[Federal Register: January 14, 1997 (Volume 62, Number 9)]
[Notices]
[Page 1889-1892]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96N-0512]
Hoechst Marion Roussel, Inc., and Baker Norton Pharmaceuticals,
Inc.; Terfenadine; Proposal To Withdraw Approval of Two New Drug
Applications and One Abbreviated New Drug Application; Opportunity for
a Hearing
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is proposing to
withdraw approval of two new drug applications (NDA's) and one
abbreviated new drug application (ANDA) for drug products containing
terfenadine. NDA 18-949 (Seldane) and NDA 19-664 (Seldane-D) are held
by Hoechst Marion Roussel (HMR), Inc., P.O. Box 9627, Kansas City, MO
64134-0627. ANDA 74-475 is held by Baker Norton Pharmaceuticals, Inc.,
4400 Biscayne Blvd., Miami, FL 33137. On July 25, 1996, FDA approved
HMR's NDA 20-625 for fexofenadine hydrochloride (Allegra). Fexofenadine
is the active metabolite of terfenadine that is responsible for the
desired beneficial properties of terfenadine. When patients take
terfenadine, parent terfenadine is ordinarily present in their blood at
very low concentrations, because the terfenadine molecule is
metabolized to form fexofenadine. Fexofenadine is responsible for
providing patients with essentially all the clinical benefits of taking
terfenadine. If terfenadine's metabolism is inhibited, either by
another drug or by intrinsic liver disease, the level of parent
terfenadine can rise to levels that can cause serious side effects in
people as a result of the effect of parent terfenadine on cardiac
potassium channels. Inhibition of these channels causes delayed cardiac
repolarization (prolonged electrocardiographic QT interval) and
increases the risk of a characteristic kind of ventricular tachycardia
called torsades de pointes and possibly the risk of other rhythm
abnormalities. Fexofenadine hydrochloride, however, has not been shown
to affect cardiac potassium channels and has been shown not to cause
prolongation of the electrocardiographic QT interval, even at larger-
than-recommended doses. Based on all data to date, fexofenadine
hydrochloride appears to lack parent terfenadine's risk of serious
cardiovascular adverse events. The basis for the proposed withdrawal of
the applications is a finding that the availability of fexofenadine
hydrochloride provides patients with an alternative that can provide
essentially all the benefits of terfenadine, because it is identical in
molecular structure to the metabolized (active) form of terfenadine,
without the serious and potentially fatal risks associated with
terfenadine when terfenadine's metabolism is inhibited either by
another drug or by intrinsic liver disease. Because of the availability
of fexofenadine hydrochloride, terfenadine is not shown to be safe for
use under the conditions of use that formed the basis upon which the
applications were approved.
DATES: A hearing request is due on February 13, 1997; data and
information in support of the hearing request are due on March 17,
1997.
ADDRESSES: A request for hearing, supporting data, and other comments
are to be identified with docket no. 96N-0512 and submitted to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT:
For information on medical/scientific issues: John K. Jenkins,
Center for Drug Evaluation and Research (HFD-570), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-
[[Page 1890]]
1050.
For general information concerning this notice: David T. Read,
Center for Drug Evaluation and Research (HFD-7), Food and Drug
Administration, 7520 Standish Pl., Rockville, MD 20855, 301-594-2041.
SUPPLEMENTARY INFORMATION:
I. Background
Terfenadine is an antihistamine, indicated for the relief of
symptoms associated with seasonal allergic rhinitis such as sneezing,
rhinorrhea, pruritus, and lacrimation. Terfenadine was the first
antihistamine approved in the United States that was not associated
with more somnolence than placebo in clinical trials. The absence of an
increased risk of somnolence over placebo is an important safety
advantage to many people who use antihistamines. NDA 18-949 for Seldane
tablets (terfenadine 60 milligrams (mg)) was approved by FDA on May 8,
1985. NDA 19-664 for Seldane-D tablets (terfenadine 60 mg and the
decongestant pseudoephedrine hydrochloride 120 mg) was approved by FDA
on August 19, 1991.
Other antihistamines now available in the United States that were
not associated with more somnolence than placebo in clinical trials are
astemizole (Hismanal) and loratadine (Claritin), approved on December
29, 1988, and April 12, 1993, respectively. Most significant to this
proceeding, on July 25, 1996, FDA approved HMR's NDA 20-625 for
fexofenadine hydrochloride 60 mg capsules (Allegra). Fexofenadine is
the metabolite of terfenadine responsible for its desired
antihistaminic efficacy. Fexofenadine hydrochloride was also not
associated with more somnolence than placebo in clinical trials.
After the approval of terfenadine in 1985, there began to be
reports of certain serious cardiac adverse events associated with
terfenadine use in patients taking certain antimicrobials or with
significant liver dysfunction. Very little parent terfenadine normally
circulates in the plasma because orally administered terfenadine
undergoes extensive first pass metabolism by a specific cytochrome P-
450 isoenzyme (CYP3A4). This metabolic pathway may be impaired in
patients with liver dysfunction (e.g., alcoholic cirrhosis) or who are
taking drugs such as ketoconazole, itraconazole, or macrolide
antimicrobials (e.g., clarithromycin, erythromycin, or troleandomycin).
These drugs are all inhibitors of the cytochrome P-450 isoenzyme.
Interference with the normal metabolism of terfenadine can lead to
elevated plasma terfenadine levels. At these elevated levels,
terfenadine can delay cardiac repolarization (prolong the
electrocardiographic QT interval) because of its effects on cardiac
potassium channels. The delayed cardiac repolarization increases the
risk of serious ventricular tachyarrhythmias, most characteristically a
kind of ventricular tachycardia called torsades de pointes. This
arrhythmia can cause dizziness and syncope when it is short-lived, but
it may persist and degenerate into unstable ventricular tachycardia or
ventricular fibrillation. Ventricular fibrillation is fatal if not
promptly reversed. These serious and possibly fatal events can occur at
the recommended dose of terfenadine if it is taken along with other
medications that interfere with its metabolism or if it is administered
to someone with significant hepatic dysfunction.
In an effort to inform the medical and patient communities about
the serious and potentially fatal cardiac adverse effects associated
with inappropriate use of terfenadine, the labeling for Seldane and
Seldane-D have been revised many times. In 1992, terfenadine labeling
was revised to include a prominent boxed warning cautioning against its
use in certain settings, particularly with the drugs that inhibit its
metabolism. In addition, ``Dear Health Care Professional'' letters
warning health care practitioners of the serious risk of inappropriate
use of terfenadine were issued by the sponsor in 1990, 1992, and 1996.
Although the revised labeling and ``Dear Health Care Professional''
letters have significantly reduced the inappropriate prescribing of
terfenadine together with the drugs that block its metabolism, such
prescribing and dispensing has not been eliminated and almost certainly
cannot be. Three recently published studies indicate that
coprescription and codispensing of medications contraindicated with
terfenadine continues to occur (Refs. 1, 2, and 3). The Cavuto study
also demonstrates that the computerized drug-interaction screening
programs used by many pharmacists, who are the last line of defense
against prescribing errors, do not completely prevent prescribing and
filling of prescriptions for potentially dangerous combinations of
terfenadine and contraindicated drugs.
Terfenadine is an antihistamine that is intended to be used when
symptoms of seasonal allergic rhinitis occur. Patients often do not
consume all of the pills they receive in a prescription of terfenadine
for a single episode of seasonal allergic rhinitis, and may keep the
remaining pills for later use when needed, as patients often do with
over-the-counter antihistamines. Because of the nature of seasonal
allergies, a long period of time (e.g., from early fall to spring) can
elapse between the time the drug and any associated warning from a
health care practitioner or pharmacist is received and the time
terfenadine is used. Such intermittent dosing of terfenadine increases
the probability that some patients may be taking one of the
contraindicated medications, such as one of the frequently prescribed
antimicrobials listed above, at the same time the patient self-
diagnoses his or her seasonal allergy symptoms and takes the remaining
terfenadine from the pill container in the medicine chest.
This problem of concomitant use is further compounded by the
growing list of medications known to inhibit the metabolism of
terfenadine, many of which are taken for chronic medical conditions and
may be prescribed by health care practitioners other than the
practitioner who prescribed the terfenadine. Labeling changes and even
perfect performance by prescribers and close attention by pharmacists,
therefore, cannot completely eliminate the risks of serious cardiac
adverse events associated with the inappropriate use of terfenadine.
Very low to undetectable blood levels of parent terfenadine are
found in patients taking the recommended dose of terfenadine. For this
reason, parent terfenadine appears to have very little, if any, impact
on the therapeutic efficacy that is associated with terfenadine use.
The discovery of terfenadine's ability to delay cardiac
repolarization and its associations with serious and sometimes fatal
cardiac adverse events when used inappropriately led to evaluation of
its principal active metabolite as a potentially safer alternative
antihistamine. It was discovered that the metabolite that is
responsible for the desired therapeutic effect of terfenadine,
fexofenadine, does not affect cardiac potassium channels. The agency,
therefore, encouraged HMR to initiate the development of a drug product
with only the active metabolite fexofenadine as the active
antihistamine. Even at doses considerably in excess of those
recommended for use, fexofenadine hydrochloride has not been shown to
prolong the QT interval. It therefore should not have, and has not been
shown to have, the serious cardiovascular adverse events potentially
associated with unmetabolized terfenadine. No new
[[Page 1891]]
adverse reaction, not already associated with terfenadine, would be
expected because the many people who have taken terfenadine have been,
in fact, exposed primarily to fexofenadine manufactured by their body.
An NDA for fexofenadine hydrochloride was approved by FDA on July
25, 1996. Nearly 5 months of marketing of this product in the United
States have not resulted in any reports of serious cardiac arrhythmias.
Prior to the approval of fexofenadine hydrochloride, the agency
considered terfenadine to be safe (i.e., its benefits outweighed its
risks) despite terfenadine's known serious adverse effects when its
metabolism was blocked and despite the availability of alternative
antihistamines that, like terfenadine, were not associated with greater
somnolence than placebo in clinical trials. This is because the agency
recognizes that responses to drugs are not uniform among individuals
and, for reasons that are often unclear and difficult to discover, some
patients may respond better, with respect to therapeutic effectiveness
or tolerance, to one drug than to another. Terfenadine certainly
provided a unique therapeutic benefit when it was the only available
antihistamine that was not associated with more somnolence than placebo
in clinical trials, and it continued to provide a benefit and choice to
patients even after the approval of astemizole and loratadine (e.g.,
some patients may have found that terfenadine provided some advantage
over either of the other two products or may have been unable to
tolerate the alternative medications for a variety of medical reasons,
including drug allergy). So long as terfenadine represented a unique
molecule, the agency concluded that terfenadine's risks, which had been
greatly reduced by labeling changes and public awareness, were
acceptable in light of its benefits. It is only now, when there is an
alternative that is identical to the molecule that provides the
therapeutic benefits of terfenadine, that terfenadine's benefits do not
outweigh its risks. This is because essentially all of its benefits can
be obtained with fexofenadine hydrochloride without the cardiovascular
risk caused by QT prolongation.
Currently, there is no combination of fexofenadine hydrochloride
and pseudoephedrine approved for marketing in the United States.
Although the absence of a fexofenadine hydrochloride/pseudoephedrine
combination product may be inconvenient for patients currently taking
Seldane-D, there are available over-the-counter extended-release
pseudoephedrine 120 mg products that could be taken with fexofenadine
hydrochloride to provide symptomatic relief comparable to that provided
by Seldane-D for the treatment of seasonal allergic rhinitis. The minor
inconvenience to patients of having to take separate fexofenadine
hydrochloride and extended-release pseudoephedrine doses is more than
offset by the cardiac safety advantage of fexofenadine hydrochloride
over terfenadine.
Accordingly, the Director of the Center for Drug Evaluation and
Research concludes with respect to NDA 18-949 (terfenadine 60 mg) that:
(1) Prior to the approval of fexofenadine hydrochloride, terfenadine
provided a unique therapeutic alternative for which the risks
associated with the use of terfenadine were acceptable; (2) terfenadine
provides no therapeutic benefit to any patient population that is not
also provided by fexofenadine hydrochloride, because fexofenadine
hydrochloride is identical in molecular structure to terfenadine's
therapeutically active metabolite; (3) current data demonstrate that
fexofenadine hydrochloride lacks the serious cardiovascular risks
associated with misuse of terfenadine, and approximately 5 months of
marketing experience with fexofenadine hydrochloride in the United
States has not resulted in any reports of serious cardiac arrythmias;
(4) despite the many interventions undertaken by the agency and by HMR
(three ``Dear Health Care Professional'' letters, multiple labeling
changes, and extensive education campaigns), residual coprescribing,
codispensing, and concomitant use of terfenadine with a growing list of
medications that inhibit its metabolism continues and cannot be
expected to be completely eliminated; and (5) terfenadine, therefore,
is no longer shown to be safe for use under the conditions that formed
the basis upon which the application was initially approved. The
Director also finds that ANDA 74-475 refers to NDA 18-949 (Seldane, 60
mg terfenadine oral tablets) as the listed drug. The Director further
finds that the conclusions set out above for NDA 18-949 apply with
respect to NDA 19-664 (terfenadine 60 mg and pseudoephedrine 120 mg),
and that the inconvenience to patients of taking separate doses of
fexofenadine hydrochloride and extended-release pseudoephedrine is more
than offset by the cardiac safety advantage of fexofenadine
hydrochloride over terfenadine. The Director is proposing to withdraw
approval of NDA 18-949 and NDA 19-664 in accordance with section
505(e)(2) of the Federal Food, Drug, and Cosmetic Act (the act) (21
U.S.C. 355(e)(2)). The Director is proposing to withdraw approval of
ANDA 74-475 in accordance with section 505(j)(5) of the act.
II. Notice of Opportunity for a Hearing
The Director has evaluated the information discussed above and, on
the grounds stated, is proposing to withdraw approval of NDA 18-949,
NDA 19-664, and ANDA 74-475. Therefore, notice is given to HMR and
Baker Norton Pharmaceuticals, Inc. that the Director proposes to issue
an order under section 505(e)(2) of the act, withdrawing approval of
NDA 18-949 and NDA 19-664, and all amendments and supplements thereto,
and under section 505(j)(5) of the act, withdrawing approval of ANDA
74-475, and all amendments and supplements thereto. The Director finds
that new evidence of clinical experience, not contained in NDA 18-949
and NDA 19-664 or not available to the Director until after the
applications were approved, evaluated together with the evidence
available to the Director when the applications were approved, shows
that terfenadine is not shown to be safe for use under the conditions
which formed the basis upon which the applications were approved. The
Director also finds that ANDA 74-475 refers to the drug that is the
subject of NDA 18-949.
In accordance with section 505 of the act and part 314 (21 CFR part
314), HMR and Baker Norton Pharmaceuticals, Inc. are hereby given an
opportunity for a hearing to show why approval of the NDA's should not
be withdrawn.
An applicant who decides to seek a hearing shall file: (1) On or
before February 13, 1997, a written notice of appearance and request
for hearing, and (2) on or before March 17, 1997, the data,
information, and analyses relied on to demonstrate that there is a
genuine issue of material fact to justify a hearing, as specified in
Sec. 314.200. Any other interested person may also submit comments on
this notice. The procedures and requirements governing this notice of
opportunity for a hearing, a notice of appearance and request for a
hearing, information and analyses to justify a hearing, other comments,
and a grant or denial of a hearing are contained in Secs. 314.151 and
314.200, and in 21 CFR part 12.
The failure of an applicant to file a timely written notice of
appearance and request for hearing, as required by Sec. 314.200,
constitutes an election by that person not to use the opportunity for a
[[Page 1892]]
hearing concerning the action proposed and a waiver of any contentions
concerning the legal status of that person's drug products. Any new
drug product marketed without an approved new drug application is
subject to regulatory action at any time.
III. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Thompson, D., and G. Oster, ``Use of Terfenadine and
Contraindicated Drugs,'' Journal of the American Medical
Association, 275(17):1339-1341, 1996.
2. Cavuto, N. J., R. L. Woosley, and M. Sale, ``Pharmacies and
Prevention of Potentially Fatal Drug Interactions'' (letter),
Journal of the American Medical Association, 275(14):1086-1087,
1996.
3. Carlson, A. M., and L. S. Morris, ``Coprescription of
Terfenadine and Erythromycin and Ketoconazole: An Assessment of
Potential Harm,'' Journal of the American Pharmaceutical
Association, NS36(4):263-269, 1996.
A request for a hearing may not rest upon mere allegations or
denials, but must present specific facts showing that there is a
genuine and substantial issue of fact that requires a hearing. If it
conclusively appears from the face of the data, information, and
factual analyses in the request for a hearing that there is no genuine
and substantial issue of fact that precludes the withdrawal of approval
of the applications, or when a request for hearing is not made in the
required format or with the required analyses, the Commissioner of Food
and Drugs will enter summary judgment against the person who requests
the hearing, making findings and conclusions, and denying a hearing.
All submissions pursuant to this notice of opportunity for a
hearing are to be filed in four copies. Except for data and information
prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C.
1905, the submissions may be seen in the Dockets Management Branch
(address above) between 9 a.m. and 4 p.m., Monday through Friday.
This notice is issued under the Federal Food, Drug, and Cosmetic
Act (sec. 505 (21 U.S.C. 355)) and under authority delegated to the
Director of the Center for Drug Evaluation and Research (21 CFR 5.82).
Dated: January 7, 1997.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 97-714 Filed 1-10-97; 8:45 am]
BILLING CODE 4160-01-F