warnings, and side effects presented in a manner as to render the label likely to be understood by ordinary consumers, including individuals with low comprehension ability as assessed under customary conditions of purchase and use.
Next slide, please.
One way to assess consumers' understanding of the proposed labeling is to conduct a label comprehension study.  A label comprehension study investigates the degree to which label communicates desired information.  It usually involves measures designed to assess consumers' understanding of important label directions, warnings, and intended uses, and it's often conducted using a mall intercept methodology.
Next slide, please.
The label comprehension study for Flexeril focused on several main objectives:  consumer comprehension of label directions, warnings, and uses; accuracy of consumer self-selection for use; consumer ratings of appropriateness of use for various pre-existing conditions; and the package insert was also evaluated to investigate whether or not it affected comprehension of use and warning information.  My talk today will focus just on the package labeling.
Next slide, please.

Four hundred participants were recruited.  Participants who had suffered back or neck pain in the last 12 months and who had used prescription medication for back or neck pain sometime in the past or present were over-sampled.  The sample included 102 participants aged 65 and over, and 48 participants who had not completed a high school education.  The sample was equally divided by gender.
Next slide, please.
Participants were recruited in 14 geographically distributed malls across the United States.  After being screened for eligibility, participants were provided with a picture of the front label of the product and given the following instructions:  "Here is the front label for a new product you might see when you are shopping for nonprescription products.  Please carefully look over the label and tell me when you are finished.  Please take as much time as you need."
Next slide.
I'm sorry, go back one slide.  Thank you.

After the participant had read the front label, the back product label was provided with similar introductory instructions.  "Here is the back label from the same product.  Please carefully look over the label as you would if you were going to consider buying this product for your own use.  Please take as much time as you need and tell me when you are finished."  The participant was then informed that questioning would focus on the back label.  Both labels were left in front of the participant during questioning.  The package insert was provided after participants had finished answering questions about the back label.
Next slide.
The results were analyzed by age, age 18 to 64 versus those 65 and older, and education level, those with less than a high school graduation versus those who had graduated high school or more.  The significance level employed in the test was P or alpha, less than 0.10.
Next slide.
The results of the study can be divided into two areas, those concepts that were not well understood by participants and those concepts that were well understood.  I will start first with the concepts that were well understood.  There were a number that participants showed good comprehension on.

Ninety-six percent of participants understood that Flexeril can be used for back or neck pain due to recent muscle strain, 94 percent understood it could be used for neck or back pain due to recent muscle overuse, and 94 percent understood it could be used for spasm of the back or neck due to strain, overuse or injury.  Participants understood many of the conditions that indicate a doctor should be consulted before taking Flexeril, including whether a person had heart, thyroid, or liver disease; pain shooting down the legs or back pain that gets worse when you lie down; weakness in an arm or leg; fever; difficulty urinating; taking sedatives, tranquilizers, antidepressants or other muscle relaxants; and if they were age 65 or older.
Next slide, please.
Participants understood there were drowsiness-related side effects associated with the use of Flexeril, and that alcohol, sedatives and tranquilizers may increase the drowsiness effect.  This was assessed by agreement or disagreement with whether the statements "significant drowsiness may occur" and "alcohol, sedatives, and tranquilizers may increase the drowsiness affect" appeared on the label.

Ninety-one percent of participants understood they should take only one tablet at a time.  Eighty-eight percent of participants understood the maximum daily dose was three tablets in a 24-hour period.  Eighty-eight percent of participants understood the product should be taken for no more than 10 days in a row.
Next slide, please.
There were some concepts that consumers did not show good comprehension on.  Thirty percent of participants did not understand Flexeril works differently than a pain reliever.  This includes people who said either that Flexeril works the same as a pain reliever or that they did not know how Flexeril worked.  Participants aged 65 and older were more likely than younger participants to say they did not know how Flexeril worked.

Sixty-eight percent of participants did not understand that Flexeril can be taken concomitantly with pain relievers.  Participants who did not graduate high school were more likely to get this wrong than those with a higher education.  Forty-three percent of participants did not understand that Flexeril does not provide relief on the first day of use.  These participants believed either that Flexeril provides pain relief within an hour or so, but then the relief wears off and could then come back.  When asked to define the phrase what they thought "temporarily relieves pain, muscle tightness and spasm of the back or neck due to recent strain, overuse or minor injury" meant, 52 percent of participants said the pain is relieved in a few hours and then could come back, or the pain is relieved quickly.  This is more descriptive of an analgesic.  Both of these are incorrect in terms of how Flexeril works.  These responses point to a pattern of understanding of Flexeril as a fast-acting analgesic and not as a muscle relaxant.
Next slide, please.
The percentage of participants who said they would use Flexeril for conditions they had previously experienced but were not indicated by label instructions ranged from 49 percent for neck pain to 79 percent for back and neck pain.  The instructions on the label used indicate that Flexeril is only to be used for back or neck pain due to recent strain, overuse or injury.
Forty-two percent of participants aged 65 and over incorrectly indicate they would use Flexeril without first speaking to a doctor.  Among participants age 65 and over, 28 percent indicated they would use Flexeril for arthritis in the knees, 40 percent indicated they would use Flexeril for back or neck pain caused by arthritis, and 49 percent indicated they would use Flexeril for leg cramps.  None of these conditions are indicated by the label.
Next slide, please.

In conclusion, consumers generally understand the dosing instructions.  They understand to take one tablet at a time, no more than three in 24 hours, and for no more than 10 days in a row.  Consumers generally understand that the product can be used for back or neck pain due to recent muscle strain, overuse or injury.  However, they are less sure about conditions for which the product cannot be used, especially if they have experienced those conditions in the past.
Next slide, please.
Consumers age 65 and over may not consult a doctor before using the product.  Consumers age 65 and over may use Flexeril for inappropriate conditions, such as arthritis in the knees and leg cramps.
Next slide, please.
Consumers may expect Flexeril to act like an analgesic.  A large part of the sample indicated that Flexeril provides quick pain relief and that it works the same as a pain reliever.
In summary, there are concerns that consumers understand some but not all of the important label directions and warnings.
Thank you.
DR. BRASS:  Thank you.
Are there any questions?  Yes.

DR. LOVELL:  In only one of the questions you mentioned the differentiation between those with and without high school education.
DR. AIKIN:  Yes.
DR. LOVELL:  Can we assume from that that it didn't affect any other responses to the other questions?
DR. AIKIN:  There were no differences on education in any of the questions that I mentioned.  There were few differences between those with a lower education and a high education level on some of the other questions.
DR. BRASS:  Dr. Andreason was supposed to present the FDA's presentation on neurologic impact.  He's not available, so that presentation will be done by Dr. Katz.
DR. KATZ:  I'm Dr. Linda Katz, Deputy Director of the Division of Over-the-Counter Drug Products.  What I'm going to do is to go through Dr. Andreason's slides since he cannot be with us this morning.  I would like to request, however, if anyone has critical questions regarding study design, if you can hold that to this afternoon since he should hopefully be available for our discussion time at around 2 o'clock.
Next slide.

What Dr. Andreason did was to review six studies to talk about the sedation and psychomotor potential of Flexeril.  The major issue that comes about is whether or not sedation may be a major therapeutic effect of the product itself, and if that's actually the way that it works.  The question that was raised or addressed in all six of these studies was:  Can Flexeril produce sedation without psychomotor impairment?
As I mentioned earlier, there were six studies that were performed.  Three were two-hour post-dose studies, one was a study that explored peak pharmodynamic effects, and two studies compared Flexeril with other drugs at peak effect.
The order of the studies ‑‑ just follow with me because it's a little different than the review.  Study 012 or 12 is the first one that I will talk about.  The study objective was to measure the time course of sedation in Flexeril and comparative agents.  This was designed as a double-blind, two-day, four-dose, placebo-controlled crossover study in 28 healthy volunteers.  It compared the sedative effects of Flexeril, 5 milligrams taken three times a day, clemastine, 1 milligram BID, and diphenhydramine, 50 milligrams TID.

The study results indicated that the peak sedation occurred at approximately 4 to 6 hours post-dosing for Flexeril, and this was determined by the multiple sleep latency test.  The peak sedation for diphenhydramine occurred at approximately two hours post-dosing.  Further, Flexeril 5 milligrams TID was found to be more sedating after the fourth dose or after the fourth hour until the end of the study, when it was compared to 50 milligrams TID of diphenhydramine.  All active compounds caused some form of psychomotor impairment that roughly followed the time course of the sedation.
In conclusion for this study, Flexeril was found to be more sedating than diphenhydramine or placebo with repeated dosing; that the sedation and psychomotor effects occurred consistently; and the affects on psychomotor functioning was translatable to potentially impaired driving ability.

Studies 001, 002, and 003 are grouped together since their study designs are very similar.  Study 001 was a double-blind, single-agent, crossover trial that was done with 24 volunteers.  It was designed to compare the sedative and cognitive effects of Flexeril 2.5 and 5 milligrams with diphenhydramine taken three times a day.  Study 002 was a double-blind, four-day, 10-dose, crossover study in 18 volunteers, again to investigate the sedative and cognitive effects of multiple doses of Flexeril, 5 milligrams TID.  Study 003 was a double-blind, 4-day, 10-dose, crossover trial in 18 volunteers who were elderly, again with dosing TID, to investigate the sedative and cognitive effects of the multiple dosing of Flexeril, 5 milligrams, diphenhydramine, 50 milligrams, and placebo.
The assessment that was performed was the same in all three studies, and all studies employed self-report visual analog scales to assess subjective levels of alertness and mood, ranging from alert to drowsy.
A psychomotor testing was performed two hours post-dosing, and the assessments that were performed were for auditory sustained attention, delayed recall and recognition, finger tapping ‑‑ that one was not performed in 003 ‑‑ choice reaction time, critical flicker fusion threshold, which was also not performed in 003, continuous performance, visual sustained attention, digit span, and verbal free recall.

The summary of design and analysis power is basically seen in the next slide.  The studies were felt to be underpowered.  The sample sizes were fairly small and too small to conclude that there was no difference, that no difference means that there was no effect.  The measurement affect taken before peak affect was reached in all of these studies.  The statistical threshold for declaring no difference was too low in an analysis of safety.
The results showed that the impaired reaction time, total decision time, digit span reverse, which is I guess a compilation of memory and concentration, visual and sustained attention, all of these measures were impaired, and Flexeril turned out to be more sedating than placebo.
In conclusion for these studies, studies 001 and 003 measured sedation and psychomotor function at peak effect time for diphenhydramine but not Flexeril.  Studies 001 and 003 were felt not to be useful comparisons of Flexeril with diphenhydramine with respect to sedation or psychomotor function due to the sampling power sizes, as I mentioned earlier, and also to the problems with which the measurement times were taken.
Study 002 does not accurately measure Flexeril's potential for sedating properties, and despite the low power and off-peak effects, there was still significant drowsiness and psychomotor effects that were detected in all three of these studies.

Studies 014 and 015 are also put together since, again, their design is very similar.  Both of these are double-blind, placebo-control, crossover trial that are single dose, and they were designed to investigate the effects of Flexeril, 5 milligrams, diphenhydramine, 50 milligrams, and amitriptyline, 50 milligrams, on driving-related psychomotor skills.  The differences in these two studies were the populations that were studied.  Study 014 looked at 32 volunteers that were age 65 through 82 years old, and in study 015 there were 32 volunteers age 21 through 40.
The assessments that were made in this trial were the visual analog scales, the divided attention task, also known as DAT, critical tracking task, CTT, vigilance task, VIG.  In studies 014 and 015, psychomotor testing was performed 1 to 2 hours after diphenhydramine and 4 to 5 hours after Flexeril dosing.  Driving simulators were not employed in any of these studies.
The results showed that critical tracking and vigilance were worse than placebo but roughly similar to diphenhydramine; that the impairment in psychomotor function occurred in the absence of perceived sedation in 014 for those individuals receiving Flexeril.  The following is just a summary of the vigilance task with the response times and the errors that are seen in each of the groups.
As you'll see for diphenhydramine, the response time was 2.35 seconds, with an error of 16.5.  For Flexeril it was 1.85, with errors that were 11.6.

In conclusion, Flexeril was found in these studies to be more sedating than placebo.  Psychomotor impairment occurs in the absence of significantly perceived sedation.
The overall conclusions that were reached from these six studies were:  sedation at night may be beneficial, but during the day it was be an adverse event.  Peak sedative and psychomotor impairment occurs 4 to 6 hours after dosing.  Psychomotor impairment may occur in the absence of marked perceived drowsiness, and psychomotor impairment risk needs to be conveyed in understandable labeling terms.
DR. BRASS:  Thank you.
Are there any questions for Dr. Katz?
DR. KODA-KIMBLE:  This is not a neurologic question.  Is it standard FDA procedure to use a P of 0.1 for safety?

DR. KATZ:  For this kind of a trial ‑‑ and again, probably this question may be best answered by Dr. Andreason when he comes in, because these trial designs are designed a little differently than some of the trials we look at for safety and efficacy.  But the 0.1 that was used is standard, to my understanding, of what Dr. Andreason has said.  But I think if we could, could you defer that question to when he comes?
DR. KODA-KIMBLE:  Sure.  I think this is a question you can answer too.  I believe the studies involved diphenhydramine 50 milligrams, and is it not true that the OTC dose is 25 milligrams?
DR. KATZ:  It's 25 to 50.
DR. KODA-KIMBLE:  Oh, okay.
DR. BRASS:  Could you turn off your mike?
Other questions?
(No response.)
DR. BRASS:  If not, thank you very much, and we will take our break now.  We're a little bit ahead of schedule, so I'd like to reconvene at 10:10, if there's no objections.
(Recess.)
DR. BRASS:  As we reconvene, if I could ask members of the audience who are here to present in the open public forum if they could be sure to touch bases with Dr. Titus during the lunch break so we have an accurate list of who has requested time in the open public forum.
I'd like to introduce Dr. Edwin Hemwall from Merck, who will lead the sponsor's presentation.

DR. HEMWALL:  Good morning, advisory committee members, FDA staff, guests.  I'm Ed Hemwall, representing Regulatory Affairs for Merck Research Labs and Johnson & Johnson-Merck Consumer Pharmaceuticals.  We're here today to present the results of our development program which formed the basis for our conclusion that Flexeril 5 milligrams available in nonprescription form will offer a safe and effective treatment option for millions of Americans who suffer from occasional muscle spasm or strain of the back or neck.
Back problems are a common medical condition in the United States.  By one measure, approximately 15 million adults report disabling low back pain each year.  Approximately 50 percent will self-medicate before consulting a primary care physician, and another study concludes that roughly 60 percent of the people with acute episodes will suffer a recurrence within one year.  So it's clear that back pain is something that affects the daily lives of a large number of the American public, and these numbers don't even include the chronic conditions or pain from other regions of the back or neck.

Indeed, it's probable that most of you in this audience have either suffered from acute back pain or know someone who has at some time or another.  Thus, it should not really be surprising that over 30 million prescriptions are dispensed each year for drugs in the muscle relaxant category.
Within that muscle relaxant category, the most commonly prescribed product is Flexeril or its generic equivalent, cyclobenzaprine hydrochloride.  Flexeril has been available by prescription in the United States, as you heard, since 1977 at a recommended dose of 10 milligrams three times daily.  As you know, it's indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute painful musculoskeletal conditions.  Despite being available generically since 1989, and therefore not promoted, the use of cyclobenzaprine has continued to increase to a current rate of over 10 million prescriptions per year, and this continued growth provides a measure of the reliance and the value that physicians place upon this product as safe and effective treatment of this common medical condition.

The idea that Flexeril or other muscle relaxants would be reasonable for OTC availability has often been considered, as you heard this morning.  In fact, the muscle relaxant category is a new concept in the U.S., but the general concept of treating muscle pain as an indication for treating back pain or spasm is not.  Millions of Americans purchase a variety of NSAIDs, non-specific analgesics, topical balms, and yet still find it necessary to visit a physician to obtain access to the more effective relief from prescription-only medications.
Several muscle relaxant drugs, not including cyclobenzaprine, have been available over-the-counter in Canada for over 20 years.  In fact, they were reevaluated in 1995 and were moved from a more restrictive, behind-the-counter, third-class to the more open, front-of-the-counter status in all the provinces, attesting to a history of consumer safe self-medication of common back problems.
As you also heard this morning, in 1995 your predecessors on these two advisory committees spent an afternoon discussing in general terms the pros and cons of OTC availability of this diverse range of drugs in this category, and during those deliberations, certain key considerations or challenges were identified for sponsors seeking to develop a nonprescription version of a muscle relaxant drug, and these included proof of efficacy that is not only statistically significant but clinically meaningful, establishing a safety profile that is consistent with and appropriate for OTC use, and demonstrated consumer ability to use the product correctly.

One of the committee's recurring observations, however, was the lack of quality data to address these questions.  We listened to those concerns, and the Flexeril OTC development program, which includes 13 clinical trials, was carried out to address these issues and others specific to cyclobenzaprine.  Today we're pleased to be able to review for you compelling new findings which establish for the first time a data-driven foundation for considering OTC use for a muscle relaxant product.
The effectiveness of the 10 milligram prescription dose of cyclobenzaprine has already been established and validated by over 20 years of clinical use.  In order to establish efficacy of the lower 5 milligram dose in the OTC indication, we conducted two large multi-center placebo-controlled studies in patients with painful muscle spasm of the neck or low back.  Beyond satisfying the primary endpoint success criteria from patient self-assessments, data from these studies addressed the other questions which are on your mind of dose response, time to the onset of relief, physician-verified reduction of palpable muscle spasm, the role of sedation in efficacy, and the magnitude of the treatment effect.

In order to assess safety as it applies to OTC availability of the lower 5 milligram dose, we examined all clinical studies databases for all doses.  We also examined the extensive marketed use experience with the 10 milligram prescription dose, including nonprescription spontaneous adverse event reports from over 100 million prescriptions dispensed over 20 years, and two postmarket surveillance studies in over 7,600 patients, safety in overdose, both alone and in combination with other agents, and the potential for abuse or recreational use.
In addition, as you heard this morning, we conducted four clinical pharmacokinetic studies, six special clinical pharmacology studies designed to assess the sedative properties of the lower 5 milligram dose relative to other OTC drugs and whether or not that sedation or drowsiness translated to impaired psychomotor function in both young and elderly subjects.
Finally, a key component of any Rx to OTC switch program is demonstrating the ability to use the product correctly in a simulated OTC environment.  We developed multiple sequential iterations of the draft label with FDA input at various stages along the way.  As you've already heard, our program included a pattern of use study in which patients with self-diagnosed painful muscle spasm, tightness or soreness of the back or neck, were given a 10-day supply of the product and instructed to take it according to the label.

Additionally, we performed a comprehension study from which we applied the learnings to improve the final proposed label provided in your background package, and this study assessed the ability of the carton back panel and package insert to communicate key label messages, such as how and when to use the product, who should or should not use it, when to see a doctor, the potential to cause drowsiness, and the delayed onset of action.
The proposed indication or use for the 5 milligram dose is for relief of painful muscle tightness and spasm of the back or neck due to a recent strain, overuse, or minor injury.  One tablet should be taken every 6 to 8 hours; no more than three tablets daily for no more than 10 days duration.  A range of additional information including warnings is also provided, some of which are standard OTC labeling language.  Much, however, is unique to the use of the Flexeril product and its attributes, and as noted, it has been substantially enhanced to address the shortcomings of the version that were seen in the comprehension study, as reviewed by Dr. Aikin.
As stated earlier, label development is an interactive process, and we look forward to continued collaboration with FDA experts to further improve the labeling for this new category.

So, to summarize, in the presentation that Dr. Scott Korn will provide today, you will see that we do have a strong rationale for proposing OTC availability for Flexeril product, and you will see that we have addressed the important questions, perhaps even some misunderstandings that have existed before now, and we believe that our program has demonstrated clinically meaningful and statistically significant efficacy of the lower 5 milligram dose in the target OTC population.  We have provided an extensive safety profile from over 20 years of prescription use of the 10 milligram dose, and from new studies of sedation potential which are consistent with and acceptable for OTC availability.
Finally, we have produced a basis for informative labeling which enables consumers to safety self-treat this common medical condition.

We have the following independent consultants with expertise in several topics today to provide additional perspective on some of the questions which may arise during your deliberations:  Dr. Moore, a rheumatologist and former member of the Arthritis Drugs Advisory Committee; Dr. Borenstein, a rheumatologist and expert in back pain management; Dr. Preskorn, clinical psychiatrist and expert in pharmacokinetic/pharmacodynamic relationships; Dr. Wilkinson, the lead investigator in the driving skills psychomotor studies; Dr. Lesser, a neurologist and expert in the study of seizures; Dr. Barbey, a cardiologist and clinical pharmacologist and expert in drug electrophysiology; Dr. Jones, formerly of the FDA and expert in pharmacovigilance; and Dr. Koch, an expert in clinical trial design and statistics.
The concludes my introduction.  I'd now like to introduce Dr. Scott Korn from Merck Research Labs Clinical Research.  Dr. Korn will review with you the most important features of our OTC program, which is covered in much greater detail in your background information package.
Thank you.
DR. KORN:  Good morning.  As Dr. Hemwall stated, the nonprescription cyclobenzaprine program had three primary objectives.  First, to evaluate the efficacy and safety of cyclobenzaprine in doses of less than 10 milligrams.  Second, to evaluate the potential of the proposed OTC dose to impair performance.  Third, to develop and test a label that could clearly convey the key information required for safe self-medication.
This morning's presentation will review the efficacy, then pharmacokinetic, then safety, then label development studies.  In each section, I will highlight data that is pertinent to the questions that you have been asked to discuss this afternoon.

Protocols 6 and 8 were the two pivotal trials, and they examined the following two questions.  First, is there a dose less than 10 milligrams that is effective and less sedating than the 10 milligram dose?  We recognized that the proposed OTC dose should be statistically different than placebo and provide a clinically significant difference as well.  We also wanted to examine in these studies whether the proposed OTC dose actually reduces palpable muscle spasm as evaluated by a physician.
The two trials had similar designs.  Both were double-blind, randomized, placebo-control.  In Protocol 6, we have included the 10 milligram dose, the proposed OTC dose of 5 milligrams, and placebo.  Protocol 8 was conducted after Protocol 6 already showed that 5 milligrams was effective, so we did not include the 10 milligram dose but instead put a 2.5 milligram TID dose in to better characterize the entire dose-response curve for efficacy.
In both trials patients with acute physician-rated moderate or moderately severe spasm were enrolled.  Concomitant analgesics and nonsteroidal anti-inflammatory drugs were prohibited during the two trials.

This schematic shows that patients had three office visits during the study, on Day 1 when they were randomized to medication, on Day 3 or 4 which was their first on-treatment evaluation, and on Day 8 after they had completed 7 days of medication.  There were two rating scales that the patients completed at Visits 2 and 3, their on-treatment visits, and there was a diary that patients filled out each evening that included one rating scale.
Dr. Witter reviewed the rating scales this morning.  Each of them was a 5-category scale.  The clinical global impression of change and medication helpfulness scales were completed at the office visits.  The relief from daily backache question diary was completed each evening.  On each of the 5-category scales, we predefined that the top three scores would be considered responders, and the lower two scores would be considered non-responders for our secondary analysis of responders.
We predefined what the criteria would be for a successful treatment.  At either Visit 2 or at Visit 3, an effective treatment needed to be significantly superior to placebo for two of the three patient ratings, namely the clinical global impression of change, the medication helpfulness, or the patient's daily diary.  We prespecified that the treatments would be compared using a P value of less than or equal to 0.03 to provide an overall alpha level for the experiment of 0.05 or less.

Protocols 6 and 8 had similar patient demographics.  Patients were slightly more females than males, mean age approximately 42, predominantly Caucasian.  About two-thirds of the patients had low back pain and one-third had neck pain.  By design, the two studies differed in the duration of symptoms before randomization.  In Protocol 6, patients were allowed to be symptomatic for up to 14 days before entry.  In Protocol 8, we wanted more acute patients, so we limited enrollment to patients who had been symptomatic for less than 7 days.
We see on this slide the primary results from Protocol 6 for the three primary endpoints.  The means for each of the three parameters are shown.  We notice in the far-right column that cyclobenzaprine 10 milligrams was significantly different than placebo, as indicated by the asterisks, for each of the three parameters at each of the two primary time points for each parameter.  So cyclobenzaprine 10 milligrams was clearly effective according to the predefined criteria.

Cyclobenzaprine 5 milligrams was also clearly effective, being statistically significantly different than placebo in each endpoint at each of the primary time points.  The only difference between the 5 and the 10 milligram dose was that the 5 milligram dose, as expected, had slightly slower onset of action than 10 milligrams.  At the primary time points, however, the means for 5 and 10 were virtually identical.
This slide displays the results of Protocol 8 in the same format.  This study confirmed that 5 milligrams is an effective dose.  Looking at the far-right column for Protocol 8, 5 milligrams was significantly better than placebo for each of the primary endpoints at the final visit of the study.  In contrast, 2.5 milligram dose was only significantly better than placebo on one of the parameters at one of the time points.  So Protocol 8 confirms that 5 milligrams is effective.
The difference between 5 milligrams and placebo was consistent across the two trials.  The mean relief from starting backache for 5 milligram and placebo are shown on this slide from both studies.  The diary ratings show that the relative efficacy of 5 milligrams was similar in the two trials.  The placebo response on Day 2 in the second trial was slightly higher, and that probably explains why the differences between 5 milligrams and placebo were significant at Visit 2 in Protocol 6 but not in Protocol 8.

In order to examine whether the difference from placebo was clinically meaningful in addition to statistically significant, we conducted three secondary analyses.  The first analysis was time to any patient reported in their diary that they had a lot or complete relief, what I'll call substantial relief.  This slide shows the cumulative proportion of patients who recorded in their diary that they had a lot or complete relief by study day in Protocol 6.  The 5 milligram group in the yellow color and the 10 milligram group in the pink color had significantly different distributions than did placebo.  The median time to a lot or complete relief with 5 milligrams and 10 milligrams was approximately 5 days, and that was about 2 days less than with placebo.  Two days in a 7-day period is clearly a clinically meaningful difference, since the sooner a patient gets pain relief, the sooner they should be able to resume their normal activities.
This slide shows the same analysis for Protocol 8, and the results are similar.  The 5 milligram group in the yellow was significantly different than the placebo group in the white, and the median time to a lot or complete relief was approximately 2 days less with 5 milligrams than with placebo.

The second analysis we conducted concerned the magnitude of effect looking at the difference in the proportion of responders between the 5 milligram group and the placebo group.  In Protocol 6, the differences in the proportion of responders between 5 milligrams and placebo ranged from 11 to 17 percent.  The advantage for 5 milligrams relative to placebo was as large as the difference between 10 milligrams and placebo, and both differences for 5 and 10 are large enough to be clinically meaningful.
The difference that we see in this slide is actually very similar to the order of magnitude that has been shown with the H2 blockers in their nonprescription studies for heartburn relief.
Looking at Protocol 8, we see the same phenomenon.  On 5 milligrams relative to placebo, the 5 milligram group had a 12 to 20 percentage point increase versus placebo.  In contrast, the 2.5 milligram group generally had a less than 10 percentage point difference versus placebo.

The third analysis we performed was to place the observed differences in a clinical context by calculating the standardized difference from placebo, otherwise known as effect size.  This is defined as the difference in means divided by the pooled standard deviation for all the treatment groups in the trial.  It's a unitless measure that can be used to provide a common metric for comparing drugs within and across studies.  The values for 5 milligrams in both of our trials ranged from 0.24 to 0.41, which is modest but consistent with the other analyses that I've just presented.
These values actually compare quite favorably with published values for antihistamines used to treat symptoms of the common cold.  In a published meta-analysis, the pooled estimate for the antihistamine effect was 0.153 to 0.291, which is, if anything, a little less favorable and less robust than the difference for cyclobenzaprine.
So the analysis of effect size was the third analysis that showed that the difference between 5 milligrams and placebo was clinically meaningful.

We predefined in a planned combined analysis of Protocols 6 and 8 to look at whether sedation was required for efficacy.  In Protocols 6 and 8, there were 321 patients who received 5 milligrams and did not report sedation at any point during the trial.  There were also 412 patients in those trials who received placebo and did not report sedation.  The display on the screen here shows the proportion of responders for the clinical global impression of change rating at Visit 2.  Three values are shown for the 5 milligram group and three values are shown for placebo.  For 5 milligrams, we see the point estimate for percent of responders for all patients, those 321 who did not report sedation and the 132 who reported sedation.  For placebo, the same three subgroups, all patients and those who did not report sedation.
Looking at the proportion of responders, we see that the difference between 5 and placebo in those who did not report drowsiness is as large as the difference between 5 and placebo in the all patients treated analysis.  To us, this demonstrates that clinically apparent sedation is not required for the product to be effective.  Efficacy is not a result of just inducing drowsiness.
Turning our attention to the physician ratings, at each of the visits the patients were examined and their muscle spasm was rated by a physician using this 5-category scale that was based on the hardness and consistency of the muscles.  Patients had to have a score of 2 or 3 to be randomized into the trial, a rating of moderate or moderately severe.

A secondary analysis specified in our protocols was to look at the degree of reduction in muscle spasm at the follow-up visits.  This slide summarizes the mean muscle spasms by treatment group and visits in the two protocols.  At baseline, the treatment groups were similar.  In Protocol 6, at both Visit 2 and Visit 3, both 5 and 10 milligrams had significantly less spasm than did placebo.  In Protocol 8, the 5 milligram group had significantly less muscle spasm than placebo at Visit 3, while the 2.5 milligram group did not.
So both trials demonstrated that, according to physician examination, a greater reduction in muscle spasm occurs with 5 milligrams than with placebo.
One of the questions you've been asked to consider this morning is whether patients can tell that their condition is improving.  We looked at the correlation between the physician ratings of muscle spasm and the patient global ratings that were the primary endpoints in this trial.  There was an appreciable correlation between the physician ratings of spasm and the patient global ratings.  The Spearman correlation coefficient summarized on this slide ranged from 0.297 to 0.644.  These correlation coefficients show that patients with acute painful muscle spasm of the back or neck can indeed assess whether their spasm is improving.

Another question that you've been asked to consider today is what is the evidence that patients can self-diagnose this condition.  We went back and looked at the screening logs from the sites in the two studies to help address this question.  Fourteen of the 20 sites in Protocols 6 and 8 included the phrase "muscle spasm" in advertisements that were used to recruit patients.  Looking at those 14 sites, there were 439 patients who were screened, and of those 439 patients, only 6 percent were excluded from the studies because they did not have cervical or lumbar muscle spasm on examination.  This data indicates that patients who respond to advertisements for patients with muscle spasm do indeed have physician-confirmed muscle spasm when they're enrolled in the trial.
The data we have reviewed from Protocols 6 and 8 demonstrate that cyclobenzaprine 5 milligrams TID are statistically and clinically superior to placebo for acute painful muscle spasm of the back or neck.  The overall efficacy of 5 milligrams TID is similar to 10 milligrams TID, examining the mean scores at the primary time points.  The only difference is that 10 milligrams has a faster onset of efficacy, as you would expect.
Muscle spasm has been shown to resolve more quickly with both 5 and 10 milligrams TID than with placebo, and patients can indeed recognize when they have painful muscle spasm, and they can accurately determine whether that condition is improving with treatment.

Turning our attention to safety, at therapeutic plasma concentrations of cyclobenzaprine, we know there are two pharmacologic effects.  The first is an antihistaminic effect on the H1 receptor, and the second is an antimuscarinic or anticholinergic effect.  As we examine the safety data from our clinical trials, we will see that the clinical adverse experiences reported are consistent with both of these known pharmacologic effects of the drug.
Since safety can be influenced by pharmacokinetics, I will review what we know about the kinetics of cyclobenzaprine first, and I will then discuss the safety data from our nonprescription clinical studies, both the adverse experience data and the psychomotor data that Dr. Katz presented.  I will then review the information from the marketed use of the 10 milligram product, and that includes the spontaneous reports to Merck or the FDA, the Poison Control Center data, and the Drug Abuse Warning Network data.

The pharmacokinetics of cyclobenzaprine have been examined in earlier studies, as well as part of this nonprescription development program.  As Dr. Lee presented, the drug is well absorbed, it has a high clearance, a large volume of distribution, and it is highly protein bound.  The Tmax is reached in four hours, and after 7 days of dosing TID, the plasma concentration at steady state in younger subjects is about four-fold higher than a single dose, and in elderly subjects about eight-fold higher than after a single dose.
This is a slide similar to what you've been shown this morning.  There are three treatment groups on the slide, 5 milligrams TID in the yellow.  In the elderly patients, 65 to 79 years old, it's a closed square.  In the younger patients, 22 to 40, it's a closed circle.  We see that after a single dose, the levels in the elderly and the young are similar after 5 milligrams, and peak concentration is approximately half of that after 10 milligrams.  Looking at steady state after 7 days of dosing, a slightly different picture.  In the young, this is the plasma concentration at steady state.  The elderly patients who have 5 milligrams TID develop plasma concentrations that are similar to younger subjects who take the current prescription dose of 10 milligrams TID.
Now, we have submitted the information to the agency for our prescription product as well, and we have submitted draft labeling incorporating this revision and the hepatic impairment data, and we look forward to the agency's review of that data and approval to change our current prescription circular.

As Dr. Lee mentioned, there was a radiolabeled oral study done as part of the original NDA over 20 years ago.  Approximately 50 percent of the drug was observed to come out in the urine.  The major fraction in the urine was a glucuronide.  There were four oxidative metabolites identified, each about 3 to 7 percent of the total radio activity, and those were mediated through several P450 isozymes, 3A4, 1A2, and 2D6.  There were also a number of unidentified low concentration metabolites and one that's approximately 6 percent.
We reviewed this data and we believe that the drug has a low potential for drug-drug interactions.  First, it is unlikely that other drugs will significantly exhibit the excretion of cyclobenzaprine since there are multiple elimination pathways.  There's fecal excretion of unchanged drug, there's urinary excretion of a glucuronide, and there's oxidative metabolism using several different enzymes.  We also have in vitro data that shows that cyclobenzaprine does not inhibit the major P450 isozymes, although we do not have that data for 2C19.  So it's unlikely to inhibit the metabolism of other drugs that rely on 3A4 or 2D6.

We have had extensive marketed experience with cyclobenzaprine, and there are no documented pharmacokinetic interactions reported in the literature.  What I mean by documented is there are no case reports where the plasma concentration of either cyclobenzaprine or another drug was shown to have been altered by concomitant administration.
I'd like to now turn our attention to the clinical adverse experience profile.  Information about adverse experiences was collected by open-ended questioning in all of our studies.  Merck defines an adverse experience as any unfavorable clinical event, whether or not it is considered related to the study medication.  The event only needs to occur once during the trial and it is counted as an adverse experience.  At the end of the trial the investigator is asked to assess the relationship to study medication for any events that have been reported.
The most commonly observed adverse experiences with 5 milligrams in Protocols 6 and 8 are presented on this slide.  We see that the incidence of adverse experiences is clearly dose related, ranging from 35 percent on placebo to 44 percent on 2.5, 55 percent on 5, and 62 percent on 10 milligrams administered TID for seven days.

The most common adverse experiences were drowsiness and dry mouth, which are both reflections of the antihistaminic and anticholinergic properties of the drug.  Approximately 29 percent of the patients who received 5 milligrams reported drowsiness, and this compared to approximately 10 percent of the patients who received placebo.  Twenty-one percent of the patients who received 5 milligrams reported dry mouth, compared to approximately 7 percent of the patients who received placebo.
Asthenia and fatigue, which are terms used by some investigators to describe drowsiness or related experiences, also appear to be dose related, ranging from 2.6 up to 6 percent.
Headache and nausea were not dose related, and indeed the incidence of headache and nausea with 5 milligrams were actually less than with placebo.
While 55 percent of the patients who received cyclobenzaprine 5 milligrams reported one or more adverse experiences, very few discontinued medication because of an adverse experience.  This slide summarizes the discontinuations due to adverse experiences in the Phase III studies, including the 469-patient use study.  Discontinuations due to adverse experiences were dose related.  We see them ranging from 1.6 percent on placebo up to 7.5 percent on 10 milligrams.  Four percent of the patients who received 5 milligrams discontinued for an adverse experience, versus 7.5 percent of the patients who received the current prescription dose.

The most common adverse experience prompting discontinuation was somnolence.  Two and a half percent of the patients who received cyclobenzaprine 5 milligrams discontinued the medication because of somnolence.
The investigators were asked to rate the intensity of all adverse experiences on a 3-point scale:  mild, indicating that the patient was aware of the symptom but it was easily tolerated; moderate, indicating that the symptom may have interfered with the patient's usual activity; and severe, which is the inability to work or do the patient's usual activity.
We see on this slide a chart illustrating the maximum intensity of somnolence at any point for patients who received 5 milligrams in Protocols 6 and 8.  Seventy percent of the patients did not experience any somnolence.  Seventeen and a half percent said the worst their somnolence was was mild, 9.3 percent said they had moderate drowsiness at some point, and only 2.4 percent reported that their drowsiness was severe enough to interfere with their daily activities at any point during the study.

When did the somnolence or drowsiness start in these patients?  The proportion of patients who received 5 milligrams TID and first reported somnolence on a given day is displayed on this slide.  We see that approximately 16 percent of the patients reported drowsiness starting on the first day, and an additional 10 percent reported drowsiness beginning on the second day.  But from the third day on, very few patients reported the onset of somnolence.  So based on this data, we conclude that when somnolence occurs, it generally starts on the first or second day of dosing.
One might expect that elderly patients would have more adverse experiences than younger patients given that their plasma concentration for an equal dose would be higher, but our clinical data does not show that.  In the Phase III studies, the incidence of adverse experiences in the 74 patients age 65 and older was not greater than in the patients who were less than 65 years old.  This slide displays those adverse experiences that were reported by two or more of the patients who were 65 years old.  The incidence of somnolence in the elderly patients was not different than in the younger patients.  The incidence of dry mouth and constipation and abdominal pain did appear to be slightly higher, and these are reflections of the anticholinergic properties of the drug.

As Dr. Neuner discussed, many patients use cyclobenzaprine for up to 10 days in the use study.  So based on the safety data from that use study and our two pivotal trials, we've concluded that cyclobenzaprine 5 milligrams TID is generally well tolerated when used for up to 10 days.  Somnolence and dry mouth are the most common adverse experiences, and they are both dose related.  Most patients who reported somnolence develop it on the first or second day of dosing, but most episodes of somnolence are mild or moderate and do not prompt discontinuation of the treatment.

In order to better understand the characteristics of the drowsiness that can occur with cyclobenzaprine and whether it leads to impaired performance, we conducted six psychomotor studies, two of which were in elderly subjects.  An alert/drowsy visual analog scale was used in all six studies to assess the subjective sensation of drowsiness, and one study included the multiple sleep latency test.  We included computer-based measures of psychomotor performance in all trials, and although our package warns against driving until you know how the product reacts with you, we know that some people will drive while taking a potentially sedating medication, and therefore we did two studies designed to specifically address the extent to which cyclobenzaprine 5 milligrams could impair driving-related skills.   In answer to Dr. Koda-Kimble's question, we were not aware at the time the studies were planned or conducted that they would be evaluated at a P value level of 0.1.
The first four trials were basically exploratory in nature.  What we learned from these studies is that cyclobenzaprine 5 milligrams is more sedating than placebo in subjects who are less than 50 years old.  The onset of sedation occurs later than with diphenhydramine.  Peak sedation with cyclobenzaprine is approximately four hours post-dose, and with diphenhydramine it's approximately one to two hours post-dose.  Of interest in our multiple-dose studies, we did not see sedation continue to increase over the course of 10 doses.
The MSLT study, or multiple sleep latency study, did demonstrate that cyclobenzaprine reduces the amount of time it takes to fall asleep in an unstimulated environment when you're told to try and fall asleep, and it does so by about one to two minutes more than the maximum OTC dose of either diphenhydramine or clemastine, which is known as Tavist.  In all four studies, however, there was no consistent impairment either at 0.05 or at 0.1 of substantial psychomotor impairment.

We took the results of these four trials and we then designed the two trials that looked specifically at driving-related skills.  We designed those studies to assess psychomotor performance at the time when maximum sedation would be expected based on the results of these four exploratory trials.
We conducted the two studies, one in the elderly, age 65 and older, and one in subjects age 21 to 40.  Both are summarized in your background package.  I will in the interest of time only present the results of the elderly since those subjects are assumed to have had higher plasma concentrations than the younger subjects and would be expected to have, if anything, greater impairment.  Both trials were double-blind, 4-period crossover studies.  The subjects received three doses of cyclobenzaprine on Day 1 and the fourth dose the morning of Day 2, four hours before the test battery was begun.  They also received in the other periods amitriptyline 50 milligrams, diphenhydramine 50 milligrams, and placebo.
We selected amitriptyline as the positive control based on the extensive information available in the literature that it indeed is associated with impairment in test batteries like this, and actually an increased risk of traffic accidents in epidemiologic data.  Diphenhydramine was included to evaluate how cyclobenzaprine compares to a currently marketed OTC antihistamine.

Subjects completed a visual analog scale at the beginning of the test battery, and then three driving-related tests were conducted.  Now, this test battery was selected instead of a driving simulator as it has been well validated over the years.  It is a multidimensional test battery that has evolved from over 25 years of laboratory work by the investigators and has been shown to be sensitive to the effects of alcohol, drugs, and aging.  Skills impairment in this battery mirrors the blood alcohol concentration curve and its relationship to crash risk.  The battery has an excellent test/retest reliability, and it produces results that are consistent with a state of the art driving simulator as was recently shown in a study by the investigators for the Department of Transportation.
I will explain what the three tests are and then show the relevant primary endpoint data for each of the three parameters.

The first psychomotor test is critical tracking, which is the ability to control movement of a machine in use during very focused brief periods of attention.  The test consists of a subject trying to follow a cursor on a computer monitor by using a joystick.  The cursor moves more and more quickly as the trial progresses, and it becomes more and more difficult to follow with the joystick.  The primary parameter in this study is the lambda score, which is the level of difficulty the subject is able to complete.  So a higher score is a higher level of difficulty and represents less impairment.
The mean lambda score and the 95 percent confidence interval is shown for each of the treatment groups in this slide.  We see amitriptyline on the far right has the worst level of performance, and placebo on the far left had the best.  Cyclobenzaprine was significantly different than placebo, but the difference is quite small and actually is less than 10 percent and not significantly different from the level of diphenhydramine in this test parameter.
The second test was divided attention, which models the demands of driving on a highway.  It's the ability to simultaneously perform tracking, which you can think of as steering, and visual searching, which is looking to the sides of the vehicle.  When you do the visual searching, you're monitoring for cues that require a response.  This is a very complex, high-demand task, and it's a very good analog for driving.
The primary parameter for this test is an overall performance score which incorporates a measure of tracking error or weaving and response time to a visual signal, reaction time.

The overall performance score and 95 percent confidence interval for each treatment are shown on this slide.  The data is normalized to a score of 50, so a lower score in this parameter indicates less impairment.  Amitriptyline on the far right had significantly more impairment than placebo.  Cyclobenzaprine and diphenhydramine were not significantly different than placebo, and cyclobenzaprine was not significantly different than diphenhydramine either.
The third test is vigilance, which is the ability to maintain attention to a monotonous task over 40 minutes in a sound-proof booth.  This is actually the opposite of the MSLT test, where subjects are told to fall asleep as fast as they can.  Here the subject is told to stay awake during the monotonous period in the booth.  The primary parameter in this test is the reaction time to an infrequently appearing signal, and the higher score or the higher reaction time represents more impairment.  So while they're in the booth, there's a signal that appear intermittently and they're supposed to react and indicate that they've acknowledged that signal when it occurs.  So a higher reaction time is worse.

A secondary parameter for this test is actually the number of errors, either the number of times they've missed a signal and did not acknowledge it, or the number of times they acknowledged a signal that actually never occurred.
The mean response time in seconds and the 95 percent confidence interval are shown on this slide. Amitriptyline and diphenhydramine had significantly prolonged reaction times compared to placebo, while cyclobenzaprine was not associated with a significant increase in reaction time.  The 1-second difference between amitriptyline and placebo may not look like a lot on this slide, but if we remember that a car traveling 55 miles an hour travels 80 feet in that one second, a 1-second prolongation is clinically meaningful.
A secondary endpoint in this trial was the number of errors, the signals they missed or the signals they acknowledged that weren't there.  Here we see that amitriptyline and diphenhydramine and cyclobenzaprine were associated with more what we'll call false alarms or signals received that weren't there than was placebo, but clearly cyclobenzaprine is not as bad as amitriptyline, and cyclobenzaprine is not significantly worse than diphenhydramine.

The driving-related skills study in the younger subjects showed even smaller differences than these that were seen between cyclobenzaprine and placebo in the elderly subjects.  Based on all six psychomotor studies, we conclude that cyclobenzaprine 5 milligrams TID is associated with sedation that is similar to that seen with OTC doses of diphenhydramine and clemastine as measured by a visual analog scale.  Cyclobenzaprine 5 milligrams does assist in falling asleep when someone is trying to do that, but it does not substantially interfere with critical driving skills either in young or elderly subjects to a substantial extent.  Subjects can generally overcome their drowsiness and perform adequately in these laboratory studies.  In both the young and the elderly, performance in the laboratory study was not worse than with the maximum OTC dose of diphenhydramine.

I would now like to move on to the next section of the talk which deals with what we know about the safety of the 10 milligram product that's been marketed since 1977.  Merck conducted two open-label postmarketing surveillance studies.  These enrolled approximately 7,600 patients, and 567 of those patients were 65 years old or older.  The elderly patients in these two studies did not have a higher incidence of adverse experiences than the younger patients.  Approximately 20 percent of the elderly patients and 19 percent of the younger patients reported an adverse experience in these large trials conducted 20 years ago.  Looking at the profile of adverse experiences, they were generally similar in the elderly to the younger groups.
Merck collects spontaneous reports of adverse experiences on all of its products and enters that data in a database that we refer to as our Worldwide Adverse Experience System.  All voluntary reports to Merck of adverse experiences after use of a Merck product are entered into this database regardless of whether the reporting physician or a company physician feel that the case is causally related to the product.
It's worth noting that reporting practices have changed since 1977.  The terminology of adverse experiences used by both us and the FDA has changed over that time, and the regulatory definition of what is a serious adverse experience has changed over time.

We estimate that since 1977, physicians have written over 100 million prescriptions for cyclobenzaprine in the United States, and during that time, Merck has distributed over 1.5 billion tablets in the United States.  Since 1989, generic cyclobenzaprine has been available, so this is actually an undercount of the amount of cyclobenzaprine tablets that have been used.  As Dr. Hemwall mentioned, we've had 993 reports of spontaneous adverse experiences reported to us.  Two hundred and thirty-eight of those reports met the regulatory definition in effect at that time for what a serious adverse experience would be.  Most of the adverse experiences related to the central nervous system, which is not surprising given the safety profile of the drug in clinical trials and the known pharmacologic effects.
Unfortunately, our WAES database does contain 52 reports describing 65 patients who died while taking or after taking cyclobenzaprine.  Reviewing these 65 patients shows that there were 15 reports describing 22 patients who intentionally overdosed with the product.  There were three reports of fetal death after a mother had taken cyclobenzaprine at some point during her pregnancy.  But in the remaining reports, there was no clear pattern to suggest that cyclobenzaprine was causally related to the deaths.  The majority of the reports, 29 to be exact, were confounded by the presence of underlying diseases or the use of other medications.  There were six patients with underlying heart disease, four with pulmonary disease, three with hepatic disease, three with cancer.  Clearly, a spattering and a cross-section of concomitant illnesses that do not indicate a clear pattern.

We have gone and looked at the FDA's spontaneous report system database to see what is in that database concerning cyclobenzaprine, and we are aware of 25 reports of death that did not originate from Merck that are in those databases.  Twenty-one of the 25 reports have been available to us already for review through the Freedom of Information, and we know within those 21 reports that there are five duplicates within the 21.  We also know that two of those reports have also been sent in by Merck.  So within the 21 reports we've been able to review, there were 14 unique patients that Merck was not aware of.  They may have been reported by other manufacturers of generic products, or they may have been reported by manufacturers of other ethical products that the patients were using concomitantly.
There were five overdoses in the 14 reports, two fetal deaths, three heart attacks, and a spattering of other diseases.  So again, within the FDA's database, looking at reports that did not come from Merck, no consistent pattern to suggest causality.

We know that cyclobenzaprine is chemically related to amitriptyline, a drug that is associated with cardiac arrhythmias and seizures in overdose.  We have examined the available data to determine whether cyclobenzaprine is associated with life-threatening arrhythmias or seizures in either therapeutic use or overdose.  The WAES database contains 16 reports of life-threatening dysrhythmias, which we classify as ventricular tachycardia, ventricular fibrillation or cardiac arrest.  Eight of those patients died and were included in the summary slides I just presented.  Of the remaining eight cases, there were two reports of ventricular tachycardia or fibrillation occurring during surgery, one in a patient who received droperidol, and one who was in septic shock undergoing an exploratory laparotomy.  There were five reports of cardiac arrest with little information available, except in one case we know that there was a documented mycoplasma infection which may have been associated with a heart block, and there was one non-fatal overdose with several other drugs.
We've looked at the FDA's SRS database and we found three reports of life-threatening dysrhythmias that did not come from Merck and were entered in the database.  There was a fatal overdose with other drugs, including oxycodone and acetaminophen, a person who developed chest pain and then a cardiac arrest and died, and there is a person with a history of angina on multiple medications who developed respiratory depression, psychosis, and ventricular fibrillation, but was resuscitated.

So given the limited number of reports in both Merck's database and the FDA's database, we conclude that there does not appear to be an appreciable risk of life-threatening arrhythmias in patients who take therapeutic doses of cyclobenzaprine 10 milligrams.
Our WAES database contains 29 reports of seizures in patients who had taken cyclobenzaprine.  Two reports involved overdoses.  Of the remaining 27 reports, 12 would meet the criteria for serious that exists today.  Eleven of these 12 reports were confounded.  In three of the cases, the patients had a previous known history of seizures.  In 10 cases, there was not enough information to assess causality in a reasonable manner.  In four cases, cyclobenzaprine may have been associated with a seizure, and in two cases, when we reviewed the case, it doesn't sound like a seizure that's being described at all.

We also reviewed the FDA database looking at seizures and cyclobenzaprine, and we found six reports that did not come from Merck.  There were four reports that were serious, including one that was a fatality.  The other three reports all had a prior history of seizures.  Now, given the limited number of reports in our database and in the FDA database, the risk of a seizure secondary to therapeutic use of cyclobenzaprine appears to be quite negligible.
Dr. Klein presented data from several sources this morning, from the American Association of Poison Control Centers and the Drug Abuse Warning Network.  I'd like to try to put some of the numbers in perspective that we all looked at this morning.  This slide summarizes for a 4-year period, 1994 through 1997, what the most commonly reported drugs are to the American Association of Poison Control Centers, and we see cyclobenzaprine during that 3-year period had 15,000 reports, which is an order of magnitude less than is seen with ibuprofen, multi-vitamins, or acetaminophen.  So we are not minimizing the fact that there are 15,000 reports, but we'd like to put that in the context of all the other reports that the Poison Control Centers do receive.

The Poison Control Center database collects information about overdoses from all across the country, and their data actually show that cyclobenzaprine has a large margin of safety in overdose.  There were three reported deaths with cyclobenzaprine alone.  We know that one of those patients reportedly took 800 milligrams, which is 13 milligrams per kilogram, the equivalent of 165 milligram tablets.  We do not know the dose ingested in the other two cases.  There were 36 deaths in the database in patients who took cyclobenzaprine and multiple other drugs, most commonly benzodiazepines and tricyclic antidepressants.  The most common symptoms in overdoses were drowsiness and sinus tachycardia.  Serious ventricular arrhythmias or seizures were reported in less than 0.4 percent of the cases of cyclobenzaprine overdose alone.
Looking at the Poison Control database reinforces that cyclobenzaprine is not the same as amitriptyline.  If we look at the 101,000 overdose reports in the Poison Control Center database over a 10-year period and compare that with the 11,000 cases of cyclobenzaprine alone, we see that the mortality rate with cyclobenzaprine, three out of that, is much lower than the 1 percent rate with tricyclic antidepressants.  And even when cyclobenzaprine is taken as part of a multi-drug overdose, the mortality rate is lower than with the tricyclic antidepressants.
Turning our attention to the Drug Abuse Warning Network data, the last year that we have data available for all drugs is 1993, and cyclobenzaprine appears as Number 42 on their list, with 2,600 mentions in that year.  That's slightly less than caffeine in that year, naproxen, OTC sleep aids, and substantially less than the drugs that everyone recognizes are drugs of abuse.

Information from multiple sources indicates that there is a low risk of abuse with cyclobenzaprine.  There are no published reports of recreational use or addiction to cyclobenzaprine.  Merck has not received any spontaneous reports of addiction to cyclobenzaprine.  The Drug Abuse Warning Network, as Dr. Klein explained, collects information from emergency departments and medical examiners across the country, and the emergency department mentions indicate that less than 2 percent of the time that a patient ended up in an emergency room after taking cyclobenzaprine did the patient state they were taking it for recreational purposes.  Most of the time it was an intentional overdose.

Based on the extensive marketed use of the product, over 100 million prescriptions over a 20-year period, we conclude that cyclobenzaprine 10 milligrams TID is generally well tolerated.  The most common adverse experiences are related to the central nervous system, and they are generally mild.  The number of spontaneously reported serious events differs slightly between our database and the FDA's database, but the pattern within both databases is consistent.  Both databases indicate that reports of serious cardiac or neurologic events are rare.  There's a low potential for abuse and a large margin of safety in overdose.
We acknowledge that cyclobenzaprine 5 milligrams can cause drowsiness, and we have developed a label that informs potential consumers about the risk of sedation with the product.  In addition to the standard sedation warnings that are included on the back panel, and these are based on the diphenhydramine monograph, we propose to put a flag on the front panel of the box to clearly indicate that the drug may cause drowsiness.
We have also taken a conservative position concerning who should use this product.  We propose that patients less than 18 years old and patients 65 or older speak to a physician before using the product.  Our new pharmacokinetic data shows that elderly patients taking 5 milligrams TID will have plasma concentrations similar to younger patients taking the current prescription dose, and physicians may wish to advise those patients to decrease the dosing interval or amount taken.

We propose to include warnings advising patients with heart disease, liver disease, thyroid disease, glaucoma or difficulty urinating to consult a doctor before using this product.  These precautions are all carried forward from the prescription circular that we have, and they are not unique to this product.  They are already on some OTC products such as cough and cold products and decongestants which contain sympathomimetic or anticholinergic drugs.  In addition, we propose on the back panel to include specific symptoms that would indicate that a patient might have a condition other than an uncomplicated back strain and should see a physician for diagnosis and treatment.  These red flags are consistent with those developed by the AHCPR guidelines that are an appendix to your package.
We recognize, as Dr. Hemwall stated, that label development is an iterative process.  The label included in the NDA and your background package is not the label that was tested in the use study, and it's not the label that was tested in the label comprehension study.  The use study tested an early version of the label that did not include a package insert.  The label comprehension study tested a label similar to what we have here, as well as an insert.  Based on the results of the use study and our label comprehension study, we made modifications to the label, and those are included in the version that you see that was submitted with the NDA.

As Dr. Aikin indicated, the label clearly communicated to consumers that the products should be used for acute neck and back pain with spasm, what the proper dosing instructions are, that the product can cause drowsiness, and that they should consult a physician before using the product or after starting the medication if they have certain symptoms or conditions.
As Dr. Aikin mentioned, comprehension was excellent, ranging from 80 to 95 percent, for when a patient should ask a doctor before using the product.  Consumers also clearly understood that the product may cause drowsiness, with comprehension ranging from 96 to 98 percent.  They also understood that they should stop the medication and see a physician if they were not better in 10 days.
We agree that some concepts that were tested have room for improvement.  There was some confusion about the difference from analgesics and whether cyclobenzaprine can be taken with pain relievers.  Some people did not understand that the product did not work immediately, and some thought that the product could be used to treat leg cramps or arthritis pain.  We have data, however, that I will show you that the package insert actually helps to reduce these misunderstandings.

This slide summarizes the percent of consumers who understood that cyclobenzaprine works differently than analgesics.  After reading the label alone, 70 percent of the representative sample recognized that this was different than an analgesic.  Comprehension improved to 88 percent after they also read the insert.  The same pattern of improvement was seen in the elderly subjects and the subjects who did not complete high school.
This slide summarizes whether people understood that cyclobenzaprine does not necessarily provide immediate relief.  After reading the label, 57 percent of the representative sample understood that.  Comprehension went up to 75 percent after reading the insert as well.  Comprehension also improved in the elderly group, from 46 to 70 percent, and in the less than high school grads, from 52 to 65.

We made several revisions to the label after we saw the results of the use study.  The first revision was to delete the word "temporarily" from the uses section of the label.  "Temporarily" appears in the indication for OTC analgesics, "temporary relief of mild to moderate pain."  The agency asked us to include "temporary" in our uses section for the version that was tested in the label comprehension study, and we believe that that word helped confuse consumers.  Because that was so similar to what they're used to with analgesics, we believe that actually helped confuse them and we took it out of the label we submitted.
We increased the font size to make it easier for everyone to read, not just the elderly, and we added to the insert examples of inappropriate use, namely that the product does not work for treatment of leg cramps or arthritis.  We also added an explanation to the insert about why the elderly should ask a doctor before using the product.
We also recognized that both the label and the insert have even more room for improvement.  We look forward to hearing suggestions this afternoon, and one of the statements that we know we'd like to include is to clarify in the insert that there's not an absolute contra-indication to driving, as may have been interpreted, but clearly what we're advising people and the spirit of the label with diphenhydramine as well is not to drive until you know how you'll react to the medication, and you should not drive if you become drowsy or dizzy with the medication.  But if you're comfortable and have taken the medication before, it's hard to say that it's absolutely wrong to drive once you've had experience with the medication.

The pattern of use study was conducted to examine how patients would self-medicate with cyclobenzaprine.  It was not conducted to establish efficacy, and it was not conducted to establish effectiveness.  The protocol that we wrote and submitted to the agency was designed to look at how patients would use the product, how many tablets per day and how many days they would take it.  We enrolled 468 patients who believed that they had acute painful muscle spasm of the back or neck.  These patients were given 30 tablets, the first version of our label, and a diary card.
The majority of patients complied with directions regarding how many tablets to take per dose and per day.  Eighty-seven percent of patients never took more than three tablets in a day, and 89 percent never took more than one tablet as a single dose.  Overall, less than 3 percent of the treatment days consisted of more than 15 milligrams, and less than 1 percent of the doses consisted of more than 5 milligrams.

Forty-four percent of the people took the drug as labeled for seven or fewer days, and 48 percent took the medication for eight to ten days.  To us, this indicates that some patients actually require more than seven days of medication, and this is consistent with the natural history of the condition and the dosing instructions in the current prescription circular, which, after all, has a similar indication.
Since analgesic labeling allows for use up to 10 days before seeing a physician, we propose, since analgesics can also be used to treat acute back pain, to minimize the potential for confusion among consumers, that we should have the same duration on our product as are on the nonprescription analgesics.  So we will propose in the insert and label you have that 10 days would be the maximum duration of treatment before a patient should see a physician.
We examined analgesic use during the use study, and 35 percent of the patients in the use study did take an analgesic on one or more days during the study.  They were used for a number of reasons, be it headaches, arthritis pain, dysmenorrhea.  Fifteen percent reported that they used the analgesic to treat the same condition, whether it was neck or back pain with spasm, that they were using the cyclobenzaprine for.  If we look at the global ratings of the 15 percent of the patients who used analgesics for their back pain, it's no different than the patients who did not use analgesics during the trial.

Now, assessing whether patients avoided driving was not a primary objective of the study.  In fact, the question about driving was added after the study was ongoing, and only approximately half of the patients were able to complete that question.  We recognize the question was poorly worded.  It did not clearly ask about did you drive if the medicine made you sleepy.  We believe that in a future study, we need to clarify how we ask that question, because the label did not say in bold letters "Do Not Drive."  The label said "avoid driving," which may be interpreted differently.
In summary, the data we have presented today shows that cyclobenzaprine 5 milligrams TID is statistically and clinically superior to placebo in patients with acute painful muscle spasm of the back or neck.  The median time to substantial relief with cyclobenzaprine is approximately two days less than with placebo.  The overall efficacy of 5 milligrams TID appeared similar to that of 10 milligrams TID, the current prescription dose.  We established that muscle spasm does indeed resolve more quickly in patients who receive 5 milligrams TID than placebo, and we have shown that patients can recognize when they have painful muscle spasm, and the correlation between patient and physician ratings demonstrates that patients can assess whether their condition is improving.

Cyclobenzaprine 5 milligrams TID was generally well tolerated in the nonprescription studies.  The most common adverse experiences were drowsiness and dry mouth, and both were dose related.  The subjective level of sedation as measured by the visual analog scale was similar with 5 milligrams to that with the maximum OTC dose of diphenhydramine.  Our laboratory studies have shown that 5 milligrams TID does not consistently or substantially impair psychomotor performance and driving-related skills in young or elderly subjects.
The extensive experience we have with the 10 milligram dose shows that that dose is generally well tolerated.  Serious adverse experiences have been infrequently reported, and the available data suggest there is a large margin of safety in overdose and a limited potential for abuse.
Our label comprehension study shows that key directions and key warnings were well understood.  The insert actually helps consumers understand the difference from analgesics.  The study identified several opportunities for improvement, and we look forward to comments from the agency and suggestions from the advisory committee this afternoon.

Our pattern of use study showed that patients do generally adhere to the proposed dosing instructions.  It's worth noting that no patient in our pattern of use study took more than six tablets in a single day.  So no patient in the use study exceeded the current prescription dose.  Some patients appear that they will need more than seven days of treatment, however, in order to have adequate improvement and resolution of their condition.
As I have presented this morning, we believe that the clinical studies have shown that cyclobenzaprine 5 milligrams TID is safe and effective.  It provides a clinically meaningful benefit to patients with an acute and common problem.  The overall risks and benefits are comparable to that of some existing OTC products.  We believe we can develop labeling and refine it to allow a consumer to safely and appropriately self-medicate.
I'd like to thank you for your attention this morning and reintroduce Dr. Hemwall, who has a few concluding remarks.
DR. HEMWALL:  Thank you, Scott.
I actually have two objectives here right now.  One is to provide a wrap-up and put some of this in context, and the other is to give Scott a chance to catch his breath before the questioning starts.

This is an opportunity where I would just like to take a few minutes to place into perspective the important questions that you've been asked today, questions relating to whether or not American consumers will be able to, at their own discretion, buy Flexeril OTC off a store shelf, take it home, follow the directions, and use it safely and effectively.
You heard me speak earlier about the prevalence of the back pain problem in the United States, a problem that affects the day-to-day quality of life for millions of adults each year.  In addition to seeking help through the health care system, many consumers currently self-treat back pain and neck pain with OTC analgesics, rubs, dietary supplements, mechanical manipulations of all kinds.  Some of these products even have label claims to be effective against spasm or other terms.  In fact, self-treatment of back pain, neck pain, strain, tightness, spasm, whatever words best describe it, has clearly been a part of the consumer mindset for years.

While it is clear that consumers are comfortable with using OTCs to treat this common condition, it is also clear that currently available OTC choices do not always provide adequate relief, and many consumers end up in the doctor's office seeking additional options.  Thus, it's no wonder that, as I said before, over 30 million prescriptions are written each year for muscle relaxant drugs, of which roughly one out of three of those are for Flexeril or generic cyclobenzaprine.
For a substantial subset of that population, an OTC Flexeril product would offer real benefit, benefit to informed consumers who are seeking efficient access to an effective product for back and neck pain, access without having to endure the delay, the expense, and the inconvenience of a physician visit, especially for a problem that is often recurring, access to a medication with demonstrated efficacy, providing meaningful relief for many patients up to two days sooner than with placebo.

So OTC Flexeril can provide this real benefit, and you've already heard that the sedative properties are within limits and manageable by OTC labeling.  So the question really becomes:  How does the benefit relate to any potential risk?  Well, consider this.  Those of you who are on the Arthritis Drugs Committee are faced constantly with assessing safety of a new chemical entity with clinical experience and perhaps a few thousand patients, and maybe a few hundred of those have been treated for six months or a year, and despite having a clean profile in that NDA, there often remains a lingering concern regarding the potential for rare or unexpected adverse events that might occur in a widespread marketed use outside the setting of controlled clinical trials.
Today, these joint committees have a fairly unique opportunity to look at a molecule with a long history of use in the prescription setting, and we have reviewed for you the extensive safety data of Flexeril 10 milligrams, spanning over 20 years and over 100 million prescriptions.  This represents a degree of experience that is uncommon in the evaluation of an Rx to OTC switch.  It provides important perspective on the low incidence of the serious adverse effects associated with the use of the 10 milligram prescription dose, a dose twice that proposed for OTC use, and similarly this large experience supports the low potential for abuse and for serious consequences in an overdose situation.
In addition to demonstrating efficacy and safety appropriate for OTC use, we have developed a solid basis for consumer labeling aimed at efficiently managing consumer expectations of how this product works and directing consumer behavior to maximize the safe use.  We appreciate the care and the caution with which decisions must be made while considering a new class of medication for OTC use, and the FDA reviewers have raised important questions which we have addressed in our background book and in Dr. Korn's presentation today.

We're eager to learn from your discussions today.  Our team of Merck scientists and outside consultants are ready to assist in your assessment of these challenging issues, and we'll be willing to respond to any and all questions which may arise.
Thank you very much for your attention.
DR. BRASS:  Thank you.
At this point, we will begin a session which I expect will carry over to the afternoon of questions for both the sponsor and the FDA.  I suspect that there are a number of people on the committees who have large numbers of questions, and so I would ask that initially we each limit ourselves to one or two questions so that we avoid monopolizing.
The question can be addressed to either sponsor or FDA, both or either, and I would encourage the sponsor or the FDA, if they would wish to comment on a question directed towards the other, to please do so.
Additionally, a reminder to both sponsor and FDA.  When responding to a question, please identify yourself for purposes of transcription.

I think I'll take the chair's prerogative and ask the first question, specifically related to the issue of safety.  I am concerned that the use of mean data for describing safety monitoring may be misleading, and that, in fact, in a drug that is used in a wide population, one might be concerned about the percentage of people taking the drug who would have significant impairment.  We know that 2.5 percent of the patients in the trials had to discontinue medication use because of severe sedation.
You use a responder/nonresponder profile to describe efficacy, and I'd be interested in an impairment/nonimpairment profile in the safety analysis, particularly for the psychomotor type of testing.  Can you define a clinically significant degree of impairment, and what percentage of subjects actually exceeded that level?
Additionally, given the relatively small numbers of patients used in those types of testing, are you confident that there are not 5 percent of the general population who will be severely impaired at the 5 milligram dose?
That was a question.
(Laughter.)
DR. KORN:  Dr. Korn from Merck.  We'll have a slide coming up to address that.

We did not look at a responder type analysis, but we did look at scatter or variability within the data using these box and whisker displays.  Here, for the elderly study which I included in the presentation, we see a box and whisker plot with the median, 25th, and 75th percentiles for the data for vigilance time, reaction time.  So it's in seconds.  What we see is clearly the median for amitriptyline is higher than for diphenhydramine, for cyclobenzaprine or for placebo.  There is some spread to the data, but there are no bad outliers out there in this group of 32 patients or subjects.  They were healthy subjects.
It was reasonably tight data, and again, not skewed far off from that with placebo.  Is that the direction you were looking for?
DR. BRASS:  I assume this is the best of those scatters?  Do you have the others, just to give a sense of particularly the driving skills test, for example?

DR. KORN:  Sure.  Number 733.  Here's the divided attention task overall performance score, which is a composite of tracking and reaction time.  Again, we see amitriptyline on the far right, cyclobenzaprine looking a lot like placebo, one outlier with amitriptyline up at the far end.  We can do the same thing if you'd like with 735.  This is tracking error inside that test, which is the weaving motion.  Again, cyclobenzaprine overlapping pretty much with placebo, amitriptyline not that different but with an outlier.
DR. BRASS:  Thank you.
Other questions from the panel?
DR. ELASHOFF:  It seems to me fairly likely that in practice many patients will be taking an over-the-counter antihistamine when they take Flexeril, and many antihistamines also have strong drowsiness warnings.  But I haven't seen any information whatsoever as to what happens if you take both at the same time, and there doesn't appear to be anything on the label suggesting that you ought not to take other things that might be causing drowsiness.
DR. KORN:  Scott Korn.  You're right.  We do not have data in psychomotor trials looking at additive effects, whether it's alcohol, antihistamines, benzodiazepines.  We would assume that there would be an additive effect as opposed to a multiplicative effect, and we're certainly open to suggestions about other drugs that we should include on the back panel that patients should avoid if they were taking cyclobenzaprine.  We could certainly add antihistamines to the list of the sedatives and tranquilizers.
DR. ELASHOFF:  But we don't in fact know that it's not more than additive, even.

DR. KORN:  Right.  We would assume that certainly the anticholinergic properties would be additive.  We have not looked at psychomotor properties.
DR. BRASS:  Dr. Gilliam?
DR. GILLIAM:  This is two questions, both I guess toward the sponsor.  Have there been any studies looking at the use of Tylenol and/or NSAIDs compared to Tylenol and/or NSAIDs with Flexeril?  That's the first question.
DR. KORN:  We have not conducted any head-to-head trials that were double-blind and compared use with an analgesic or a nonsteroidal anti-inflammatory drug.  There are some published studies, including one done by Dr. Borenstein, that were open-label looking at naproxen sodium and Flexeril versus naproxen sodium alone that appeared to suggest a benefit.
Certainly we know that 85 percent of the prescriptions for cyclobenzaprine are accompanied by a prescription for either a non-narcotic or narcotic analgesic.  So physicians' practice over the past 20 years has been to prescribe both a muscle relaxant and an analgesic in conjunction, but I do not have double-blind data for that.

DR. GILLIAM:  In Study 9, there were 46 percent of patients who had muscle spasm previously.  Were there any differences in pattern between those who had diagnosed muscle spasm previously compared to those who had not in that study?
DR. KORN:  Can you clarify?  By "previously," do you mean they used cyclobenzaprine before?
DR. GILLIAM:  Yes.
DR. KORN:  Okay.  We have a slide for that.  We see on this slide the proportion of responders on that 5-category global scale.  So top three categories for all patients in the use study, for patients who never used cyclobenzaprine before, and for patients who had previously used cyclobenzaprine before.  Certainly the mean number of responders appears similar, maybe a little greater variability in the previous Flexeril users.  Certainly it's not surprising to us that some of the people on the far right exceeded the dosing directions for what we told them to do, but that may have been because their physician previously told them to take 10 milligrams, so all they were doing was following the directions their physician had given them before.
DR. GILLIAM:  But they had no idea that they were using Flexeril, right?  This was a double-blind study, so they didn't really know what they were using.

DR. KORN:  This was an open-label, uncontrolled trial.  They knew it was Flexeril.  The label said it.
DR. BRASS:  Dr. Pucino?
DR. PUCINO:  For the driving-related skills study in the elderly patients, do you have data going out more than four doses; i.e., if the half-life in elderly patients is somewhere around 33 hours, do you have something like 8 days dosing?
DR. KORN:  We do not have psychomotor data drifting out 8 or 10 days.  So we don't have psychomotor data at steady state in the elderly.  We have sedation data.
DR. BRASS:  Dr. Gerber?
DR. GERBER:  Many of us subscribe to the view that the ultimate outcome of health care is good function.  Pain is clearly one element that may contribute to that, but I'm wondering whether or not you have in this population of patients any data that indicate whether or not they were in fact able to perform usual activities either at home or at work as a result of taking the Flexeril.
DR. KORN:  No.  We did not collect outcome measures such as Roland-Morris or cut-down days as part of those trials.

DR. GERBER:  It's a very critical issue given that sedation, especially in the elderly, may in fact provide good resting activity at home and markedly reduce daily routines.
DR. BRASS:  Dr. Yocum?
DR. YOCUM:  I guess I would like to follow up Dr. Gerber's comments, that the premise of releasing this compound OTC is to get the millions of patients who have back pain back to work and functioning, but yet the scores that are being looked at are basically pain relief and global scores without any function.  I guess I would pose a question to the FDA, because maybe the company has been misled the whole time.  Is this typical for the plan for an OTC muscle relaxant not to look at function, which has been the focus of most rheumatologists for years?  I'm unclear as to why function is not included.
Also, I think Dr. Witter alluded to that there were secondary endpoints to be looked at which looked at there was a little bit more on functionality, but I am unable to find any data related to those secondary endpoints.  Are they presented at all in any sort of way?
So I guess one is, is this an okay thing for the FDA to not look at function?  And two, why aren't we seeing at least the secondary endpoint data?

DR. BRASS:  I'll ask Dr. Hyde or Dr. Katz to comment, but I think the point you raise is going to be part of our discussion this afternoon.  But if Dr. Hyde or Dr. Katz wants to comment.
DR. HYDE:  I don't know that we have a real response to that.  I mean, one of the issues was that it was already an approved product and part of this development was to explore the dosing range to see if lower over-the-counter might be appropriate.  I don't know if that completely answers your question.
DR. BRASS:  Dr. Witter, do you want to comment on the referred-to secondary endpoints?
DR. WITTER:  The secondary endpoint that I thought was most useful was what I had presented, which was the physician confirmation of spasm.  The other ones, maybe the sponsor might want to discuss them in a bit more detail, but I didn't find them to be of the same kind of use.
I just might comment, Dr. Yocum, that I put up there the World Health Organization proposals and that was part of the discussion that preceded this.  I think maybe that's an answer for you.
DR. BRASS:  Dr. Harris.

DR. HARRIS:  This is to the sponsor.  One of my major concerns remains whether or not patients are going to be able to distinguish between back and neck pain alone versus back and neck pain plus spasm.  Although there is data showing that the physician and patient concur with respect to their understanding of spasm, I'm still not convinced that patients won't take this as they might an analgesic with back and neck pain alone, that it will end up being in the minds of many patients an analgesic rather than being used for spasm.
I'll ask if you have any data that distinguishes or determines whether or not, or really would convince me that patients won't use this as an analgesic, even without spasm.
DR. KORN:  We have not done a study looking specifically at accuracy of self-diagnosis, whether they have spasm and would they be likely to use this for conditions when they don't have spasm.  Again, we've done label comprehension work, but the patients were not acutely ill then.  They were normal subjects walking through a shopping mall.  So we haven't looked at patients who were symptomatic and done label comprehension in those groups where maybe you would get the answer to that question.
DR. BRASS:  Dr. Sachs?

DR. SACHS:  Since one of the goals of releasing this over-the-counter would be to allow people to treat themselves and therefore get symptom relief faster, I was wondering if you did have some data which showed if you started the drug earlier you did feel better.  Also, if you are showing that the drug is relief two days sooner, on the one hand then why would you need to take it longer for symptom relief?
DR. KORN:  To answer the second part of your question first, the current prescription circular states that the product can be used for up to two to three weeks, and indeed if we look at our populations after seven days, less than half the patients had complete relief at the end of seven days, which is not surprising given the natural history of the condition.  So some of those patients may have given the drug a very high medication helpfulness score.  They thought it was helpful.  They just hadn't gotten back up to the level of function or pain relief that they really wanted.
So to us, it's not surprising that seven days might not be the ultimate duration of treatment and they may need a little longer.
716, please?

To look at, I believe, the first element of your question, within Protocol 6 and 8, in Protocol 6 patients were allowed to be symptomatic for up to 14 days, but some did enroll after less than seven days or less than three days.  In Protocol 8, patients had to be symptomatic for less than seven days, but some did enroll in less than three days.  We see that the difference between 5 and placebo, the difference in mean scores for global impression of change at Visit 2 was basically consistent whether they were patients in the all-patients-treated analysis or the patients who had been symptomatic for a shorter period of time, whether it was seven days or three days.
In Protocol 8, the patients who had been symptomatic for shorter actually had a better differentiation from placebo than the patients who had been symptomatic up to seven days.
DR. BRASS:  Dr. Abramson?
DR. ABRAMSON:  I just had a question relating to the label recommendation that people over 65 consult a physician.  I guess it was both with respect to the practicality and the rationale for that.  So it's a two-part kind of question.  One is, is there a precedent where OTC drugs make that kind of recommendation, that the patient consults a doctor?  And what's the likelihood that that's going to be effective?

But perhaps more importantly, there's a notion that at age 65, all of a sudden the clearance decreases and plasma levels go up.  So the question is the basis of the data that shows the trend during which time with age plasma levels increase, and what happens at age 60 and 55 for example?
DR. KORN:  We are aware of precedent for a different labeling for geriatric patients and analgesics.  If you look at naproxen sodium, there are different dosing directions for patients who are 65 or older versus patients who are less than 65.
DR. ABRAMSON:  Requiring them to consult with their doctor?

DR. KORN:  No.  It's for a different dose.  We're going one step past that.  We're saying, gee, we don't want you titrating the dose or adjusting the dose, we think you ought to see a physician, because if we're attracting a population that has acute back pain, and I think the AHCPR guidelines are consistent with this, the risk that a 65 or 70-year-old patient with a new onset of acute back pain that's substantial has an underlying condition requiring diagnosis and treatment is quite higher than a 20-year-old who was out shoveling snow.  So not just from a kinetic basis but as well as a diagnosis and a risk of misdiagnosis, we believe that elderly patients should be triaged to their physician if they've got acute back pain with spasm.
You're absolutely right, there's not a threshold effect where the clearance goes up at 65.  The clearance would start to go up presumably whenever functional hepatic mass starts to go down, and it is a continuum.  Where you draw the cutoff is unclear.  But certainly even patients who are 65 and take the product end up with plasma concentrations that they would have gotten if they were younger and currently took the Rx product.  So we think that lowering the dose by half gives us a safety margin even if patients disregard the instruction to see their doctor or those patients are 62 and think it's okay and have a higher level.
DR. BRASS:  Dr. Sherrer?

DR. SHERRER:  Hi.  Yvonne Sherrer.  I have a question.  You gave us information about the rise in prescription usage of Flexeril over the years and its apparent safety, but I know as a rheumatologist, at least in recent years, prescribing patterns for Flexeril has changed.  It's often used more in chronic pain as a single nighttime dose for pain modulation and sleep modulation, which, if that reflects a substantial portion of those prescription increases, may reflect a different safety pattern than what you presented in current usage, or at least usage in these studies.
Can you give me an idea of the prescriptions that are given out in the community?  How many of them are in fact for acute pain versus chronic pain, a single nighttime usage?
DR. KORN:  Slide 804.  This slide summarizes data from Medco.  In 1997 and 1998, there were 681,000 prescriptions for cyclobenzaprine, and we see that 28 percent of the prescriptions were given as a one-time dose, I assume at night, for probably fibromyalgia.  But 54 percent of the prescriptions were written as TID dosing, probably for acute back pain.
DR. BRASS:  Yes, Dr. Lovell?

DR. LOVELL:  It seems the hypothesis for your psychomotor impairment with your drug is that it's secondary to sedation, and if that's the case, then it makes sense to do it early in the use before it gets into steady state concentration.  Could you show us data to compare psychomotor results in patients who reported sedation and didn't report sedation?  It seems that an alternative hypothesis is that psychomotor impairment could be due to the fact that this drug is centrally acting on the nervous system and may have impairment independent of its sedating effect, in which case steady state information would be very relevant I think.
DR. KORN:  Looking at our psychomotor data in the two driving-related studies, the median visual analog scale in all treatment groups combined, the median rating before the driving tests were begun was about 47.  So we've gone back and looked at the data, the performance data in patients who had a visual analog score of 50 or more at the beginning of the test versus a visual analog score of less than 50.
DR. LOVELL:  You mean for sedation?
DR. KORN:  For sedation, right.  So it was alert/drowsy on the visual analog scale.  If they were over 50 on the visual analog scale, there were a higher number of errors in the vigilance test than if they had a visual analog score less than 50.  So sedation as reflected on visual analog did seem to predict an increase in errors in the vigilance test, which is a test of basically maintaining wakefulness for 40 minutes.  But again, not a steady state.
DR. BRASS:  Dr. Anderson, did you have a question?

DR. ANDERSON:  Yes.  I had a couple of questions, one about the correlation between muscle spasm as assessed by the M.D. and the patient findings.  I was wondering what the sample sizes were for those correlations that you presented on Slide 41.  Then my second question has to do with the reporting of the driving skills.  I was wondering why you used geometric means in all of those slides.
DR. KORN:  In Slide 41, the correlations between physician and patient ratings, the sample sizes were combined from 6 and 8.  So there were 200 patients on 10 milligrams, 200 on 2.5.
DR. ANDERSON:  So there wasn't missing data.
DR. KORN:  No, not at the first visit.  We did this at the early time point, at Visit 2.  At Visit 3, there was some missing data, but the correlations were just as strong.
DR. ANDERSON:  The second question was about geometric means.
DR. KORN:  I'm going to let our statistician answer that for you.

MR. TIPPING:  Bob Tipping from Merck.  The reason that we used geometric means are two reasons.  One, it helps with the distributional assumptions of the analysis.  It puts it into a normal scale.  The second reason is it's a little more intuitive in terms of describing what clinically meaningful differences is.  Sometimes in talking about ratios, 10 percent worse or 20 percent worse, the geometric mean ratio analysis done on a log scale transforms to that sort of a definition of what may be clinically meaningful.
DR. BRASS:  Dr. Krenzelok?
DR. KORN:  I was going to follow up.  We do have one slide to address your question about how the correlations looked, as opposed to just giving a correlation coefficient.  This shows at Visit 3 the responses on the left-hand side are the physician ratings of spasm:  none, mild, moderate, severe.  On the right-hand side is the patient global ratings, showing marked improvement at the bottom, worsening at the top.  The height of the bars represents the proportion of patients.
If there were a perfect correlation between the physician and the patient, the clustering of 12 blocks would be straight along the diagonal.  What we see is that, in general, they are clustered along the center in these three areas.  There are very few cases where the physician thought that the patient was worse but the patient thought they were improved, and conversely, where the patient thought they were worse but the physician thought they were improved.

DR. BRASS:  Dr. Krenzelok?
DR. KRENZELOK:  Thank you.  This question is to the sponsor, and it really addresses the issue more of label readability.  As I observed your presentation, it would appear that there was, at least from my perspective, in the recruitment of patients to determine label readability, there may have been some selection bias.  In one case you recruited patients, I think in the open-label study, using newspaper ads as one medium for selection, and 56 percent of the people were recruited that way.  The other was the mall intercept methodology, again which may interject a fair amount of bias.
I guess my concern is, I wonder if you really have addressed the needs of the people who are illiterate, which are said to be at least 20 percent of the people in this country, and did you do further readability testing on the label to see how the label reads using something as simple as, say, a Gunning Fog Index that you might find on Word or whatever?  Thank you.

DR. KORN:  We have looked at the Smog test measure of readability, and it's a reasonable level of readability.  We went to the mall intercept method looking for patients who had low literacy because we thought it would be easier to find that than through a newspaper certainly, and I think that what we have seen is that we need to skew where we go, what malls we go to, to better enrich either the geriatric setting or the low literacy level.  We did not assess literacy directly by some realm or some other measure.  We looked at education level as a correlate, and it appears that some people may over-report how many years.  They may be embarrassed to state that they did not finish high school.
So we know that we have to work harder in our next label comp study to find people who have low literacy skills.
DR. BRASS:  Dr. Neill?
DR. NEILL:  I have one question for sponsor, one question for the FDA.
In looking at the package label, I noticed that apparently the proposed marketing form is for four days of medication, and given the data that I've seen that suggests that the duration of treatment that will benefit a patient is likely to be longer than that, I'm wondering why a package with four days of medication was chosen.
A second issue related to that deals with the somnolence data, which suggests that the maximum somnolence occurs within that first four days.

The second question for the FDA has to do with a change in the labeling indication for the OTC versus prescription product.  The labeling for the prescription product includes the phrase "for use as an adjunct with physical therapy and rest," and the OTC labeling does not include that phrase, and I'm curious to know why it doesn't and do we need to consider that as a different indication given that we've had no data for use of Flexeril at this dose as an adjunct to physical therapy and rest.
DR. KORN:  The answer actually does talk about non-pharmacologic methods of treatment, be it heat or other methods, and we would hope that that would be in lieu of on the top.  We propose to have multiple package sizes.  The smallest would be four days.  There certainly would be a package size with 30 tablets, which would be a 10-day course of treatment.  Many consumers, if they've never tried a product before, would like to not lay out a lot of money and would like to take a smaller investment and make sure they tolerate the product before, if necessary, going back and getting more.
So over time, what we've seen with the H2s and others is they start out small and then purchase larger packages the next time they need the medication because they know they tolerate the drug.

DR. BRASS:  Comment from the FDA on the indication question?
DR. KATZ:  At this point in time, actually I think the sponsor answered the question regarding the indication.  Since what you're seeing now are preliminary labeling as proposed by the sponsor, what you might see as an indication might change later on down the line.
DR. BRASS:  Ms. Hamilton?
MS. HAMILTON:  I have a few questions for the FDA on the label comprehension range of questions.  Some of this is sort of a refresher course for me, I guess.  Basic questions.
Do we know how many patients read inserts?
A second question is, do we know how far down the label they read?
Do we have any data indicating how often consumers actually consult their physician when they're directed to do that on a label, and do consumers typically recognize the technical terminology from other medications they may be taking?

DR. AIKIN:  Hi.  Kathryn Aikin.  The answer to most of your questions is no.  We do not know how many consumers actually read the label insert.  We do not know exactly what they focus on in the label.  Some preliminary indications would be that they tend to focus on the directions first instead of the warnings.  We do not have information on how many people actually consult a doctor when instructed to do so.  And your final question was?
MS. HAMILTON:  Understanding and recognizing the technical name of other medications they might be taking?
DR. AIKIN:  They're more likely to understand the technical name if the actual name of the product is next to it and they have taken it previously, which is why there is often the name of the product next to the technical name.
MS. HAMILTON:  Thank you.
DR. BRASS:  Dr. Koda-Kimble?

DR. KODA-KIMBLE:  I have a basic question to either members of the Arthritis Committee or perhaps Merck's consultants.  I'm interested in the pathophysiology of pain related to back and neck pain.  I mean, what is garden variety back and neck pain?  I don't think people say, "I've got a spasm, I've got strain, I've got back pain, I've got a stiff neck."  In the AHCPR guidelines that we received, at that point there were several experts who questioned the importance of spasm in the cause of pain.  So could somebody bring me up to date on that?  If somebody says, "I've got back or neck pain," what is the cause of the pain?
DR. BORENSTEIN:  David Borenstein.  I'm supposed to answer this question.  I've written a 700-page book on back pain, so I want to make this answer brief.  It's a very difficult question to answer, because back pain can mean very different things for different people.  I think in the run of the mill circumstance in mechanical low back pain, one is talking about a muscle injury frequently.  This will be debated among rheumatologists and orthopedists as to whether the disk is the primary focus of the problem or is it a muscle syndrome.
I do believe certainly in younger individuals, where the drug is supposed to be used primarily, it is a muscle pain syndrome.  In that circumstance, I do believe there is muscle injury.  As part of the muscle injury, I do believe there is contraction of the muscle as part of that on a reflex basis, which I feel we are able to determine in many individuals on physical examination, as well as some range of motion.

Now, some of these statements can be debated as to how specifically one is able to determine that.  But if you ask patients, they have different terms in regards to whether they are able to function or not and whether they feel that they are tight or limited in their motion.  If it's a tightness that they feel, I think they equate that with spasm.  In my experience, that is where these medications, the muscle relaxants and Flexeril, can be quite helpful.
So I do think individuals do use terms which describe muscle spasm as a component of pain.  Now, which one comes first and how much is what depends more on an individual basis.  But I do believe that contraction and pain do play a role in those common musculoskeletal problems of the lumbar spine.  Hopefully I've answered that to a certain degree, but I can go even further if you want.
DR. KODA-KIMBLE:  Is that 90 percent of the time?  I mean, what I'm just saying is if somebody says "I've got back or neck pain," what fraction of the time is that related to spasm?  Well, we're using the term "spasm."

DR. BORENSTEIN:  The answer to that ‑‑ and I'm not trying to dodge the question ‑‑ depends.  If you have someone like me, it's a smaller percentage because I see only the more difficult patients.  I think you see the whole spectrum of individuals.  Ninety percent of individuals with back pain have it on a mechanical basis, which means part of this is that it's based upon joints and muscles being affected.  Depending upon the age range, you will have more arthritis in the older group, while the younger group will have it more on the basis of muscle injury.
So if you're talking about younger individuals, I think a vast majority of those individuals have it on that basis.  The older you get, the less it becomes a problem of muscle and more it becomes one of either joint or disk problems, things of that sort.
DR. KODA-KIMBLE:  I have one other question.  This relates to the use of the pharmacokinetic data you have on patients with liver disease.  In the study, it says you studied people with a Pugh-Child classification of 5 to 11.  Could somebody explain to me what that is and whether someone would be able to recognize their liver disease at that level?
DR. KORN:  The patients in the study who have a Pugh-Child score that's large enough to qualify have known cirrhosis, and they certainly can't assess their own laboratory parameters, whether it's a low serum albumin or a high prothrombin.  The transaminases are actually not part of the score.  So in general, they will not know whether they're a Child-Pugh 2, 3, et cetera.  They will know, hopefully from their physician, that they have liver disease, and that's the term we're putting on the box.
DR. BRASS:  Dr. Gerber?

DR. GERBER:  I am trying to sort out the issue of spasm and pain and how that really does clinically relate to what you are calling efficacy of Flexeril.  As I review Slide 40, which is the physician rating of muscle spasm that you report, specifically in the model of the most acute back pain or most acute spasm, there seems to be some interesting information there that doesn't really support my clinical experience of more than 25 years of treating these kinds of problems in that if you have an acute spasm and your medication is effective, it should be working within the first several days.
This data suggests that essentially at Visit 2, there is no significant difference between placebo and cyclobenzaprine 5, and no difference between placebo and 2.5.  It takes about eight days average, because that what your Visit 3 is, to show a difference at the 5 milligram level, and that doesn't quite sit with my clinical formulation.  Also, looking at the issue of having an acute problem that has an acute relief, I wonder if you'd elaborate a little bit or perhaps give me your interpretation of that.

DR. KORN:  We think that 5 milligrams was effective at Visit 2 in Protocol 6.  So what we're seeing is that Protocol 8 had less discriminatory ability at the early time point.
DR. GERBER:  I am talking about Protocol 8 because that's the shorter duration group that was selected for treatment.  They had their acute onset within a week of selection into the study.
DR. KORN:  Again, we're not sure why 8 didn't turn out like 6.  Even when we look at the subgroup in 6 of patients with more acute pain, we saw better differentiation of 5 milligrams from placebo.  So we cannot explain why, but we can say that when you look at the more acute subset of 6, which would also be like the patients you're thinking are appropriate, we do see significant differences.

DR. GERBER:  The only other observation I would make about that which I think is worthy of comment, at least from the clinical perspective, is the natural history of what the physician is calling muscle spasm.  By Visit 3, which is Day 8, there's better than a 50 percent reduction in symptoms as determined by the physician, presumably by palpation or some of the other things that Dr. Borenstein was referring to, in the placebo group.  So that shows you that you have an appreciable reduction over a one-week period with no intervention, telling you a little bit about the natural history of the symptoms.  So one would expect if you're seeing efficacy, to see if relatively early in the course.
DR. KORN:  Could I just show one slide here?  There is a secondary analysis in Protocol 8 looking at proportion of responders in the all-patients-treated approach with the clinical global impression of change, and these bar graphs show the distribution of the ratings.  We see that 5 milligrams had 78 percent responders, versus 66 percent with placebo, and that was a significant P value of 0.007.  So in our primary analysis of mean scores, we did not show a significant difference at the early time point, but we certainly did in the secondary analysis of percent responders.
DR. BRASS:  At this time, I'm going to break us for lunch.  Before everybody disappears, we are going to reconvene promptly at 1:00 with the open public hearing.
Before we depart, Dr. Titus has a few words of wisdom.
DR. TITUS:  I have two announcements for the committee members.
I'm sorry.  You'd better do it.

DR. BRASS:  While I'm pulling out my glasses again and trying to decipher handwriting, I will remind committee members that they are not to discuss issues related to today's subject during lunch.
These announcements look like they say, for the committee members, in the restaurant there's a reserved table in the rear, as always, for participants.  We have travel assistance available ‑‑ too late for Dr. Abramson.  We have travel assistance available at the reception table.
I think that's it.  Is that it?  Okay.
Thank you all very much.  We'll reconvene at 1:00.
(Whereupon, at 12:07 p.m., the meeting was recessed for lunch, to reconvene at 1:00 p.m.)

	AFTERNOON SESSION	(1:00 p.m.)

DR. BRASS:  Good afternoon.  As we begin to reconvene, I just want to go over again briefly what the format for the afternoon's agenda will be.  We will begin with the open public hearing, and my understanding is we have one individual who has requested time.  We will then continue with our questioning of the FDA and sponsor concerning the presentations from this morning.  We will then shift to a more focused discussion of the questions posed to the committees by the FDA, during which there will undoubtedly be opportunities and need for additional questioning of both the FDA and sponsor presenters.
Having stalled long enough, we will now begin with the open public hearing.  Dr. Larry Sasich from Public Citizen has requested five minutes of time.
DR. SASICH:  Thank you very much for this opportunity to speak before the committee.  Before I begin with my comments, I would like to say that due to litigation that Public Citizen has been involved with against the Food and Drug Administration, the FDA's reviews that were distributed to these advisory committees are available to the public now.  I believe that this is the first time that FDA review documents have been available at the time of an FDA advisory committee, and I would like to urge all members of the media to take a look at those documents if they have time before they write their stories, and hopefully at some point in the future these documents will be available prior to the time of advisory committee meetings.

Public Citizen firmly believes that for any drug approval process to be truly safe, it must be as transparent as possible to the public.
Thank you.  I'll go on with my comments.
Public Citizen's Health Research Group has not seen evidence presented today that cyclobenzaprine in a 5 milligram dose given three times a day is as effective as existing nonprescription analgesics and anti-inflammatory drugs in relieving the pain of local muscle spasm, and it has a higher risk of serious adverse effects.  Perception of pain is critical in your consideration of this drug's switch from prescription to OTC status because it appears that the three primary efficacy endpoints used in the two pivotal protocols, 006 and 008, depends on patients' assessment of pain rather than muscle spasm.

Since we have no evidence that cyclobenzaprine 5 milligram is as effective as currently available nonprescription analgesics, this raises the issue of consumers increasing the dose of cyclobenzaprine to 10 milligrams three times a day from 5.  At the 10 milligram dose of the drug, the current cyclobenzaprine labeling indicates that 40 percent of patients will experience drowsiness.  The FDA in its review found the efficacy of cyclobenzaprine, and I quote, "to be clinically modest."  Though there may be a statistical difference between cyclobenzaprine 5 milligrams and placebo, the clinical significance of this result remains to be unknown.
A fundamental requirement of any over-the-counter drug is the condition for which the drug is indicated can be accurately and safely self-diagnosed by consumers.  In the two pivotal trials just mentioned, an exclusion criteria for participating in these trials included, and I quote, "vertebral body or percussive tenderness."  A consumer would have to be remarkably flexible to percuss the entire length of his or her spine alone.
This drug is associated with a number of clinically significant drug interactions, including widely prescribed drugs such as tricyclic antidepressants, and there is a potential for seizure when this drug is used in combination with tramadol, a prescription pain reliever better known as Ultram.  There are also a number of medical contraindications to the use of cyclobenzaprine.  These include a recent heart attack, heart rhythm disturbances, and congestive heart failure.  This drug should be used with caution, if at all, in patients with glaucoma or predisposition to glaucoma, urinary retention, heart block, or hyperthyroidism.

Cyclobenzaprine has been available in this country since 1977.  The drug's long use, with the sponsor claiming over 100 million total prescriptions dispensed since it was first introduced, and we have no reason to doubt that, this number would be much more reassuring from a safety standpoint if we had an adverse drug reaction reporting system that could accurately estimate the number of individuals harmed by prescription drugs.
The sponsor made reference to the muscle relaxants methocarbamol, orthenadrene, and chlorzoxazone as being available over-the-counter in Canada, either alone or in combination with analgesics.  Chlorzoxazone was relabeled in this country in 1996 with strengthened warnings regarding its liver toxicity.  Cyclobenzaprine has been associated with abnormal liver function, hepatitis, jaundice, and cholestasis in less than 1 percent of patients using the drug.  This is from the current FDA approved labeling for the product.

The reason that I mention this, I would like to remind everybody that the openness of other drug regulatory authorities, such as the Canadian, is not the same as the FDA.  The dangerous antihistamines terfenadine and astemizole were also available without prescription in Canada, and because of the lack of transparency in the Canadian drug approval process, we do not know what the basis for allowing the use of the muscle relaxants or terfenadine and astemizole in Canada were.
We remain very concerned about the severe drowsiness that the 5 milligram dose of cyclobenzaprine can cause, 2.6 percent in Protocols 006 and 008, the psychomotor impairment that can occur in the absence of perceived drowsiness by patients, its drug interactions, medical contraindications, and cyclobenzaprine's use by the elderly.  We are also concerned about the consumer's ability to differentiate mild muscle injury from a serious injury to the spine.  The data presented by the FDA about the comprehension by consumers of some important information about cyclobenzaprine is troubling.
In summary, this drug has demonstrated only minimal efficacy to differentiate it, as the FDA so correctly pointed out, from effectiveness, and may not be equivalent to available over-the-counter analgesics and anti-inflammatory drugs, and is clearly less safe than these drugs.  In conclusion, we would urge that this committee not recommend that cyclobenzaprine be made available for nonprescription drug use in the United States.
Thank you very much for your attention.
DR. BRASS:  Thank you.

I'd like to now continue the questioning of the sponsor and the FDA, and again perhaps I will begin with a few questions concerning the pharmacokinetics of the compound.
First, in clarification, the current material makes reference to a half-life of 18 hours.  Yet the previous package insert and a variety of literature suggests a longer half-life for the compound.  I'd appreciate clarification of where the 18 hours was derived.
DR. WINCHELL:  I'm Greg Winchell from Merck.  In answer to your question, the 18-hour half-life that's in our current label is an accumulation half-life based on the accumulation of drug.  The previous half-life was a terminal half-life, but the terminal determination was confounded by the presence of interhepatic circulation.  So if you look at the terminal elimination phase, you get different slopes depending on when you get interhepatic recirculation.
DR. BRASS:  So how was the 18 hours determined?
DR. WINCHELL:  By fitting a monoexponential to the accumulation of drug to the trough concentrations on daily dosing.  That's why it's an effective half-life.
DR. BRASS:  Okay.  I think I know the answer to this, but it may help explain some things.  Why is a drug with an 18-hour half-life being dosed TID?

DR. KORN:  We adopted the historical precedent, since the 10 milligram prescription dose had been dosed TID for 20 years, we decided not to try to confuse people by shifting the dose recommendation to a less frequent interval.  We certainly recognize that you would reach steady state at a reasonable time, but we think that given the fact that there is a response between the amount of drowsiness and the amount of a single dose, we'd rather have smaller doses taken more frequently than larger doses taken more infrequently.
DR. BRASS:  Concern was raised about the drug metabolism spectrum and profile.  You presented an in vivo profile of metabolites recovered in the urine, and in vitro P450 profiling, and the concern was that the in vitro was using much higher concentrations of the drug.  I was wondering if you tried to predict the in vivo metabolite profile as compared to the predicted products from the in vitro data based on the P450 profiling and whether it is both predictive qualitatively and quantitatively to give some confidence to that in vitro data.

DR. WINCHELL:  In regard to the in vitro data that was done at high concentration, we do believe that the FDA's concerns with regard to that were well founded.  We're actually in the process of conducting more in vitro studies, of which I have some very preliminary results, at lower concentrations.  In terms of the profile, one of the reasons we went to high doses was because in vitro we were only able to get ND methylation, and then we had to run at very high concentrations in order to get a sufficient amount of the D-methyl metabolite to measure.  In the studies we're doing at lower doses, we're looking at the disappearance of parent drug.  But again, we won't know the metabolic profile of that because it will be too low.
DR. BRASS:  Do all three of the P450s identified catalyze the D-methylation reaction, or do differential products from the three P450s in vitro that were active?
DR. WINCHELL:  At high concentration, all three were involved.  At low concentrations, our very preliminary data, which hasn't been reviewed by the FDA, where we used monoclonal antibodies against individually 3A4, 1A2, and 2D6, none of them individually was able to substantially block the disappearance of cyclobenzaprine at low concentration.
DR. BRASS:  Okay.  I think we'll hold that because that data is preliminary and the discussion is in the spirit of what is necessary.  I think that answer will suffice.

Yes, Dr. Pucino?
DR. PUCINO:  Yes, a couple of things along the same line.  Do we know anything about the activity of the metabolites?
DR. WINCHELL:  The answer to that is no.  We don't have (inaudible).
DR. PUCINO:  Is there any data using inhibitors of at least the two primary cytochrome P450 systems, the 3A4 and the 1A2?  Inhibiting in vivo.
DR. WINCHELL:  No.  We have no clinical data on inhibitors of those two.
DR. BRASS:  Okay.  I guess I will continue, then, with some additional questions.
The issue of the predictability of the adverse events has been inferred several times, that a patient who self-diagnoses sedation will be able to avoid engaging in the high-risk behaviors.  Do you have data to substantiate that self-assessment in a predictive way that will be helpful in reassuring?  Just like you self-diagnose the indication, can you truly self-diagnose the contraindication activity?

DR. KORN:  No.  We have not looked at the positive predictive value of sedation.  What we do know is that in the clinical trials we've looked at impairment at the time of peak sedation, but we haven't looked at differentially those who were or were not.
DR. BRASS:  One of the concerns about the toxicity has been drawn from the parallelism between cyclobenzaprine and tricyclic antidepressants.  In the area of arrhythmias, is there any data that at the concentrations achieved of cyclobenzaprine in either therapeutic or even in overdose situations, that there's any class 1A type electrophysiologic effects of the compound and/or QRS prolongation in non-fatal overdoses?
DR. KORN:  No.  Both with 5 milligrams TID and 10 milligrams TID, we have not seen QRS widening, QT prolongation.
DR. BRASS:  What about in the overdose situation?
DR. KORN:  Again, in the overdose situation ‑‑ and Dr. Krenzelok might be able to speak to this as well.  In his review of approximately 500 overdoses, life-threatening arrhythmias were just very uncommon in doses of less than 1 gram.

DR. BRASS:  I understand.  Was QRS prolongation looked for and identified?  Because again, I'm looking for parallels, the strengths of the analogy between the tricyclics, and the tricyclic proarrhythmic effects are thought to be related to direct effects which are manifested as Class 1A antiarrhythmic effects and electrocardiographically early as prolonged QRS complex.
DR. KORN:  We have not seen QRS widening in a dog study at up to 40 times the human plasma concentration at therapeutic doses.  We don't have data on people at that high dose.
DR. BRASS:  One of the additional issues that has come up is how this drug will be used in actual use, particularly duration of use, and whether consumers will self-limit their use.  Your actual use study was designed to be seven days.  In actuality, there was substantial use for 10 days, and in some of the materials it was viewed as there was very little use past 10 days.  But I think it's very important to point out two things.  One, the final visit was scheduled to be between 8 and 10 days, and therefore use beyond 10 days you wouldn't be able to detect, and they were only given 30 pills.  So I think drawing the conclusion that consumers will not use the drug for longer than 10 days cannot be drawn from that study, and that, in fact, a conclusion that can be drawn, they did use it longer than was expected or they were told to use it.

Is there reason to be concerned that, in fact, they will use it longer than 10 days when we tell them to stop at 10 days?
DR. KORN:  Well, we have no data to suggest they would be any more likely to do that than they would be to take ibuprofen or acetaminophen for longer than the 10 days that those products are currently labeled.  We also recognize that patients who have reached steady state concentrations, it was certainly by the 7 days or the 10 days that they took the drug.  So we have had an opportunity to assess safety at steady state concentrations.
DR. KRENZELOK:  I'll just make a comment regarding the QRS prolongation and widening and so on.  Back when this drug came out in 1977, we were very concerned that it would have the same profile as, say, the tricyclic antidepressants, and so we were pretty vigilant about making sure these people were admitted according to the tricyclic antidepressant protocol.  They were admitted for three days of continuous monitoring and so on, and the safety profile has been very, very good and hasn't even come close to the tricyclics.
So in response to your question, Dr. Korn's answer was absolutely correct.  It's a very safe drug.  In overdose, we very rarely see any dysrhythmias at all.

DR. BRASS:  Dr. Gerber?
DR. GERBER:  In pursuing the mechanism of action and its efficacy in muscle spasm, I wonder if the sponsor would comment.  In any of your secondary analyses, have you looked at those patients who respond that they have had significant ‑‑ that is, major ‑‑ improvement in symptoms, and those same patients potentially reporting increased drowsiness or sedation?  I'm looking for concordance between response and sedation.
DR. KORN:  We have data that we showed this morning that looks at the percent responders in those who were not sedated versus those who voluntarily reported clinically apparent sedation.  Again, the difference in the means in proportion responders for those who did not report sedation was at least as large, in general, as the all patients treated.  The sample size gets too small in the placebo group that reported sedation to draw conclusions about that.
DR. BRASS:  Dr. Yocum.

DR. YOCUM:  I have a couple of questions.  The first really relates to concerns about following up on the duration of use of this therapy.  We're hoping that patients who have chronicity, which is a concern here, will consult their physician if they have long-term back problems.  Do we have any data from the prescription Flexeril use that, in fact, physicians limit use to less than 10 days?  Because if the patients are going to go to the physician, and the physicians are already not using it in that way, I don't think it's going to be a limiting factor.  That's question number one, which is to the sponsor.
Question number two relates to the comprehension studies, because I'm not sure whether they're the same studies, one by the FDA, one by the company, or whether they were the same analyzed in a different way.  I was very confused about that, because the conclusions of the FDA were a little bit confusing in that it seemed like the first conclusion suggested everybody understood what was going on, but then later on suggested that, in fact, that the elderly consumers may not consult a physician, so that gets rid of that, hopefully, stop point for misuse.  That other is that the elderly consumers may use Flexeril for inappropriate conditions, which is also of concern, especially if they're going to use it for chronic situations.

Nowhere in this analysis did I see whether you asked the patient did they understand that if they had back pain for more than two weeks, that they were to consult their physician and whether they clearly understood that.  On Slide 89, there's no percentage of whether the patients comprehended that or not.  So I'd ask both the FDA, was that comprehended if it was the same questionnaire, and the sponsor too, did they ask that, and do the patients comprehend the issue of chronicity versus acute nature, because I think the labeling concerns me, that while in fine print it says "acute," there's nothing else in the labeling that talks about acute.
DR. KORN:  I'd like to introduce Dr. Mary Moore to address the first part of the question.
DR. MOORE:  Well, I'm a rheumatologist and I'll address the first part of the question from that point of view.  It was said earlier today that many clinicians, many rheumatologists and chronic pain doctors have begun to use prescription Flexeril chronically.  For fibromyalgia and for chronic pain, it's often given as a single dose at bedtime, and other people give it during the day.  So there are out there now hundreds of patients, if not thousands, that are taking the prescription dose chronically without any problem.  So that would be my comment as a clinician about the chronic use.

DR. LOVELL:  The prescription dose is 10 milligrams TID, and I don't think that's commonly used for treatment of fibromyalgia, is it?
DR. MOORE:  Very often varying doses are given either at bedtime or during the day.  So anywhere from 10 to 30 milligrams at bedtime is given.  Other people prefer to give it during the day.  All I can say is that it's not uncommon to see 30 milligrams given daily for many months at a time for fibromyalgia and other chronic pain.
DR. YOCUM:  So my conclusion would be that it's unlikely that the physician is going to limit the patient to 10 days or less.  So we may well be looking at OTC use for extended use, because there is going to be no limiting factor.
DR. BRASS:  I think, again, just from the OTC perspective, just in general, those kinds of warnings are there for two reasons.  One is so that if there's another condition present, that the physician has the opportunity to intervene in the chronic use, or if there's a contraindication for chronic use.  So I think your assessment is right, but we would still hope that we'd want the patient to still seek attention.
Dr. Aikin, do you want to respond to the questions about the comprehension?
DR. AIKIN:  They were indeed the same study, so I don't want to have that be confusing.

In terms of stopping use and asking a doctor, the question "In which of the following situations does the label say that someone should stop using this product and ask a doctor?", 99 percent of the participants answered correctly, if their symptoms do not improve within 10 days.  That would imply if they still have pain after 10 days, not would they continue to use after 10 days.
I'm sorry if the conclusions about the general sample and the subsamples ‑‑ and I think you're referring specifically to the people 65 and over ‑‑ were not quite the same.  I tried to present those concepts that were well understood first, which include dosing, and the concepts that were not well understood, and that is the similarity possibly to analgesics.  In that case, participants age 65 and over were more likely to say that they would use it when it was clear they should be contacting a doctor first.
DR. BRASS:  Yes, Dr. Abramson.

DR. ABRAMSON:  I just had a question about how realistic it is to think that patients can separate muscle tightness and spasm from chronic pain and arthritis.  I think as Dr. Borenstein was talking about with low back pain or neck pain, it's hard even for physicians often to understand where that pain is coming from.  My question is, how reliable, even among physicians, is interobserver diagnosis of muscle spasm?  My own experience is that we can differ quite a bit, even from doctor to doctor, about our perception of that.  So is there any data on the reliability among physicians, and then by extension the reliability of patients in diagnosing muscle spasm or tightness versus arthritis-derived neck or back pain, since we're relying on the patient to make that distinction?
DR. KORN:  First, there is conflicting data in the literature as to what the interobserver agreement would be on assessment of spasm.  In view of that, we had the same physician examine an individual patient each time they were in the clinic, because certainly we believe within-physician variability should be less than across the physicians.  We do not have data on what the accuracy of the diagnosis would be among physicians.  We would hope that rheumatologists would be making an accurate diagnosis and know from history before they even resort to the radiograph of the likelihood of osteoarthritis.
DR. BRASS:  Yes, Dr. Koda-Kimble.

DR. KODA-KIMBLE:  I believe in the actual use study, about 15 percent of patients were using an analgesic or an anti-inflammatory agent of some kind.  Perhaps you could give me more detail, but it seems as though, as a surrogate marker at least, the number of people who decreased their use of analgesics did not increase.  Do you know what I'm saying?  I mean, they didn't decrease their use of analgesics over time.
DR. KORN:  That's correct.  On Slide 462, we see that the percent of patients using an analgesic on any day during the first seven days of the study was relatively constant, and we would surmise that if they were using an analgesic because the cyclobenzaprine had not been effective and they needed something to tide them over until it kicked in, I would have expected to see more use early on and then trail off.  But here it's pretty flat throughout the study.
DR. BRASS:  I have a question for Dr. Lee from the FDA that I'd appreciate clarification on.  You expressed concern in your conclusions that there was inadequate data in the pediatric and geriatric populations.  Philosophically, how big a concern is that if the label says that those populations should not use the drug without physician consent?
DR. LEE:  My concern is that if the label says to ask a doctor and the doctor goes to the PDR without any information in it, basically the doctor has nothing to recommend to the patient.  So we still think that a study is necessary so that the doctor has some information.

DR. BRASS:  Okay.  And then also clarification from Dr. Neuner from the FDA.  You made a reference to concern ‑‑ I think it was you ‑‑ about hallucinations and confusion as being a potential adverse effect.  Could you share with us the basis for that concern?
DR. NEUNER:  Yes.  There was, if you remember from my presentation, there was a slide where I listed the most frequently reported postmarketing events, and on examination of the postmarketing events that were submitted by the sponsor from their own database system, there were I believe 20 cases of psychosis, 12 of which were considered serious by our present definitions, that resulted in the hospitalization of the patients.  This is disturbing considering the fact that this drug has been around for 22 years and that in this day and age the mechanisms of reporting are probably much easier than they were 22 years ago.
DR. BRASS:  Have those cases been either specifically examined or the magnitude of that signal compared to other drugs been looked at to say that this is a likely or unlikely possibility associated with the use of the drug?

DR. NEUNER:  Due to the large volume of the postmarketing database, as you remember, my review was marked "Draft" because there are still certain elements that need to be reviewed that, unfortunately, due to the time limitations, were not completed at the time that this package needed to be submitted to the advisory committee for their review.  So that's under review.
DR. KORN:  We have data about the hallucinations, if you'd like to see it.
DR. BRASS:  Okay.
DR. KORN:  Slide 369.  In the WAES database over the past 20 years, we've collected 82 reports of hallucinations, 79 of which occurred in patients who had not taken an overdose.  What's interesting to note here is that 58 percent of the time, when we knew the age of the patient, they were over 65.  So this is a signal perhaps that the elderly are at an increased risk of an anticholinergic mental dysfunction.  Many of the cases were confounded by the use of other drugs or underlying illness.  Many of the cases had visual hallucinations, which is consistent with this.  But again, the only signal we see out of this relatively small number is the elderly.
Next slide.

If we look at the FDA database, there are 20 serious reports of hallucinations that did not originate from Merck.  There's one death in a patient with other medications as well.  There are 13 non-fatal cases of hallucinations where the patients were taking one or more other CNS-active drugs, and 69 percent of the time the patients were over 65.  So we view this data, again, as a risk that we can modify and minimize by having the elderly see a doctor before using the product.
DR. BRASS:  Yes?
DR. ELASHOFF:  The "you should see a doctor before using" does not include pregnancy or nursing, although at the very bottom in smaller print it says that if you're pregnant or nursing the baby, you should talk to a "health professional."  It seems to me that that ought to be in the other spot.
DR. BRASS:  Let me just point out, for those of you who are not on the OTC committee, that there is a standard revision going on of the format of the label and the organization of those materials, which this label was prepared prior to.  But if the sponsor would like to comment?
DR. KORN:  No.  We just followed the standard FDA format in the now-final rule for OTC labeling.

DR. DeLAP:  I think we just want to be clear that we're separating two different issues here.  One is communicating the information in the labeling, and the other is what the consumer actually does with that information if they do get it from the labeling.  Those are potentially quite different issues, and I think that we all recognize that people can be very independent and can decide for themselves that what it says on the label doesn't apply to them.  We've had the discussion, I think at the Nonprescription Drugs Advisory Committee, about how many people follow the directions on some of the packages I think.
DR. BRASS:  Only a thousand times.
DR. DeLAP:  And you can probably express that better than I can from memory, but I seem to recall something about the vaginal antifungal products that say to see a doctor if you've never had this before before you start using this product on your own.  In fact, somewhere close to half of the people who buy the product have never had this problem before and are buying it and using it despite the label saying otherwise.

DR. BRASS:  My last question for the sponsor has to do with what the basis for the differential ‑‑ why individuals seem to respond differently both in terms of efficacy and more particularly in terms of the magnitude of sedation.  I was wondering specifically whether any pharmacodynamic modeling had been done to look at whether or not those differences lie in pharmacokinetic differences across the population or pharmacodynamic susceptibility, and how predictable these types of relationships are for future considerations.
DR. KORN:  The short answer is no.  No modeling has been done.
DR. BRASS:  Yes, Dr. Yocum?
DR. YOCUM:  I guess again, Dr. Aikin, with the comprehension study, we're seeing a lot of these toxicities that are reported, especially where other narcotic and non-narcotic analgesics are combined with Flexeril or cyclobenzaprine.  In the comprehension study, was there any indication ‑‑ because in the labeling there are some examples of what patients shouldn't take together with this.  Maybe you stated the question.  Did they understand that they shouldn't mix these drugs, or not?  Was that a well understood concept?
DR. AIKIN:  Well, they talked about whether you could take Flexeril with recommended doses of pain relievers.  But as far as other drugs ‑‑ and I don't have a good idea of exactly what was in the label comprehension study right off the top of my head.  Maybe the sponsor has the answer for that.

DR. YOCUM:  I'm just interested because I'm convinced that a lot of elderly with chronic back pain are going to be scarfing up this medicine out there, and they will have visited a pain clinic.  We've already looked at some data along this line, and it's 20 or 25 percent of patients with chronic back pain, especially with arthritis, are taking quite a few medications.  I guess my concern is the toxicities really seemed to escalate once you begin to mix these drugs together.  I don't know.
DR. AIKIN:  Alcohol and tranquilizers were certainly mentioned.  But by name, I don't think they tested by name.
DR. KORN:  Slide 448.  There was an element of self-selection assessed in the label comprehension study, and if we look just at the left-hand column, we see that of the people that thought they could use it but we considered that they shouldn't use it, very few of those shouldn't use it because they're taking other drugs, whether it's the antidepressants, muscle relaxants.  Again, the caveat, the limitation to this question was we didn't say "If you're taking muscle relaxants at the same time."  So they may have thought they could use this in place of what they were taking now, not necessarily in addition to.

DR. YOCUM:  But it looks like there's a difference here in that patients over 65 are more likely to make errors.  Is that true?
DR. KORN:  Well, this is saying that of those who were over 65 and made an error, obviously all of them were considered to be wrong because they were over 65.  So that's where the 100 comes in.  For the rest of it, there's really nothing that's really noticeably different than in the younger.
DR. BRASS:  Yes?
DR. LOVELL:  Can you indicate what percentage of the patients who had demonstrated deficits in driving-related psychomotor tests were not sedated or didn't report sedation as a side effect?  Because in the FDA's review, they talk about that sedation is not predictive of that.
DR. KORN:  Most of the patients in the studies, no matter what treatment period they were in, reported sedation, probably as a result of boredom, sitting in the clinic waiting for the testing to begin.  We did not see a difference, although we have not classified people as impaired versus non-impaired looking for a difference in whether they were sedated or not by report and whether they were impaired or not by report.

DR. BRASS:  At this point, I think we will shift gears a little bit.  As I indicated, there will be an opportunity to address specific issues that become relevant during our discussion.  But we'll shift to a discussion of the issues that the FDA would like us to discuss, as well as what we would like to discuss, and ask Dr. Katz to charge the committee.
DR. KATZ:  Actually, given the nature of the discussion that's been going on for the last hour, and then for the preceding hour before we broke for lunch, I'm not sure at this point it's necessary for me to give a formal charge to the committee, since the committee seems to have already been grappling with some of the issues before them that I would have liked to have drawn to their attention.  So, with that, basically I would like to focus the attention on the questions that the FDA has put before the committee to address during the rest of the afternoon's presentations for deliberation.
One additional comment is that Dr. Andreason has joined us, so if there are any questions that anybody has specifically related to his presentation, he's here to be able to answer those now too.  Thank you.
DR. BRASS:  Okay.  You all have a copy of the questions, and I'd like to do them individually.  So I will read the first question.

"The data in the original NDA support the use of a Flexeril dose of 10 milligrams TID (in the range of 20 to 40 milligrams total daily dose) as a prescription product.  In the current submission for OTC use, do both Study 006 and Study 008 demonstrate a clinically significant effect of Flexeril 5 milligrams TID for relief of painful muscle tightness and spasm of the back or neck due to a recent strain, overuse, or minor injury?  In answering this question, please describe the endpoints and analyses that caused you to come to your conclusion."  So we want to specifically focus on efficacy and efficacy as modified by clinically significant as posed by the agency.
Is there somebody who would like to get us started?  Just like in school, if there are no volunteers, I will call on somebody.
(Laughter.)
DR. BRASS:  Dr. Yocum.
DR. YOCUM:  I feel that the endpoints that were used, the global measures, have not proven to be very effective or good at showing efficacy in arthritis models, and I'm concerned that the primary endpoints don't give me a great deal of security that this is a clinically effective result.  So based on the endpoints used for analysis, I do not feel that these show clinically effective responses, to make a point shortly.

DR. BRASS:  Are there endpoints that you would find superior and satisfying if they were positive?
DR. YOCUM:  Yes.  I think something is basic, and maybe Dr. Gerber can enhance our knowledge on some better functional endpoints.  She commented on function earlier on, but just basic things along the line of a modified health assessment questionnaire or something along that line to show that there was better functioning, because my assumption again is that the release of this compound is to significantly reduce the number of people who are out there suffering so that they can function better.  If it's just to relieve pain, I think we should go back and compare analgesics.  This doesn't give me that sound of a clinical feeling that it gives great responses.
DR. BRASS:  I'll call on Dr. Gerber in a second, but just in relationship to the last caveat you put out, when we review an analgesic, we usually do not ask that it be superior to another analgesic for it to be used, only that it be an effective alternative.  So are you saying that standard is inappropriate for this class?

DR. YOCUM:  Well, one, I don't think we're dealing with analgesic class, so maybe I was inappropriate in bringing in analgesics.  We have no positive comparator in these studies, so that we have nothing to compare with other than placebo.  So we only have placebo-controlled trials in primarily global primary endpoints with no functional.  So on that basis, it's rather marginal data as far as I'm concerned.  If we're to get into things such as analgesics and comparators and long-term functioning, then I think again we get into a different class.  But based on this data which is placebo-controlled and based only on global data, it's rather marginal to go OTC.
DR. BRASS:  Dr. Gerber.
DR. GERBER:  I would support the relatively easy self-report questionnaires such as the SF-36 or the Modified Health Assessment questionnaire or the Sickness Impact Profile; easy to do, functionally based, very valid, et cetera.  I do think that there's one other point, and that is that if this is truly a request, as the sponsors have I thought very succinctly put, for a new class of drugs to come on the market as OTC, then the endpoint, the sort of self-selected or the sine qua non endpoint really relates to such measures as muscle spasm or muscle tenderness or tender points or whatever terms now we are using for more of the soft tissue aspects of back, not neuropathic and not rheumatologic or not orthopedic/arthritic.

In that regard, the endpoints that are cited in Study 009 leaves much to be desired both in terms of the robustness of the differences among the groups, and that is dose-response or placebo compared, and also ‑‑ and this is the one that really does concern me ‑‑ the time course of responsiveness.  So we've got a kinetic problem here.  We've also got a robustness of findings, from my perspective.
The third thing is the overwhelming observation that untreated, people get better.  I think that really sort of lays the ground for where the work has to be done to convince me, at least, or a potential consumer I would hope, that this would be worth taking any risk taking this medication.
DR. BRASS:  Dr. Neill?

DR. NEILL:  Yes.  I basically want to emphasize the last point Dr. Gerber made, which relates a little bit to your question about whether and why we ought to consider NSAIDs or other analgesics in comparison to this.  It's because I believe that AHCPR has found that NSAIDs in general are more effective, and if that suggests an appropriate sequence of treatment, then the question before me would be both, A, for my patient that comes in, should you take any medicine as opposed to just waiting and getting better; if you decide to take a medicine, which should you take or consider first given your particular circumstance?
That would make me want evidence that suggests that patients are able to step through that sequence just as I would do as a physician if we make what amounts to, in my mind, a second-line agent available over-the-counter given that the data that is already sitting on the table suggests they cannot distinguish between this and an analgesic, and they cannot then logically place this in a sequence that would give them best chance for improvement with the lowest chance for side effects.
So to more directly answer your question earlier I think you directed towards Dr. Yocum, should we consider a new standard for OTC medicines, analgesics or, in this instance, muscle relaxants in not just demonstrating effectiveness against placebo but effectiveness against other agents, I think the answer clearly is yes when there's good evidence to suggest that there is superiority of one over another and when we can infer a time sequence of course of treatment.
And, no, I don't want to do that this afternoon.
DR. BRASS:  I didn't ask.
DR. NEILL:  Good.

DR. BRASS:  Other comments or questions?  How do our consumer representatives feel about the issue of defining clinically significant efficacy?
MS. MALONE:  Well, I think people are largely looking for pain relief and for function, better function, and we have nothing to prove that there actually is better function using this.
One other thing.  Before it was said about the inserts.  I think today people do read them more than they did five years ago, but they're very difficult to read.  Even your label is difficult.  I'm wearing glasses and I've just had my eyes checked, and I had difficulty reading the small print.  My worry is that people over 65, if they bother to read it, will have a difficult time.
Also in line with that, it's not just the label and the package insert.  In today's market, there's a lot of media and t.v. marketing done, and the way people are portrayed in the commercials really is attractive for someone to go and use these medicines.
DR. BRASS:  And it's probably not an accident.
Kathleen?

MS. HAMILTON:  I have a smaller sort of lingering question about how effective this product is in terms of restoring practical function to a consumer as opposed to just relieving pain.  So I'm sort of struggling with that.
I also have a sort of nit-picky lay person's question.  I noticed throughout this discussion and all the materials that we've been provided that there's a persistent reference to back or neck spasm due to recent strain, overuse, or minor injury, and I haven't seen any of the data that talk about symptomatic relief related directly to muscle spasm or neck or back pain that's specifically related to strain, overuse, or minor injury.  Since I know that one of the concerns is the potential for misuse of this product for other situations, I'm concerned that there wasn't any specific relationship between the data and those situations.
DR. BRASS:  Does sponsor have any data on an identifiable recent precipitant in the patients in any of the studies?
DR. KORN:  No.  We know the physicians diagnosed the condition as acute muscle strain, whether it was cervical or lumbar in most cases, but we don't know the precipitating factor.

DR. BRASS:  Can any of the rheumatologists or consultants help us understand whether or not there is any reason to believe that the outcome measures used are surrogates for the other outcome variables?  Are there any data to suggest that in patients with back pain, that use of these types of instruments are predictive of or not predictive of response to other instruments?  Are there any such data?
DR. MOORE:  Dr. Moore.  With due respect to the physiatrists, I'm a little concerned about separating pain and function.  It seems only common sense to me as a physician that the major reason people would be handicapped by a back or a neck problem would be because of the pain, and therefore if you help the pain, it seems to me that you're going to be ‑‑ that I can think of that as a very reasonable surrogate for function.  That might not be true in rheumatoid arthritis, for example, but here we have a very localized, very acute situation, and we know that when we look at pain in general, that it is the patient's perception of pain on a visual analog scale which is the best way that you can possibly measure that.  No machine can measure that.
So in my mind, I think that that's a very reasonable measure.  I might also point out that the people were not only asked about pain, they were asked another question which had to do with medication helpfulness.  Now, that's a much broader question.  "Did the medication help you?"  "Yes."

So I think if you put those two together, you would not be getting much of a different kind of an answer in this acute, localized situation than if you asked directly a question about function.
DR. YOCUM:  I'm sorry, but I didn't see any visual analog scale data.  Do you have VAS data?  I only see global data.  I'd love to see some VAS.
DR. KORN:  We only have 5-category global.
DR. YOCUM:  I don't think you're presenting the most accurate presentation of pain here, which is a VAS.  Globals are not, and we know from other conditions that while tenderness is important, it doesn't correlate well at all with functional measures in many ways, especially here when we're confounded by the factors of drowsiness and sleepiness and not being able to tell whether the two are definitely linked or not.
DR. BRASS:  Dr. Gerber?
DR. GERBER:  I'm in complete agreement with Dr. Yocum.  I'd like to say I trained you, but that's not quite right.
(Laughter.)

DR. GERBER:  There is one other issue about the question of visual analog scale.  It is reported as a moment in time, which does not necessarily accurately reflect daily routines and activities.  So the P values are close, but they are not identical.  The reason that one does not rely exclusively on visual analog scale and pain reporting in low back pain is that it's confounded with all kinds of other motivational and financial issues, and number two, which is very important, that activity can be seen as both the impact of pain on an initial event and/or the ability to sustain activity over time.  Both are extremely important for evaluating function, and a pain scale usually does not get at the second one, which is the ability to sustain meaningful activity over time.
DR. BRASS:  So if I can begin to develop a consensus here ‑‑ and I will allow more comment, but I just want to see if we're on the right track here.  In terms of the clinical significance, it is not the magnitude of response on the instruments used.  It's the instruments used.  Is that what both of you are saying?
Transcriber, they are nodding yes.
Dr. Sachs?

DR. SACHS:  I guess I was going to comment on the magnitude of response.  Just as being kind of a practical pediatrician who thinks very simplistically, if you look at the numbers reported, what you guys are saying is significant is rating a C.  An A is marked improvement, a B is moderate improvement, a C is mild improvement.  We are accepting a C as efficacy.  Personally, I would rather see an A or a B.
DR. BRASS:  Dr. Anderson?
DR. ANDERSON:  I was looking at the proposed WHO core set of outcome criteria for low back pain, and they include both patient global and ‑‑ well, there's actually a test there of forward flexion and a QRL index and a disability index, which suggests that, at least in the eyes of the people who developed those criteria, there was some difference between function and pain.  So I don't know the history of this and how far along it's gone and what studies there are to support the inclusion of both of these, but it does suggest on the face of it that there are some different dimensions here.
DR. BRASS:  Dr. Koda-Kimble?

DR. KODA-KIMBLE:  I have a question for the FDA.  In previous discussions about Rx to OTC switches, we really haven't discussed efficacy.  The assumption was that when a drug was approved for prescription use, that it was efficacious.  I do understand that it's been available as 10 milligrams, but I did read in the materials I think that it had been approved as a 5 milligram dose but had not been marketed in that way.  Could you clarify why we're discussing this?
DR. KATZ:  Actually, the product as approved was approved at 10 milligrams, either two 5 milligram tablets or one 10 milligram tablet three times a day, with a total cumulative dose of 20 to 40 milligrams.  So in the past, most of the switches that may have come before you have been true switches in the sense that the prescription product was moving to the OTC world and there might not be any prescription product left.  Here what we're talking about is a lower dose.  So therefore because the dose is lower, efficacy needs to be proved.
DR. BRASS:  And if I could just expand on that, the other reason for dwelling on it a little bit is when we start talking about risk, to allow an understanding of what benefit we're talking about to offset whatever risk we end up talking about.

DR. KATZ:  One additional clarification is that because, again, we're talking about a 5 milligram dose, with a total dose of 5 milligrams TID or 15 milligrams, that it's likely that the prescription dose will remain prescription and that what we'll have is sort of a switch as what we've seen with some of the nonsteroidal types of drugs that have gone over-the-counter where the dose is lower for OTC use as an analgesic and the anti-inflammatory dose is the dose that remains Rx.
DR. BLEWITT:  Well, I just wanted to summarize my own feelings and my own interpretation of the data as I see them.  For many years I've been looking at muscle relaxants and looking at efficacy criteria and whether these things work at all, and we've always wondered about that, and that's in the practice guidelines.
To me, as I saw this package, these were the first hard data to support that this muscle relaxant actually works.  Now, you can look in hindsight at what the efficacy criteria should be, but my concern is that I felt that the sponsor took the approach that this is going to be consumer self-diagnosis, that OTC drugs are generally for symptomatic treatment, and therefore we/they would use symptomatic criteria for efficacy as opposed to quantitative scales or anything like that.  So that was their approach.

Because this program was intended to support approval of a nonprescription dose, the primary endpoints involved patient-reported assessments of relief.  Then I think the question comes down to what are the requirements for efficacy and what are the criteria for efficacy, which I think I've addressed, and then should there be performance standards, such as functionality, do you need to go beyond efficacy and into functionality.
In my experience, I don't know of any drugs that were really required ‑‑ maybe somebody can correct me ‑‑ to show functionality.  If you approve an analgesic for headache, a new analgesic for headache for switch, do you now have to show that they get back to work quicker because their headache is better?  I don't see that as having to be the case.  So I don't see why, in the case of muscle relaxants, we need to have those kinds of standards for efficacy.
So, in a word, in my interpretation, first, it was nice to see hard data, in my view, that these things do work, two well-controlled studies, and secondly that these are consumer-oriented.  Thirdly, the diagnosis was confirmed by a physician, and in my own view, I think that from the standpoint of efficacy, that there's little doubt that the sponsor has shown what they set out to do, and I think the committee ought to look at it in that light.

DR. BRASS:  Certainly from the perspective of the OTC committee, and my own personal perspective, making patients feel better isn't all bad.  What that translates into, how much better, what it means, I agree are legitimate questions.  But again, for those of us on the OTC committee, we have seen ‑‑ and now just looking only at the efficacy hurdle in this equation ‑‑ lots of products that have had either response rates or magnitude of responses on whatever instruments were used that were significantly less than what has been demonstrated for this product in the two pivotal trials in terms of the definition of efficacy.
DR. SHERRER:  Hi.  I have a comment.  I'm not on the OTC committee, so I don't really know what your charge is, and I'm actually new to the Arthritis Committee.  But for me, even if you assume that the efficacy data is good and hard data, I'm with Dr. Sachs, that the improvement is modest, and my concern as a rheumatologist and as a consumer is that is the improvement in relief, given that we have other drugs that also give improvement in relief that are already available, is the improvement seen here compelling enough to warrant putting on the market a drug that we know has mind-altering effects, that while may be low in absolute percentage, when you start talking about huge numbers of consumers using them, then you're talking about large numbers of potentially impaired drivers on the road?
For me, thus far I haven't seen compelling enough data for me to say that it's worth putting that type of drug out there to everyone.

DR. BRASS:  Yes.  I appreciate your points, but you're skipping ahead three steps.
DR. SHERRER:  All right.
DR. BRASS:  And I really want to focus on addressing the agency's concern about what is and isn't efficacy, then what is and isn't toxicity, and then what is or isn't a risk-to-benefit ratio in that kind of equation.
DR. BLEWITT:  I just had one other comment I had forgotten earlier, and that is that the sponsor had set out to determine, a priori, what would be a clinically significant outcome, and I think that they did that as well.
DR. BRASS:  Yes, do you want to comment?
DR. HEMWALL:  Yes.  I just wanted to briefly remind the committee in factoring into their deliberations the fact that we did review these protocols when we started out the program with FDA, and there were no discussions at that time about having a functional endpoint.  Actually, the studies were done in sequence, so we had the results of the first study before we started out the second study.  So often thinking changes and science advances, and the overall criteria may change, but at the time these studies were conducted in agreement with FDA, functional endpoints were not a consideration.

DR. BRASS:  If I could just focus on the issue that was raised by several people, certainly anecdotal data suggest that if one is treating chronic inflammatory disease with NSAID X, patient doesn't respond, they may respond to NSAID Y.  Is there an individualized response in this type of back pain that suggests that individual patients may respond better to an NSAID versus a muscle relaxant and that there is individualization of responses?  Are there any data that would help us understand that in terms of the need or desirability of comparison?
(No response.)
DR. BRASS:  I take that as a paucity of data.
Other comments about the efficacy endpoint?  Dr. Katz, are there other issues that we haven't hashed that you'd like us to hash out?

DR. GANLEY:  This is Charlie Ganley.  One of the nuances of the question has to do with looking at mean values of categorical data and how that's analyzed.  That's one issue.  Also, when you see those mean changes, how do you put some clinically relevant decision on that?  That's really what we're trying to address here in whether a categorical analysis would be a better analysis, where you see actually what categories people had fallen into.  I think the statistical review that you had seen from the FDA gave you some examples of that in a bar graph.  So that's really the two issues of the question we wanted to focus on also.
DR. BRASS:  Are you talking about the responder/nonresponder type of predefined response?
DR. GANLEY:  No, the actual ‑‑ when the global questions actually are giving a whole number and it's treated really as a continuous number and given a mean value rather than looking at a categorical analysis.  Okay?  And also, when you look at those mean numbers and you see a 0.2 difference or something, how do you really interpret that when you can only make steps or jumps of 1?
DR. BRASS:  And just so I'm absolutely clear, are you asking from a statistical standpoint or a clinical interpretation standpoint?
DR. GANLEY:  Well, both.  I'd be interested in what the statistician would have to say because I brought this issue up to the company about why a categorical analysis wasn't a primary analysis.  I find it very hard to look at mean values like that and make some interpretation.  You can say possibly that there's a treatment effect, but is that treatment effect clinically significant?

DR. BRASS:  I think this goes back to Dr. Sachs' point, and I think in general, on these kinds of 5-point scales, unless you have a wonder drug, antibiotic kills strep, that it's very difficult to get the kind of quintal changes on a mean scale that you're talking about, and some type of categorical characterization is often helpful.
DR. ELASHOFF:  Apropos of your question, sponsor cites 33 and 34, which are timed to a lot of or complete relief, show that approximately 50 percent of people feel better by the end of a week.  It's a little bit lower than 50 percent for the placebo group and a little bit higher than 50 percent for the drug group.  It's sort of consistent, and you can see that it's creeping up there.  It was described by the sponsor as one or two days of relief, but if you look at it a different way, where are you at the end of seven days, slightly fewer than 50 percent of people feel better by the end of seven days if they're on placebo, and slightly more than 50 percent of people feel better by the end of seven days if they're on the 5 milligram dose.
So that's a way of looking at it that doesn't deal with the means at all.

DR. BRASS:  I will point out, though ‑‑ I think I'm correct, and sponsor can correct me ‑‑ that Slides 33 and 34 contradict the prospective definition on Slide 27 of what a responder would be, which included one lower value on the 5-point scale, if I'm interpreting those slides correctly.  So those two slides are not the prospective definition of the responder/nonresponder class.  Is that correct?
DR. KORN:  You're correct, Dr. Brass.  The definition is a little different on the "time to" slides than in the prospective definition.
But to address Dr. Ganley's question, we have done a logistic regression analysis, which may be more appropriate for the data, and if you'd like, the statistician can show you the one slide that has that.

MR. TIPPING:  This slide represents an analysis for all three primary endpoints for both of the protocols using what some would consider a more appropriate analysis for ordered categorical data.  Again, this is not an analysis assigning a score and proceeding forward analyzing means, but this is an analysis that actually looks at the distribution of patients across each of those five categories.  What you see here as a representation of that analysis is the odds ratio, and I think you see some very strong results here across all the endpoints, odds ratios on the order of 1.5 to 2, which would correspond to a 50 percent to a 100 percent chance of a better response, a 1-category better response on the 5 milligram dose of Flexeril than on placebo.
DR. BRASS:  Yes, Dr. Lovell?
DR. LOVELL:  I was wondering if the statistician could stand back up and explain the bars again?  It's hard to read from back here, at least for me.
MR. TIPPING:  Okay.  The yellow dots represent the point estimate for the odds ratio, and the bars represent the 95 percent confidence interval around that odds ratio.  To orient you a little bit more with an odds ratio, an odds ratio of 1 would indicate equivalence between the treatments, or no difference I should say.  So odds ratios falling greater than 1 suggest that Flex 5 is performing better than placebo.
DR. BRASS:  And that's the odds of a 1-point improvement or more on a scale?
MR. TIPPING:  That's the odds of a random patient having a 1-category better response on Flex 5 than on placebo.
PARTICIPANT:  Can we get a comment from the FDA or panel statisticians?
DR. BRASS:  Is there a statistician in the house?

DR. ANDERSON:  I can comment.  They're talking about a proportional odds model, or rather an ordinal response model.  So it is one per unit.
MR. TIPPING:  That's right, proportional odds model.
DR. ANDERSON:  Yes.  So those look perfectly valid to me.  What sort of other comment would you like?
DR. GANLEY:  That's fine.
DR. BRASS:  Any other comments about Question 1?  Yes.
DR. PUCINO:  Does the company have that same data for a 2-categorical jump, which would be a more marked jump?
MR. TIPPING:  Well, the odds ratio really represents all those probabilities pooled together.  So you can think of it in terms of the odds of a 1-category jump, but it really is representative of an analysis across the whole 5 points of the scale.  I don't know if Dr. Gary Koch would like to add anything to this analysis.

DR. KOCH:  Gary Koch.  The analysis basically focuses on odds of better versus poorer outcome at each point in the scale.  So if you have five categories, it would correspond to the odds of categories 1 to 4 versus zero, the odds of 2 to 4 versus zero or 1, the odds of 3 or 4 versus zero to 2, and the odds of 4 versus zero to 3.  Basically, it looks at the extent to which the odds of better versus poorer outcome throughout the scale is higher for one group than the other.  So what you're told is that the point estimates are in the vicinity of 1.5 to 2, and this basically means the odds of better versus poorer outcome is approximately 2-to-1 throughout the entire scale of the distribution.
DR. BRASS:  Dr. Neill?
DR. NEILL:  To clarify that for me, the odds ratio being 1.5 to 2 says nothing about the magnitude of the difference, except that it is greater.  Correct?  Given that we have no way to measure the difference, I don't know what the difference ‑‑ even though it's one unit, and I understand the unit is good to a lot, I don't know what that means clinically, an odds 1 unit.
MR. TIPPING:  What an odds ratio of 2 means is that if in the control group at a particular cut point, like zero to 2 versus 3 to 4, suppose that the odds of that in the control group is 50 percent.  An odds ratio of 2 would mean in the test treatment group it would be about 67 percent, because 67 percent over 33 percent is 2, whereas 50 over 50 is 1.  So if you're in the middle of the distribution, then an odds ratio of 2 corresponds to about 17 percent.

DR. NEILL:  That I understand.
MR. TIPPING:  As you move towards the tails of the distribution, it corresponds to a smaller percent.
DR. NEILL:  That I understand.  I want to make sure that I'm correct in understanding that while the odds inform me about how likely the two groups are different, it says nothing about the magnitude of the difference.
MR. TIPPING:  Well, again, it says that the difference, if you're talking about an outcome with 50 percent prevalence, is about 17 percent.  If you're talking about an outcome that has 67 percent prevalence, then the difference is about 13 percent.  So as you move throughout the scale of the distribution, you have higher or lower base rates.
DR. NEILL:  I guess what I'm getting at is that you say the difference is 67 percent or a difference of 50 percent, and what I'm not hearing is 50 percent of what.  The what in my mind is the difference between good and a lot, and I don't think any of us know what that difference is, despite our being able to tell that one group is 50 percent more of it than the other.  Does that make sense?

MR. TIPPING:  What you're being told by the odds ratio is that the one group has 10 to 15 percent better response than the other group, which is what you saw on the responder analysis.
DR. NEILL:  Right.
MR. TIPPING:  And the odds ratio simply reaffirms what you saw on the responder analysis using a method for categorized data that incorporates the information in the entire scale.  So what you have already seen is reconfirmed by several other methods.  There's no add-on to what you've already seen.
DR. NEILL:  Great.
Question for the sponsor.  I'm curious whether you have a slide that indicates the time to response, including that third good category which is the cut-off between fair and good that you used for responder and nonresponder.  So it would look a lot like Slide 33 or 34, but instead the title would be "Time to Response, Time to No Response," or "Time to Good, A Lot, or Complete."
DR. KORN:  It's coming up in a second.  This is using the definition of the top three of the five as a responder.  Again, this is Protocol 6.  We have the pink box being 10 milligrams and the yellow being 5, and the median times are ‑‑ I don't know what you want to read off the slide ‑‑ a day, a day and a half, approximately.

DR. BRASS:  If there are no additional questions or comments, we will go on to Question 2.  Question 2 is shorter, so it must be easier.
"Is muscle spasm of the back or neck a consumer self-diagnosable condition?  In answering this question, please describe the data relied upon from the application."
Volunteers?  Yes, Dr. Lovell?
DR. LOVELL:  Well, I'd like to put a challenge to the company.  I don't think there is any study done by the sponsor where you looked at the direct question being patients who say they have back spasm and then subsequently be evaluated by a physician to test the accuracy of that self-diagnosis.  Do you have any studies to address that particular question?
DR. KORN:  No.
DR. BRASS:  I think the only data we saw that was like that was the ad for muscle spasm and what percentage of those patients, when examined, actually had muscle spasm, and that was a very high percentage.  But other than that, I don't think we've seen any data.
Do any of our experts know of data from the literature or other studies or experiences that would help us understand this issue?
Yes, Dr. Abramson?

DR. ABRAMSON:  I don't know of any data from the literature, unfortunately, but I do think it's a difficult thing to expect patients to make an accurate diagnosis, at least it's a potential problem.  Even looking at the spasm rating by physicians of Slide 39, there were certain criteria the physician was supposed to use based on palpation of the muscle, and that's assuming the physicians can do that well, and I have a certain degree of experience in making that assessment and I'm not sure that's easily transferrable to patients, nor is the location of these muscles always easily accessible.
So I think my thought about this is that it would be hard to rely on the patient.  Some of the transferral of this from prescription to OTC depends I think in part on the patient making this kind of assessment, and I think one of the hazards may be that a greater proportion of people with back pain or other pain not due to spasm may begin to use this drug and associating it, making that self-assessment.  So I think it's a difficult thing for a patient to make objectively.

DR. BRASS:  Putting aside the leg cramps and all the other kinds of things people used it for, if we looked at patients in this age group presenting to a physician with back pain, do we know what percentage of them who met any kind of simple clinical definition ‑‑ duration less than, precipitating event ‑‑ or any criteria that would allow us to define a high prevalence of spasm population?
DR. ABRAMSON:  I think perhaps Dr. Borenstein addressed this before.  I think it's very difficult to come up with that number.  I think clearly many people with backaches will have some degree of spasm.  I don't know what the percentage is, and I think it may vary among physicians and other health professionals when they assess the patient as to what their impression is.  It's not an easily objectively documentable physical finding in many people, in many of the patients.  I don't know in what percentage people think that's the major or significant component.
DR. BRASS:  Yes?

DR. SHERRER:  I think this is a really tough issue, and in part it's subjective despite the criteria, and people's muscles can feel differently.  Athletic individuals can have very firm muscles and may be misdiagnosed as spasm.  In addition, there are people who have spasm and it's asymptomatic.  So I think unless you have a control group of individuals who come in, who are symptomatic versus those who are not, and you have the same physicians diagnose them without knowing whether they're symptomatic and give a rating, you're not going to be able to judge this.
As a physician who examines patients daily, I examine patients in whom I pick up spasm in areas where they don't complain of pain, and there are individuals who complain of pain who don't have spasm, and vice versa.
DR. BRASS:  Yes, Dr. Sachs?
DR. SACHS:  I think the large question that we're kind of asking here is if you gave this medicine to a consumer who is experiencing pain, would a serious diagnosis be missed or treatment for a serious diagnosis be postponed?  I don't know that I've seen information on that.  I don't know if any parallels would be drawn with the prescription information, like, for example, if somebody really has a slipped disk and you treat them, with neuropathy, what long-term harm happens.

DR. BRASS:  Again, because the OTC group frames this question a lot, there are two sides to it.  One is, will you be exposing patients to the risk of a medication unnecessarily because they have a benign condition which stands no chance of responding?  And second, are you delaying diagnosis of a condition which a delay of 10 days makes a difference?  So there are two sides to the question, and I think there was suggestive data that the significant other, where delay of diagnosis would be clinically significant, is thought to be very low in this age group, but again, nobody could put a number on it.  I think the other concern that I'm hearing from some of the practitioners is that there's a benign disease that stands no chance of responding, and that therefore the patient shouldn't be exposed to the risk.  Is that fair or unfair?
Dr. Lovell?
DR. LOVELL:  I think it's fair, and I think in the absence of either the sponsor or any of the experts to stand up, we can't answer the second question.  I mean, there is no data to answer this question, and I think this is a key question, and it's an answerable question.  I mean, it's not an overwhelming type of burden to put on a sponsor.  But I think it's a key and critical question, and we have no data to address the question.  So I think that it's something that should be studied and answered or the question be addressed and data be generated before we move farther in this particular area.

DR. BRASS:  Again, just to be crystal clear for the agency's further deliberations, are you asking for data specifically about the ability of patients to self-diagnose, and if so, is a physician an adequate gold standard?  Or are you asking for efficacy data like a 009 type of study of the drug that is placebo-controlled which would incorporate that self-selection into the efficacy analysis?  In other words, there are two different sets of data that would reassure you on this point.  If 009 was placebo-controlled, so that patients self-selected, whether correctly or not, and benefitted, that would reassure some people.  Other people may not be reassured unless they knew for a fact that the condition itself was properly self-diagnosed.  So I'm asking which of the two would be required to satisfy you.
Dr. Lovell, having posed the question, which of the two data sets would be necessary?
DR. LOVELL:  I think that actually both questions very succinctly and nicely differentiated the two questions, and I think they're both very important questions and both should be at least addressed and answered before we move ahead.
DR. BRASS:  Yes, Dr. Korn?

DR. KORN:  We can point you to data to address the second element of that question.  Certainly the Agency for Health Care Policy guidelines panel and other groups that have tried to create algorithms for the treatment of acute back pain have all concluded that in a representative population, the risk of a very serious underlying disease requiring definitive emergency management that cannot wait 10 days is exceedingly low in the absence of recognized red flags, and that's why physicians are not advised to get radiographs routinely in patients who present to the office in the absence of significant trauma with new onset of low back pain.
So certainly we've already accepted that patients with new onset back pain can treat for 10 days with acetaminophen or ibuprofen.  The risk is no greater presumably if they have spasm.
DR. BRASS:  Yes, Dr. Hamilton?
MS. HAMILTON:  I always love it when you promote me to a doctor at these meetings.
(Laughter.)

MS. HAMILTON:  A general observation.  As you pointed out numerous times, a common point of discussion among the OTC Committee members, but I'd like to suggest that the FDA at some point consider some general studies that aren't specific to products or symptoms that help us determine a consumer's general ability to self-diagnose.  This is a consistent question, and we tend to deal with it on a per-product or a per-symptom kind of basis, and in the absence of data on this, I have an instinct that most consumers are probably more accurately tuned in to what's wrong with them and what might be hurting them to at least present in a reasonably helpful way initially to physicians.
But we consistently don't have general research and data on which to make some of those suppositions.  So just like I tend to ask general questions about how useful inserts and package labels are, which we can't determine if we don't have hard and fast data about consumer utilization and the depth to which they're willing to go to get educated, I think we need the same sort of basic information about a lay person's ability to self-diagnose.
DR. BRASS:  Yes, I would just endorse that recommendation, and I think the FDA in many of these areas has the opportunity to provide very important general data that no sponsor is ever going to generate that would really help the agency, but also the advisory committees advising the agency.  When we do these risk-benefit types of subjective assessments, implicit in them always is what percentage of the consumers are actually going to do what they're supposed to do, and the risk-to-benefit changes dramatically if you knew that consumers behaved in certain prototypical kinds of ways.  I think the absence of that data is constantly crippling to the committee.
Yes, Dr. Harris?

DR. HARRIS:  Just a minor note, though, that in terms of self-diagnosis, certainly if one has a headache or menstrual cramps, I think that that's self-diagnosable.  That's much easier than something like muscle cramps or muscle spasm.  This is really where I have some difficulty, because there are certainly some conditions that I feel relatively confident people can easily self-diagnose.  This one is, in my mind, in a separate category.  So even with the proper studies, we still may have some difficulty with this.
DR. BRASS:  Again, this goes back to how consumers ‑‑ and as long as we're giving our editorials, I will again say the editorial about ethnic diversity and what these terms mean to different ethnic groups, because it's vastly different in terms of what is common, mainstream usage for what those same words will mean to a Korean immigrant or other ethnic populations.
But again, it seems to me that if you knew that when a consumer said "I have back pain," that in fact independently you could say that 98 percent of them have muscle spasm, that would relieve your concern.  But I'm not hearing any data set that looks like that, and it sounds like we're all kind of just presenting our individual anecdotal experiences.

DR. GANLEY:  Are you asking that we generate those studies or that the sponsor generate those studies?
DR. BRASS:  Well, I think both Ms. Hamilton and I were making a global, cumulative, four years worth of experience generic comment, not about this indication, not about this label, but about the paucity of information that in general allows us to make predictive decisions about consumer behaviors in the diagnosis and following directions and obeying instructions and warnings type of categories.  I think it was a global thing, and I don't think any sponsor is going to do it except under some very specific categorical diagnosis type of situations.  Somebody's got to do it sometime if the information base is going to get better.
Yes, Dr. Yocum?

DR. YOCUM:  I guess going back to one of the original questions from the FDA a little bit ago about this mean difference versus categorical, I think we're focusing that categorical may well be better, and I think we're kind of saying that and focusing in on specifically back spasm, neck spasm, which here is kind of handled globally.  Gee, I would love to see the separation of neck and back, aged versus non-aged, and so on and so forth.  That would give me a better feeling, but we just don't have that data.  I share the FDA's concern that this rather mean response score is very difficult to assess.
DR. BRASS:  Yes, Dr. Koda-Kimble?
DR. KODA-KIMBLE:  Well, I would be really very interested in the study that you suggested, which is that someone who self-diagnoses with back ‑‑ and the indication here on the label is muscle spasm or strain.  It's not just spasm.  How they respond to these agents based upon the analysis that was ‑‑ because I am not convinced that a patient is ever going to be able to diagnose spasm.  I mean, from what I'm hearing around the table.  I think most people can say, "I've got a crooked neck, a stiff neck, acute back pain," or something like that, and then the question is to what extent is this drug effective.
I was very impressed by the fact that of those patients who self-referred into the 008/009 studies, only 6 percent were not included.  That was impressive data to me.  So I do not think spasm ‑‑ anybody is going to ever be able to indicate that a patient can self-diagnose spasm.
DR. YOCUM:  Again, I am concerned about the data that you just talked about, because it's not blinded data, and the physicians obviously need to get patients in the study.  So during a lot of these studies, I'm not sure I can trust that data at all.
DR. BRASS:  Yes?

DR. LOVELL:  The study you just proposed, or the question just proposed, which is if you take patients who would self-refer themselves to be put on this drug and then just have them evaluate to see how many of them had muscle spasm, I think it would be a very informative and straightforward and simple test or study to do.  I don't think we're talking about a huge, incredibly expensive undertaking.  I think as a sponsor who is coming in with the first drug in a potentially new class of OTC drugs, that perhaps it's appropriate to ask the sponsor to perform that rather straightforward, simple study.
DR. BRASS:  Since it's now my study ‑‑
(Laughter.)
DR. BRASS:  ‑‑ I will play devil's advocate very quickly and say why do I care.  If I do 009 placebo-controlled and patients get better based on the self-referral pattern, do I care whether or not they had physician-diagnosable, confirmable muscle spasm?

DR. LOVELL:  I think you do care because once you approve a drug, you're going to open the floodgates to a huge number of patients.  This is a very large denominator we're dealing with here.  So it's one thing to say in the numerator group it is an effective drug, but it's also I think important to see if we can accurately define the denominator population that will be taking this drug.
DR. BRASS:  To minimize risk of exposure unnecessarily.
Yes?
DR. SHERRER:  And I would say that as a physician and consumer I would care, because if it's a matter of Flexeril really having an analgesic effect, then I could just optimize analgesics, which may not have the same side effect profile.
DR. BRASS:  I'm a lot more skeptical of analgesics than the rest of you, but I'll go on to Number 3, then, and I'm actually going to editorialize Question 3 because it segues nicely.
"Can consumers" ‑‑ and I will say or physicians ‑‑ "identify when Flexeril should be used, as opposed to other products such as OTC analgesics?  Can they adequately assess whether their condition is responding to treatment?  Were these conditions identified by a significant number of subjects where Flexeril use was considered when it should not have been?"

DR. GILLIAM:  I remember reading in some of the background material that the patients responding in these studies were asked:  How much did your back pain really bother you?  If I remember correctly, most of them said just mildly or just a little bit.  I've looked for that today and I can't find it, so I hope I'm remembering correctly.
That goes back to an early question that I had.  I'm wondering if Flexeril adds that much more benefit than just using Tylenol and/or NSAIDs in helping these people, and whether from that aspect, if it's only bothering them mildly or a little bit, if it's worth having this new class of OTC product put on the market, and that using NSAIDs or Tylenol and physical therapy or other modalities might be just as beneficial.  I would like to see some data along that line.
DR. McNEELY:  Correct me if I missed it, but I don't think this question was ever asked in any of these studies.  Am I wrong?  Because if you look at the pattern of use study or the actual use study, they didn't query the patients as to whether they should use Flexeril as opposed to an analgesic.  Am I right or wrong?

DR. BRASS:  Yes, you're right.  Again, we're being asked as esteemed experts with vast experience to help the agency extrapolate this aspect of the database, and to the degree it is unanswerable and it is important to answer, to convey that to the agency for future considerations.
Did you want to follow up?
DR. McNEELY:  No.  I mean, it wasn't part of the study.  So that's something that's been repeated here several times as something we have to address.
DR. BRASS:  Yes.
Dr. Sachs?
DR. SACHS:  I think the real practical point, though, is that this isn't prescribed in a vacuum.  I mean, even the prescription is used in combination.  So the reality is that this medicine, if made over-the-counter, will be used in combination with an analgesic such as NSAID or aspirin or Tylenol or Advil, whatever.
So, in a way, maybe what's important to know is whether it should be marketed that way too, as an adjunct in addition to.  I think that's the one thing, just being very practical, I actually would have liked to have seen data on nonsteroidals alone, this alone, even Benadryl alone if the sedation is a big deal.  If you have muscle spasm and pain and you take Benadryl before you go to bed, is that as effective in getting you a good night's sleep?  If you relax, maybe your muscle does relax, and you take your Advil during the day so you're awake.  That actually would have been very practical.

DR. BRASS:  Again, just to make sure I understand, are you saying that given that real use will probably be in combination with classical analgesic class drugs, that it's important to show incremental benefit on top of them, so that if it's used, there will be a rationale for it?
DR. SACHS:  Actually, as someone who really doesn't use these, as a pediatrician I don't use this, to me that was something I didn't know and that I would like to know.  And as a consumer, perhaps someone who might go out to buy this, I would like to know is it better, should I use it with it.  Just common sense from what I've heard and seen and experienced, it's been that it is actually used with.  So recommending it alone doesn't seem to really make sense.
DR. BRASS:  Dr. Yocum?

DR. YOCUM:  Is there any ‑‑ this is a question to the sponsor.  I see baseline demographic data, but only do I see baseline data on the physicians' scoring of the degree of muscle spasm, which is relatively mild to moderate.  Do they have any baseline data of how severe these patients were when they came in?  The FDA has kind of thrown this question out, and it suggests they may have some knowledge that this was mild back pain, or is this just a shot in the dark?
DR. KORN:  Okay.  To answer Mr. Gilliam's question, in Protocol 9, in the use study at baseline, there was a question:  How much has the muscle pain impaired your usual activities?  That was asked not at all, a little, somewhat, very much, extremely, and there was a bell-shaped distribution, 41 percent of the patients said somewhat, 23 and 24 percent on either side of that.  So that's the data, but the question was not asked at follow-up in that study.
Asking, though, Dr. Yocum's question, the patients did provide a rating of baseline pain severity in the pivotal trials, and looking at Protocol 6, on a 5-category scale, zero to 4, the patients in all three treatment groups rated themselves similarly, approximately 2.3 on the zero to 4 score.
DR. BRASS:  Dr. Blewitt?

DR. BLEWITT:  I just wanted to clarify a point on what data are required versus what data people would like to see.  In terms of the incremental value of a product such as this, I don't think that I can say that it is not the charge of the company or the sponsor to prove this.  The charge is to prove whether the product works in and of itself.  So I think there's a need to differentiate the need to know versus like to know.
DR. BRASS:  Yes, Dr. Lovell?
DR. LOVELL:  I would like to question the FDA as to what their intent was in Question 3A, because it would seem that a number of studies have shown that patients are reliable reporters of self-pain, and in the functional assessment scales that were mentioned in our discussion here, that patients are reliable reporters of functional ability.  So I was wondering if there was another issue that was being addressed in 3A that I wasn't aware of.
DR. BRASS:  And let me just add again that to the degree that we have data for 3A, it's that the physician's exam did correlate to the patient self-assessment over the course.  It was not a perfect correlation, but there was a correlation.
So, Dr. Katz, do you want to comment on that?
DR. ELASHOFF:  Not only not perfect, but not high.

DR. KATZ:  Part of the intent behind the question was, in a sense, if you look at Questions 1, 2, and 3, they are all related to the efficacy and the data presented to be able to say whether or not consumers can adequately pick up the product and be able to make the distinction, and whether, again, the committee felt that the data presented not only in the efficacy trials but in Trial 009, which was the actual use trial, and in the label comprehension trial, could actually give the information enough that people could feel comfortable that consumers could use the product adequately and safely.
DR. BRASS:  Dr. Elashoff, could you just expand on your comment?  It's important, and that's why I highlighted that data, because it is the data that we have available to our already-defined apparent gold standard of physician examination.
DR. ELASHOFF:  As I recall, some of the correlations ran around 0.3 and some of them ran around 0.6.  0.3 explains about 10 percent of the variance, and 0.6 explains a little bit more than a third of the variance.  Those say that there is some general relationship, but it is not a strong relationship between the two.
DR. BRASS:  Can the rheumatologists help me clarify if there are any patients for whom the use of a muscle relaxant would be used as first-line therapy before initiating or at the same time as initiating analgesic therapy?

DR. YOCUM:  I suspect that there's a significant portion of rheumatologists who may well use this to treat fibromyalgia first line, and I think Dr. Moore alluded to that earlier, that many rheumatologists will go to a drug like Flexeril or amitriptyline first-line over an analgesic.  But in my practice, other than that, unless I detect clear muscle spasm that I feel comfortable with, which again even from my perspective is difficult, I would go to an analgesic.  Even in the case of muscle spasm, I might do that anyway.  So I would say a majority of patients, other than the fibromyalgia group, are going to get analgesics first, but other rheumatologists may have different perspectives.
DR. BRASS:  Even in the prescription dose or for any other drugs that are in the "muscle relaxant class," are there any data that would address at any dose, in any population, the relative response to NSAIDs for muscle spasm versus muscle relaxants?  Again, I'm trying to establish whether this is a black and white decision or a consumer/marketplace type of decision between the different agents.

DR. ABRAMSON:  The easy answer is there's no data to address the question.  I think the reason this is so nebulous is, again, when one is treating these conditions, one doesn't know exactly where the pain is coming from.  I think the reason we may often use analgesics first or anti-inflammatories is that the muscle spasm oftentimes we think is secondary to whatever the primary problem is.  So if there's arthritis or some mechanical joint pain, there may be secondary muscle spasm.
So I think, as David said, the first inclination, without really knowing where the pain is coming from, is to treat with analgesics or anti-inflammatories.  In some people with very severe pain in whom you may think there's some muscle spasm, you may add Flexeril to that.  It's often in people who you want to calm down a put a little to rest, so you're relying a bit on the sedative component of it, rightly or wrongly.  But it's uncommon in the straightforward neck or back pain, which we think is coming not typically from the muscles first, to just go right to a muscle relaxant.
DR. YOCUM:  I would agree, Steve, that that's true, and even in the fibromyalgia group, I think most rheumatologists are relying on the cancer data for relief of pain and it has nothing to do with muscle spasm at all.
DR. BRASS:  Would that clinical assessment be true if there was an identifiable acute precipitant in a 25-year-old laborer?

DR. LOVELL:  May I make a comment?  I think perhaps Dr. Abramson and Dr. Yocum are ‑‑ perhaps your populations are skewed.  Perhaps this question would be better answered by primary care physicians who would be the ones to which this 25-year-old laborer would be more likely to go to see for his kind of acute onset back pain in an otherwise healthy lifestyle.  So I'm not sure that a rheumatologist gets very many of these virginal patients with acute back pain with muscle spasm related to sprain or injury, that sort of thing.  I pose that question to you guys.
DR. ABRAMSON:  Well, we'd be happy to teach the primary care physician the correct manner of treating these patients.  You may be right to some extent, and I don't know the acute spasm of a laborer.  I'm not sure what the right treatment for that is.  We don't clearly have data from this data set to say that it's Flexeril.  It may be, but there are no data to really address that.

DR. BRASS:  Again, what I'm trying to crystallize is the issue of the NSAID analgesic versus, and the degree to which, if it is gray, it is proof of efficacy of Flexeril against placebo in a gray area sufficient to say that, well, we don't know any better, but at least we know this works, again going back to all our other caveats about efficacy, or is there a genuine concern that there's reason to believe that there is some reason that we should not be even considering the use of Flexeril as initial sole therapy?  That's what I'm trying to differentiate.
DR. ABRAMSON:  I think the dilemma is what you were alluding to before.  I think the data speaks to the fact that the drug is efficacious in the population that was studied.  The dilemma I think is that it's restricted in the way the data was presented to muscle tightness and strain and spasm, and to exclude people with other kinds of chronic neck or back pain, and the question is do we know whether it works in that population.  Does 009 shed some light on that, as you were suggesting?

I think the concern is if you take a very narrow view of what the drug is indicated for, then the concern is that there are many more people who don't have that particular condition but have chronic backache and other concerns who will get exposed to the drug because the criteria for entry here would not be the criteria for use in the population.  So I think that's where the problem is.  If a drug is only indicated for muscle spasm, tightness, and strain, and people over 65 should call their doctor first, then there's a potential problem with putting it OTC.  If it was shown to work in backache and nondescript and didn't have those caveats, I don't think there's any question that the drug has a role.  But as narrowly constructed here, the problem is that it may get utilized in people beyond where it's been shown to work.
DR. YOCUM:  I think Dr. Lovell's comments are well taken, but I think it also emphasizes that there are whole books on back pain, and different ages, different ethnicities which you talked about earlier, different educational levels ‑‑ I think it's one of the things we've all struggled with today here.  We've compressed a very complex area into three global categorical analyses, expecting a broad range of patients over 50-some-odd years to respond, and I think the FDA's concerns are the same way.  It's categorical analysis versus a mean analysis of a very complex area.  So it's just not easy to approach.
DR. HARRIS:  At the risk of jumping a few steps ahead, I want to come back again to a point made earlier by Dr. Sherrer, that in a number of these circumstances, one would probably want to use an analgesic first ‑‑ strains, sprains, spasm, whatever.  I think as long as that option remains viable and safer, then there is the issue, again coming back, as to the use of Flexeril.

DR. BRASS:  I would point out that there's no data that it's safer.  I know an awful lot of people with adverse events from NSAIDs presenting to my hospital every day.  So I think you hit the paradox and how we set the bar.
Yes, Dr. Koda-Kimble?
DR. KODA-KIMBLE:  I forgot your instructions.  We were provided with AHCPR guidelines on acute low back problems and pain, in which they do not recommend muscle relaxants at all for this problem.  They did a very thorough review of the literature at the time and indicated that at least muscle relaxants were no more effective than NSAIDs.  So given that the first question, if we accept the AHCPR guidelines, we could say the answer is no to your question, that physicians aren't using them properly either.
DR. BRASS:  You caught the attention of one of our consultants ‑‑ one of their consultants.  Sorry.

DR. BORENSTEIN:  I just wanted to make a comment about those guidelines.  I think that you have to remember from where they came and what they were based on.  They were based upon whatever evidence was available.  Lack of evidence doesn't mean that it did not work.  What it basically said is that it was not available.  Now, in fact, we have some evidence, from whatever viewpoint you may take of the data, where in fact these drugs have been tested, particularly Flexeril has been tested by itself to see if it's efficacious.
So now, in fact, if this were published in a journal, that same group could now go back and say the muscle relaxants might work because of this very study if it was in fact in the literature.  So I think those guidelines are very important, but they did not come down from Mt. Sinai.  They're sort of guidelines which will change, and this group I believe will be looking at other guidelines which may change over time.  So I think that although we like evidence-based medicine, it's important to remember that we're only doing as well as what evidence we have available.  The fact that we don't have evidence doesn't mean that it doesn't work.  From a practical standpoint, I can certainly tell you, as a physician who sees the whole range of low back pain problems, that these are agents which work.
DR. BRASS:  Just for clarification, you are now referring to the medical school in New York.
(Laughter.)
DR. BRASS:  Dr. Blewitt?
DR. BLEWITT:  I was going to say the same thing as Dr. Borenstein, but not as well.
DR. BRASS:  Other comments about Question 3?
Yes, Dr. Blewitt?

DR. BLEWITT:  I can't find it now, but you had mentioned about concomitant use, and it seems to me that in 009, as they enrolled studies, there was a certain percentage of people who were taking them concomitantly, and it wasn't 100 percent.  In fact, it was fairly low.  Again, I can't find the page, but it seemed to be a rather low percentage, 20 or 25 percent, something like that.
DR. BRASS:  Yes, it was in there.  Twenty or 30 percent is my recollection.  But again, there was no efficacy assessment, so to the degree that's a question, that becomes a concern.
Other comments or questions about Question 3?  Is the agency satisfied with the discussion?
Question 4.  The reason we're not taking a break is I'm hoping we're going to be done in 30 minutes.
"Has the metabolism and excretion of Flexeril been adequately characterized?  If no, what additional information should be obtained (for example, better characterization of the metabolic pathway, drug-drug interactions)?  Are there any potential or known drug-drug or drug-food interactions that may impact on the safe use of this drug in the OTC setting?"

Perhaps I just want to ask one additional question of the sponsor.  In particular with respect to drug-food interactions, is there a potential to get accelerated absorption with certain types of food from this formulation that would give you higher peak, earlier peak concentrations, and then for more acute sedation?
DR. KORN:  Nothing that we're aware of.
DR. BRASS:  Because again, as you're aware, there are certain types of formulations where ingestion with fatty foods, et cetera, will change and lead to an accelerated ‑‑ and this is partly going back to why I asked about the three times a day dosing.  You're clearly concerned about high peaks, and anything that would accelerated absorption therefore would be of some concern.
Other comments or questions about this issue?

DR. PUCINO:  If you have a wish list of things, it would be nice to know the metabolites, if they're active; if they are, then to know the kinetics of the active metabolites.  It would be nice if they co-model some of the psychomotor effects with steady state concentrations, CPmax, areas under the curve.  It would be nice to have some pedes data.  It would be nice for the drug interactions, at least for things that are over-the-counter ‑‑ grapefruit juice, H2 antagonists like cimetidine.  Because it's highly protein bound, it would be nice to know about free drug kinetics, particularly as it relates to malnutrition, elderly patients, liver dysfunction, and so on and so forth.
DR. BRASS:  I'm going to ask you to expand on that because having what's nice is useful.  Having what's really critical differentiated is going to be helpful to the agency, and I think there are a couple of points you hit upon that I would just like to highlight and then ask you to comment on.
The first is the issue with the elderly.  We know that total drug concentration is significantly increased.  The free drug concentrations for the reasons you alluded to may even be more dramatically increased, and the same thing with liver disease, incidentally.  Understanding the free drug-disease/age interaction I think would be, to the degree that's going to matter in the labeling, I think would be important.
Second, in terms of the drug interactions, the argument has been put forth that identifying the diversity of the metabolic pathways is reassuring that inhibition of any one of them is extremely unlikely to cause a clinically significant drug-drug interaction.  Do you find that reassuring?

DR. PUCINO:  I mean, there's some limited data.  My understanding, at least with fluoxetine, there was some limited data that there could be an interaction, but there were no kinetics to suggest that.  There are other SSRIs where there's some concern.  We don't know about macrolides.  So maybe that's the case, but we don't have any safety data, and that's why I say at least having things that are going to be used over-the-counter ‑‑ it would be nice to be reassured, i.e., the grapefruit situation.  With some drugs, that's significant.  We hope that in this case, that would not be an issue.
DR. BRASS:  Again, to make this very specific, my understanding is the grapefruit issue is only clinically relevant, if ever, with drugs that have first-pass metabolism.  So that systemic bioavailability is increased during the acute exposure to the flavone, whatever it is in the grapefruit juice.  Therefore, one would predict it's unlikely that there would be an interaction with this drug.  Similarly, for the macrolides, if you knew that 10 percent of the metabolism was through 3A4, and you knew that as an independent fact, would you still require an erythromycin drug interaction study?
DR. PUCINO:  If you knew that.  But do we know that?
DR. BRASS:  I'm not saying that.  Again, I'm trying to differentiate what's necessary versus ‑‑

DR. PUCINO:  If I were comfortable that there was a diverse metabolism, enough that the 3A4 was not significant, then yes, that wouldn't be such an issue, either if we're talking about the intestinal tract or the liver.  But without knowing that, it would be nice to have some limited data at least to support that.
DR. BRASS:  Other questions?  Yes.
DR. BASHAW:  Dennis Bashaw.  I wanted to touch on two issues that you brought up in your discussion just recently.  There is a commitment for a study to be done with food.  That was not part of this package, but there was a negotiated commitment with the sponsor that is in the planning stages.  So this touched on that issue.
With regard to metabolism of cyclobenzaprine, it is a first-pass drug because the bioavailability is approximately 55 percent.  Yet when you look at its excreted pattern, obviously there is some degree of first-pass metabolism happening there.  So grapefruit juice could, in theory, be playing a role there, or could play a role potentially.  But when you look at the enzyme systems involved, it's probably not.  But that will be addressed, maybe not specifically with grapefruit juice, but with the in vitro methodologies.  We're hoping to capture that kind of information.

DR. BRASS:  Thank you for that clarification.  Do you think that the radioactivity recovered in the urine was higher than the systemic ‑‑ I'm sorry.  How did you determine it was first-pass elimination?
DR. BASHAW:  Well, when we looked at the excretion and we had an I.V. study ‑‑
DR. BRASS:  Oh, so you have an absolute bioavailability.
DR. BASHAW:  Yes, we do.
DR. BRASS:  Okay, thank you.
DR. BASHAW:  There was an absolute ‑‑
DR. BRASS:  That wasn't in here.  Okay.  Thank you.
Dr. Lovell?
DR. LOVELL:  To look at the database, it's overwhelmingly white, and I'm not sure if there's enough ethnic diversity in the database to answer some of the metabolic and safety questions in ethnic groups other than the ones that are overwhelmingly represented sitting at this table.

DR. YOCUM:  I share Dr. Lovell's concern.  As a rheumatologist thinking about this drug, even as I use it as a prescription drug, it is frequently not able to be taken for extended periods of time, especially in the elderly.  At least the hint that we see of the elderly pharmacokinetics is very, very scary to me, of the very high levels that they can achieve at 5 milligrams three times a day.  Based on this data, I would want to say, gee, I think it should be restricted to people less than 65, period, because in practice, a number of elderly people coming in with acute neck and back spasm or strain is relatively low and typically due to chronic arthritis or other problems, which I don't want to use this for.  So I have a problem.  I would want to strictly limit it.
DR. BRASS:  Other pharmacokinetic issues?
Yes, Dr. Harris?
DR. HARRIS:  This is somewhat informational to the OTC group.  This is an agent that has been around for quite some time.  There is extensive clinical experience with respect to its use, side effects, and so on.  What sort of additional data one might expect from getting metabolism, new metabolism and excretion data that might not already exist that could tell us something clinically is the question.

DR. BRASS:  Yes.  I think that's a general comment.  It goes back to the degree of confidence one has on our sporadic observation of adverse events as being sensitive to identifying drug-drug interactions.  We've seen what is clearly an adverse event profile in all the databases that says a percentage of the population responds differently.  There's nothing in those databases that says maybe they're all taking erythromycin, and unless somebody looked, you'd never find those kinds of things.  So I think that our understanding of rational predictive power says that to the degree we can do straightforward things and understand those risks better helps consumers, physicians, and sponsors as well.
Yes, Dr. Koda-Kimble?
DR. KODA-KIMBLE:  I don't know whether this is a pharmacokinetic question, but one of the things that did strike me right away is why isn't this drug given as a single dose at bedtime?  Because of its long half-life, its effects on sedation, the sedation would occur at night when it's supposed to, and it probably would just mess all of the studies up, I realize that, because everything has been done on a TID basis.  But it just seems that it would improve compliance.  A lot of potential concerns would be minimized.
So to the extent that pharmacokinetic data that sort of analyzed a single dose at bedtime and the adverse effects that accompanied those pharmacodynamic effects I think could be useful.

DR. BRASS:  Does sponsor want to comment on that?
DR. KORN:  Again, we adopted the historical precedent of the dosing, but we have thought about the advantage of TID dosing; namely, that a potentially sedating product like cyclobenzaprine may offer an advantage to patients with acute back pain that a nonsteroidal drug can't do.  Namely, it may help them sleep through the night.  If their pain is bad enough that they cannot sleep through the night, that could be a realistic benefit that could be measured in a clinical trial.
DR. BRASS:  Other comments or questions?
(No response.)
DR. BRASS:  Okay.  Going on to Question 5.  "Safety concerns include the adverse reactions associated with Flexeril use (especially adverse reactions similar to those seen with closely-related tricyclic antidepressants); the possibility of misuse or overdose; and any possible drug interactions.  Can consumers, including elderly individuals, safety use Flexeril in an OTC setting, taking into account the available data on adverse effects, sedation, overdose and misuse, and concomitant medications?  If not, why not?  If yes, is any additional information needed on the labeling?"

If I could just clarify, when you say including the elderly, do you mean including the elderly not using it?  Are you saying is it clear the elderly will not use it, or if they did use it would it be safe, or that if they were allowed to use it it would be safe?
DR. KATZ:  Actually, in a sense, it's all of the above.
DR. BRASS:  It always is.
(Laughter.)
DR. KATZ:  That's right, because part of the discussion is that even though we may label a product that it shouldn't be used in those greater than 65, they still may use it.  So we should have good enough knowledge of what will happen if they end up using the product.
DR. BRASS:  Okay, takers for Question 5?

DR. ABRAMSON:  I guess one of the problems is that certainly the answer is that consumers can take responsibility for reading the label and being aware of potential side effects and know not to drive.  That's their responsibility, perhaps.  But some of the side effects that one does see in practice or that have been reported are idiosyncratic, whether it's disorientation or some of the CNS effects, that a person can't change their behavior to protect themselves from, and that's where the elderly issue becomes the one concern and how practical it is to think that people over 65 will call their doctor before they take the medication.
So that's the one concern that I think one has to read into this question, is the idiosyncratic severe reactions, although rare, do happen.
DR. BRASS:  Yes, Ms. Hamilton?
MS. HAMILTON:  A couple of observations.  The question speaks to the possibility of misuse by consumers or elderly individuals, and I think there clearly is the potential.  There's been the demonstrated misuse of the product in terms of using it for arthritis or headaches.

I just want to point out that in the label, there might be a real simple explanation for that.  Sometimes it's the simplest things that we overlook.  The very first paragraph on the label, which is where I believe consumers look ‑‑ they go to look at which symptom is this product going to relieve.  Is what I'm experiencing relevant to what this product might offer?  And the two words in there that seem to me to suggest it could be used for headaches and arthritis are "tension" and "stiffness," and in the context of this discussion, we put that in the context of all those other discussions, but when you tell a lay person that this is something that will deal with the pain of tension or stiffness, if I hadn't been in this discussion, I would have thought this was appropriate for arthritis or a headache.  So I think that's one certain clarification that could at least minimize that kind of misuse should this product ever be made available on an over-the-counter basis.
The question I asked earlier about consumers' ability to recognize the technical names for other prescription products that they're using I think is an important one in looking at this label.  I can't pronounce most of what's done there in that very, very last paragraph, but until it gets into a generic description about an antidepressant and psychiatric and emotional conditions, I don't see anything simple to understand there.  So I have a real serious question about whether or not an average consumer would recognize a product that they're taking on this label, and whether or not they would then be involved in concomitant use which is not appropriate, because that information is not clearly provided in the label.

The question was raised earlier about whether or not it's not safe or appropriate to use this product in conjunction with antihistamine use.  I don't know the answer to that but I thought it was a good question, and that's such a commonly used product that it probably ought to be dealt with.
DR. BRASS:  Other comments?  Yes.
DR. KRENZELOK:  The venue that I practice in is one of high selection bias because we have everyone calling the poison center who has a potential adverse event with a product.  They've taken too much, they've taken it unintentionally ‑‑ who knows what the reason is, but generally it's a fairly significant amount, and I have to tell you that in 22 years of watching these types of overdoses, as I mentioned this morning, I'm impressed by the very high safety profile of the compound.  It's very rare that you see this drug being abused, and the poison center is often a place where these sentinel events begin to accumulate, and we see them because we're handling a bunch of them all of a sudden.  So you don't see it in combination with other drugs, trying to produce a synergistic effect with heroin or something of that nature.

So I think from a misuse standpoint, from an abuse standpoint, from an acute overdose standpoint, where you see very commonly overdoses of 100, 200, 300 milligrams if they get 90 tablets because that's what their HMO allows, you have the potential for having a 900 milligram overdose.  I'm not impressed at all with this drug from a negative standpoint.  So I think the safety profile, from my perspective, is very, very high, and I don't see a problem with the 5 milligram dosage, whether it be little kids getting into a few extra tablets or whatever.
The only one that concerns me is perhaps the drowsiness from a general consumer standpoint, and I think what I'd like to see would be some quantification of drowsiness, because many of us around this table have had some aspect of drowsiness at some point in time.
DR. BRASS:  Including today.
(Laughter.)
DR. KRENZELOK:  Yes, and how do you rank that?  Does it take three mints to keep you awake or a glass of water or a stimulating speaker?  I think that's a difference among people, but certainly I think it would be very valuable to quantify this because I'd want to know if this person was going to take this, now are they going to be dozing off at the wheel or something of that nature.  So how profound is the drowsiness?  I'd like to see that clarified.
DR. BRASS:  Do you want to see it clarified as drowsiness, or is the psychomotor testing more relevant to you?

DR. KRENZELOK:  I think the psychomotor testing would be a lot more relevant than drowsiness.  That's such a generic term and more difficult to quantify.
DR. BRASS:  If I could just follow up on that point, we've all acknowledged that use in combination with other sedating products would be very, very bad.  Do we know how bad?  I mean, do we know whether this is additive or synergistic?  If you drank a glass of wine and took one 5 milligram pill, would you then be completely incapacitated?  If you took 4 milligrams of chlorpheniramine and 5 milligrams of this, would you be completely incapacitated?  Do we have any sense of that pharmacodynamic interaction on that safety profile?
DR. YOCUM:  From personal experience, 5 milligrams is not sedating.  It's an odd effect, and what many of my patients complain about is feeling like a zombie effect.  It may not be sleeping, but I find it astounding that this is actually prescribed at 10 milligrams TID.  I give my patients 10 milligrams at bedtime.  So I'm amazed that patients could tolerate 30 to 40 milligrams a day on a regular basis, because this has quite a sedating effect and psychomotor effects.

My patients don't abuse this drug in the arthritis sense.  I don't know why.  I don't think it's an abuse-type drug.  What I would be concerned about from the pediatricians here, since we have at least two, what would be the prospects of young adolescents who get into "downers," this becoming quite a fun thing to do because, for some reason, there seem to be fads that kids go through, going into downers and some of the stuff that goes on.  Is that a potential issue?  That's probably far astray here.
DR. SACHS:  I actually was going to bring up that there doesn't seem to be a lot of data in pediatrics per se, and that was one thing I was impressed in reading most of this, until I guess one of the FDA looked at some of the overdose literature, and it was reassuring to hear about the poison control literature.  So actually that was just something that I wanted to make sure was still in the committees heads and that the labeling had to be very clear that at this point there is no indication in pediatrics.
The other concern is actually to the potential fetus.  There were some reports, though, of problems for pregnant women, and I think that the lay perception is that something over-the-counter is safe and may be safe to a pregnant woman, and if there really is clear teratogenic effects, I do have a lot of concern about making something over-the-counter.

DR. BRASS:  I think the sponsor will make a statement about that.
DR. KORN:  Slide 428, please.  I think neither we nor, if I can be so bold as to speak for the agency, don't see a signal of teratogenicity in the five anomalies that are reported here.  Each of these anomalies is reported spontaneously and known to occur at rates of 1 to 350 to several thousand in live births in this country.  So we do not see a signal.  It's well recognized that retrospective reports of use during pregnancy are much more likely to report adverse outcomes than normal healthy offspring.  So we do not see a signal here.
DR. BRASS:  And it currently carries a Class B.  Is that correct?
DR. KORN:  That's correct.  Animal studies do not show any signal.
DR. BRASS:  Yes, Dr. Lovell?
DR. LOVELL:  There's a concern I have, and that is that in the third through seventh to tenth day of taking this medication, when you're over the acute back pain and are now able to be a little more outgoing and you get back in your car, we have no data about the psychomotor effect of this drug in steady state, which, as you've shown us, is at a much higher drug level than the acute 24-hour dosing psychomotor testing you have.

So I would be very concerned that we would have that kind of psychomotor driving data available to us in the later stages of dosing, and also whether sedation itself is an adequate symptom to indicate to people they should or should not drive.
DR. BRASS:  I would just like to come back to ‑‑ because it's actually in the question ‑‑ the issue of analogy to tricyclic antidepressants, because while it is clear that it is antimuscarinic and anticholinergic, I see nothing else in either the pharmacology or the clinical signals that suggests this has any actions at the molar concentrations that you use this compound that is anything like the more idiosyncratic Class 1A QRS prolongation, other kinds of things that are seen routinely with elevation in tricyclic antidepressant plasma concentrations.
Does the agency have any reason to continue to sustain that concern?  Dr. Neuner or others, is this still an issue, or am I missing something?

DR. KATZ:  Basically, what this compound is is structurally related to the tricyclic antidepressants.  So because some of the way the data was collected, or the lack thereof, is why the question is addressed, and that's why it was raised, because even though the profile itself is reassuring with regard to some of the effects one would see, we don't have data that actually looked for some of this information, and that's why it was raised to you as the committee to see if you have any concerns that the sponsor should go back and look at some of these issues again, or if there is no concern, then that would be that as well.
DR. BRASS:  My level of concern is extremely low.  The two pieces of data, if they were available, that would help me feel even more comfortable is if, in the overdose cases, if QRS duration could be examined and addressed whether or not there was any prolongation.  If not, then it doesn't have the effects, and if there was anything in that kind of signal, in vitro testing for Class 1A-type EP properties again would clearly differentiate from a cardiac toxicity and arrhythrogenicity standpoint from the tricyclics.
DR. YOCUM:  The number of elderly in this situation were relatively few, less than 10 percent in any of these studies.  So it's kind of hard to look at some of that stuff.  The way the selection criteria went, most of the at-risk elderly is even a smaller portion of this population.  So I don't think there's a lot of data there for some of the greatest at-risk patients.

DR. BRASS:  I agree.  But again, to the degree that it's based on an analogy to the tricyclics, it's easy to differentiate whether or not you have the cardiac effects that tricyclics have.  And even in young patients at high concentrations, you get QRS prolongation uniformly, or almost uniformly in the serious overdoses.  If it's similar to Class 1A properties would be demonstratable in vitro, and whether there are any other surrogates people know about.
I agree, we don't have the data, but I'm unconvinced that there's a pressing rationale for extending that analogy in these kinds of concentration ranges, as evidenced by the fact that the drug didn't work as an antidepressant either.
DR. KRENZELOK:  If they're equimolar potent and so on, you're looking at serum concentrations that are a few nanograms versus 750 to 1,000 nanograms per milligram, where you begin to see QRS prolongation.  So there doesn't appear to be any apparent association at all.
DR. BRASS:  That's why I emphasized the molar concentration.  The only caveat is that you'd have to do free drug concentrations with the two, to the degree that would make a difference.  But they're two logs different league of concentrations on total drug.

Yes, Dr. Lovell?
DR. LOVELL:  As the other pediatrician on the committee, I feel compelled to respond to Dr. Yocum's question.  It seems as if the acute overdose database, because of the number of prescriptions written and the time that the drug has been available on the market, is very reassuring and robust in terms of safety as far as children getting into their parents' medication.  So I don't think that that itself is a concern.
The other thing you think about in pediatric use is off-label use, and the two situations that I would foresee in which this would very likely be used by pediatricians off-label is in fibromyalgia and acute muscle spasm related to sprains, just like the indication says.  Both of those are predominantly adolescent type problems.  I don't see them being big issues in preschool or in elementary school aged children.  So once you get to be an adolescent, drug dosing and metabolism for the most part is very much like adults, and I don't see that there's a real compelling issue to do pediatric PK studies in this drug.

DR. BRASS:  I would just, not as a pediatrician also, respond that the other window to that is the emergency room, and that there are a number of prescription drugs that are sold illicitly on the street to adolescent populations which then present often towed by their parents into the emergency room, certainly haloperidol, diazepam.  There's a broad list of such compounds, and I've never personally heard of cyclobenzaprine in that class.  Again, the warning system from the EDs would also highlight if there was a significant potential.  It doesn't mean tomorrow there won't be, and this is being televised.
DR. KODA-KIMBLE:  Is Dr. Andreason still here?
DR. ANDREASON:  Yes.
DR. KODA-KIMBLE:  Could you please, for my own education, explain to me why you recommend a P of 0.1 in evaluating the adverse effects?
DR. ANDREASON:  Well, the way that the sponsor set up the initial statistical analysis was actually to test the efficacy of Flexeril at producing sedation and psychomotor impairment, as opposed to looking at it for a safety concern.  At that level, that would mean that there was only a 1 in 20 chance that these findings were due to a random effect.  In that sense, we use the level of 0.1 as an exploratory value, and these are also small studies, so that if in a study that involved 50 people there is no effect, or there's no sign of an effect, that does not mean that there is no effect, especially with a level of 0.05.

At the level of 0.1, which is still fairly conservative with the small study, if there is no effect, that doesn't necessarily mean ‑‑ lack of evidence does not necessarily mean that there's a lack of an effect.  In this case, at a level of 0.1, with only a small number of people in the study, there actually was an effect.
DR. BRASS:  If I could just follow up on that, as I alluded to, I think the psychomotor data are much more relevant than the subjective sedation, and I remain concerned about the relatively small N in those studies identifying the 2 percent in the clinical studies who were self-diagnosed as severely impaired and a 2 percent kind of signal.
Now, while the distribution data was somewhat reassuring, it's still a relatively small N, and whether or not there's an X percentage ‑‑ and in terms of setting up a study to answer the question whether the population is affected or whether you could pick up X percent of the exposures who were severely impaired from exposure, statistically is a very different design.
DR. ANDREASON:  Yes.
DR. BRASS:  So I have a residual concern in that particular area in the psychomotor testing as to what is sedation and what's impairment.

DR. PUCINO:  To respond to that also, four doses, even in the young person, doesn't achieve a steady state.  So it would be nice to see the same data at 8 to 10 days out.
DR. BRASS:  This goes back to the bias that sedation is a surrogate for psychomotor impairment, and it may or may not be, and it was planned that way based on the time curve of mean sedation, which again doesn't identify outliers, individuals, and assumes that it is, in fact, a 1-to-1 surrogate for psychomotor impairment, and one could imagine it not being.  One could imagine becoming refractory to sedation and maintain a psychomotor impairment.
Yes, Dr. Harris?
DR. HARRIS:  The concern I have is about the elderly again, whether or not one should recommend that it be used at all in anybody over 65, given that it's unlikely that many people are going to call their doctors anyway, given the sort of risks that there may well be, and there is not too much data anyway to tell us one way or another.  So the issue is whether or not to recommend the use of this drug, if we get to that stage, in anybody over 65 at all.
DR. BRASS:  Could you comment on what risks you're particularly concerned being more of a problem in the elderly?

DR. HARRIS:  The psychomotor I think in particular.  I can't say the degree to which there is more of a risk based on the data I've seen here, but I think theoretically there could be.
DR. BRASS:  So again, sedation which was measured is not an adequate surrogate?
DR. HARRIS:  Well, to some degree, I guess.  I guess one could say so.
DR. BRASS:  Other safety issues or concerns?
(No response.)
DR. BRASS:  I think we answered a lot of these issues in the context of some of the other questions.
Anything from the agency's perspective that we didn't cover?
(No response.)
DR. BRASS:  Then the final question is, does anybody want to say anything else?  That's paraphrasing it. Any other issues or concerns about the discussion today that haven't been brought up that individuals would like to bring up?
(No response.)

DR. BRASS:  If not, and if the agency doesn't have any additional issues, I would just like to thank all the presenters who did such an excellent job of presenting succinct, on-time presentations, and all the members of both committees who contributed to a very lively but I think instructive discussion.  Thank you all.
The meeting is adjourned.
(Whereupon, at 3:28 p.m., the meeting was adjourned.)