(Posted: 8/28/97, Duragesic, Oxycontin, Kadian added 9/3/97, Accolate, Intal added 9/8/97)
Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.
NB: Comparison made to 1997 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
Compiled by:
Rebecca L. Bass, PharmD candidate
McWhorter School of Pharmacy
Birmingham, AL
ACCOLATE
[July 10, 1997: Zeneca]
"Hypersensitivity reactions, including urticaria angioedema and rashes, with or without blistering, have been reported in association with Accolate therapy."
ADDERALL
[July 17 & 25, 1997: Richwood]
ALDACTONE
[July 30, 1997: Searle]
CARDURA
[July 29, 1997:Pfizer]
Impaired Liver Function: Deletion of sentence - "There is no controlled experience with Cardura in patients with these conditions."
CLEOCIN
and
(clindamycin phosphate) Sterile Solution & IV Sterile Solution
[July 17, 1997: Pharmacia & Upjohn]
"Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clindamycin, and may range in severity from mild to life- threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
"Because clindamycin therapy has been associated with severe colitis which may end fatally, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in the INDICATIONS AND USAGE Section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of 'antibiotic-associated colitis'.
"After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
"Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of therapy with clindamycin."
DEXEDRINE
[July 9, 1997: SmithKline Beecham]
DURAGESIC
[July 17, 1997: Alza]
Graph: "Serum Fentanyl Concentrations Following Multiple Applications of Duragesic 100 ug/h" revised. See revised graph in new label/package insert.
Table A: "Range of Pharmacokinetic Parameters of Fentanyl in Patients" split into two tables - Table A and Table B (new text in italics)
Dose |
Maximal Concentration Tmax (h) |
Maximal Concentration Cmax (ng/mL) ["Range" deleted] |
DURAGESIC 25 ug/h |
38.1 (18.0) |
0.6 (0.3) |
DURAGESIC 50 ug/h |
34.8 (15.4) |
1.4 (0.5) |
DURAGESIC 75 ug/h |
33.5 (14.5) |
1.7 (0.7) |
DURAGESIC 100 ug/h |
36.8 (15.7) |
2.5 (1.2) |
NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in 17 hours.
(L/h) Range [70 kg] |
Vss (L/kg) Range |
T1/2 (h) Range |
|
["IV Fentanyl" deleted] |
27 - 75 |
3 - 8 |
3 - 12 |
Hepatically Impaired |
3 - 80+ |
0.8 - 8+ |
4 - 12+ |
Renally Impaired |
30 - 78 |
- |
- |
+ Estimated
NOTE: Information on volume of distribution and half-life not available for renally impaired patients.
Pharmacodynamics: Ventilatory Effects: Text deleted in first paragraph - "As a consequence, 10 of these 13 patients received naloxone, two patients had their dose reduced and one patient required no treatment beyond verbal stimulation. Of the 13 events, seven were associated with Duragesic 100 ug/h and six were associated with Duragesic 75 ug/h."
Text added at end of first paragraph - "In addition, post-marketing reports have been received of opiod-naive post-operative patients who have experienced clinically significant hypoventilation with Duragesic. Duragesic is contraindicated in the treatment of postoperative and acute pain."
New third sentence added to third paragraph - "The use of initial doses exceeding 25 ug/h is contraindicated in patients who are not tolerant to opioid therapy."
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Last sentence of first paragraph revised to read (new text in italics) - "There was no evidence of mutagenicity in the Ames Salmonella typhimurium mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c-3T3 transformation test, the mouse lymphoma assay, ("and" deleted] the human lymphocycte and CHO chromosomal aberration in-vitro assays, or the in-vivo micronucleus test."
Last paragraph in subsection deleted - "In the mouse lymphoma assay, fentanyl concentrations 2000 times greater than those seen with chronic Duragesic use were only mutagenic in the presence of metabolic activation."
Pediatric Use: First sentence revised to read (new text in italics) - "The safety and efficacy of Duragesic in pediatric patients have ["children has" deleted] not been established."
Information for Patients: Current text deleted - "Instructions for the application, removal, and disposal of Duragesic are provided in each carton."
Text added - "A patient instruction sheet is included in the package of Duragesic systems dispensed to the patients."
Table B: Table revised (new text in italics) -
TABLE C ["B" deleted] |
||
Name |
Equianalgesic Dose (mg) |
|
IM b,c ["a" deleted] |
PO |
|
morphine |
10 |
60 (30) d [ "b"deleted] |
Hydromorphone |
1.5 |
7.5 |
methadone |
10 |
20 |
oxycodone |
15 |
30 |
levorphanol |
2 |
4 |
oxymorphone |
1 |
10 (PR) |
heroin |
5 |
60 |
meperidine |
75 |
--- |
codeine |
130 |
200 |
["Note:" deleted] a All IM and PO doses in this chart are considered equivalent to 10 mg of IM morphine in analgesic effect. IM denotes intramuscular, PO oral, and PR rectal.
["a" deleted] b Based on single-dose studies in which an intramuscular dose of each drug listed was compared with morphine to establish the relative potency. Oral doses are those recommended when changing from parenteral to an oral route. Reference: Foley, K.M. (1985) The treatment of cancer pain. NEJM 313(2): 84-95.
c Although controlled studies are not available, in clinical practice it is customary to consider the doses of opioid given IM, IV or subcutaneously to be equivalent. There may be some differences in pharmacokinetic parametes such as Cmax and Tmax.
["b" deleted] d The conversion ratio of 10 mg parenteral morphine = 30 mg oral morphine is based on clinical experience in patients with chronic pain. The conversion ratio of 10 mg parenteral morphine = 60 mg oral morphine is based on a potency study in acute pain. Reference: Ashburn and Lipman (1993) Management of pain in the cancer patient. Anesth Analg 76:402-416.
["References" moved to within footnotes above]
Table C: Table revised (new text in italics) -
RECOMMENDED INITIAL DURAGESIC DOSE BASED UPON DAILY ORAL MORPHINE DOSE |
|
Morphine (mg/day) |
Dose (ug/h) |
45-134 |
25 |
135-224 |
50 |
225-314 |
75 |
315-404 |
100 |
405-494 |
125 |
495-584 |
150 |
585-674 |
175 |
675-764 |
200 |
765-854 |
225 |
855-944 |
250 |
945-1034 |
275 |
1035-1124 |
300 |
Note: In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to Duragesic.
["Although controlled studies are not available, in clinical practice it is customary to consider the doses of opioid given IM, IV or subcutaneously to be equivalent. There may be some differences in pharmacokinetic parameters such as Cmax and Tmax." deleted]
1 This table should not be used to convert from Duragesic to other therapies, because this conversion to duragesic is conservative. Use of Table D for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible. (See DOSAGE AND ADMINISTRATION - Discontinuation of Duragesic)
First sentence in last paragraph revised - "During the initial application of Duragesic, patients should use short-acting analgesics ["for the first 24 hours" deleted] as needed until analgesic efficacy with Duragesic is attained."
Dose Titration: First sentence revised (new text in italics) -
["The conversion ratio from oral morphine to Duragesic is conservative," deleted] The recommended initial Duragesic dose based upon the daily oral morphine dose is conservative, and 50% of patients are likely to require a dose increase after initial application of Duragesic."
Discontinuation of Duragesic: Text added at end of subsection -
"Table D should not be used to convert from Duragesic to other therapies, because the conversion to Duragesic is conservative. Use of Table D for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible."
FAMVIR
[July 15, 1997: SmithKline Beecham]
Addition of sentence- "In patients with underlying renal disease who have received inappropriately high doses of Famvir for their level of renal function, acute renal failure has been reported."
Pregnancy: Pregnancy Exposure Registry (new subsection): "To monitor maternal-fetal outcomes of pregnant women exposed to Famvir, SmithKline Beecham maintains a Famvir Pregnancy Registry. Physicians are encouraged to register their patients by calling (800) 366-8900, ext. 5231."
Addition of new last paragraph - "The following adverse events have been infrequently reported during post-marketing use of Famvir: rash, urticaria, hallucinations and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly)."
Addition to the end of section - "(See PRECAUTIONS, General)."
"Long-term studies of cromolyn sodium in mice (12 months intraperitoneal
["treatment followed by 6 months observation" deleted] administration at doses up to
150 mg/kg/day three days per week), hamsters
["12 months" deleted] (intraperitoneal ["treatment followed by 12 months observation"
deleted]
administration at doses up to 53
mg/kg/day three days per week
for 15 weeks followed by 17.5 mg/kg/day three days per week for 37 weeks),
and rats
(18 months subcutaneous treatment at doses up to 75 mg/kg/day six days per week)
showed no neoplastic effects. ["of cromolyn sodium." deleted]
These doses in mice, hamsters, and rats correspond to
approximately 40, 10, and 80 times, respectively, the maximum recommended daily
inhalation dose in adults on a mg/m2 basis, or, approximately 20, 5, and 40
times, respectively, the maximum recommended daily inhalation dose in
children on a mg/m2 basis.
"Cromolyn sodium showed no mutagenic potential in Ames
Salmonella/microsome plate assays, mitotic gene conversion in Saccharomyces
cerevisiae and in an in vitro cytogenetic study in human peripheral
lymphocytes.["No evidence of chromosomal damage or cytotoxicity was obtained
in various
mutagenesis studies." deleted]
"No evidence of impaired fertility was shown in laboratory reproduction studies
conducted subcutaneously in rats at the highest doses tested, 175 mg/kg/day in
males and 100 mg/kg/day in females. These doses are approximately 220 and 130
times, respectively, the maximum recommended daily inhalation dose in adults on
a mg/m2 basis."
Pregnancy: Pregnancy Category B: Subsection revised (new text in italics) -
"Reproduction studies with cromolyn sodium administered ["parenterally" deleted]
subcutaneously to pregnant mice and rats at maximum daily doses of
540 mg/kg/day and 160 mg/kg/day, respectively, and intravenously to rabbits
["in doses up to 338 times the human clinical dose" deleted] at a
maximum daily dose of 485 mg/kg/day produced no evidence of fetal
malformations. These doses represent approximately 340, 210, and 1200 times,
respectively, the maximum recommended daily inhalation dose in adults on a
mg/m2
basis. Adverse fetal effects (increased resorption and decreased fetal weight) were
noted only at ["the" deleted] very high parenteral doses that produced maternal toxicity. There are,
however, no adequate and well controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, Intal Inhaler [
"this drug" deleted]
should be used during pregnancy only if clearly needed."
Drug Interaction During Pregnancy: Subsection revised (new text in italics) -
" Cromolyn sodium and isoproterenol were studied following subcutaneous injections
in pregnant mice. Cromolyn sodium alone in doses ["of 60 to 540 mg/kg (38 to 338 times
the human
dose)" deleted] up to 540 mg/kg/day (approximately
340 times the maximum recommended daily inhalation dose in adults on a mg/m2
basis)
did not cause significant increases in resorptions or major malformations.
Isoproterenol alone at a dose of 2.7 mg/kg/day ["90 times the human dose" deleted]
(approximately 7 times the
maximum recommended daily inhalation dose in adults on a mg/m2 basis) increased
both resorptions and malformations . The addition of 540 mg/kg/day of
cromolyn sodium ["(338 times the human dose) to isoproterenol (90 times the human dose)" deleted]
(approximately 340 times the maximum recommended daily inhalation
dose in adults on a mg/m2 basis ) to 2.7 mg/kg/day of isoproterenol (approximately 7
times the maximum recommended daily inhalation dose in adults on a mg/m2
basis) appears to have increased the incidence of both resorptions and
malformations."
Addition of paragraph- "There is no clinical syndrome associated with an
overdosage of cromolyn sodium. In several animal species acute toxicity with
cromolyn sodium occurs only with very high exposure levels. No deaths occurred
at the highest oral doses tested in mice, 8000 mg/kg/day (approximately 5,100 and
2,700 times the maximum recommended daily inhalation doses in adults and
children, respectively, on a mg/m2 basis) or in rats, 8000 mg/kg
(approximately 10,000 and 5,400 times the maximum recommended daily inhalation
doses in adults and children , respectively, on a mg/m2 basis)."
"Alternatively, Kadian capsules may be opened and the entire contents sprinkled on a
small amount of applesauce immediately prior to ingestion. ["The capsules
should not be opened
, chewed, crushed, dissolved, or mixed with food." deleted] The pellets in
Kadian capsules should not be chewed, crushed, or dissolved due to the risk of
overdose.
"Taking ["broken," deleted] chewed or crushed Kadian capsules or pellets
will lead to the rapid release and absorption of a potentially toxic dose
of morphine."
Alternative Method of Administration (new subsection): "In a study of healthy
volunteers, KADIAN pellets sprinkled over applesauce were found to be bioequivalent to
KADIAN capsules swallowed whole with applesauce under fasting conditions.
Other foods have not been tested. Patients who have difficulty swallowing whole
capsules or tablets may benefit from this alternative method of administration.
"For patients with suspected sensitivity to calcitonin, skin testing should be
considered prior to treatment utilizing a dilute, sterile solution of Miacalcin
(calcitonin-salmon) Injection, Synthetic. Physicians may wish to refer patients
who require skin testing to an allergist. A detailed skin testing protocol is
available from the Medical Services Department of Sandoz Pharmaceuticals
Corporation."
Skin: - "Urticaria" added
ADVERSE REACTIONS:
Last sentence in the first paragraph was revised (new text in italics) -
"Although a definite causal relationship has not been established, the following
have been reported in patients taking this drug: instances of abnormal liver
function, ranging from transaminase elevation to hepatic coma; isolated cases
of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient
depressed mood; a few instances of scalp hair loss." [Change appears in 1997 PDR.]
New sentence added to the end of what is now 3rd paragraph - "Other measures to
detoxify the gut include administration of activated charcoal and a cathartic."
(Change appears in 1997 PDR.)
"Viracept should not be administered concurrently with terfenadine, astemizole,
cisapride, triazolam, ["or" deleted] midazolam, ["because competition for CYP3A by nelfinavir
could result in inhibition of" deleted] ergot derivatives, amiodarone or
quinidine
because Viracept may effect the hepatic metabolism of these drugs and create the
potential for serious and/or life-threatening ["cardiac arrhythmias or prolonged sedation." deleted]
adverse events. (see PRECAUTIONS,
Drug Interactions)"
New paragraph added to end of section -
"New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and
hyperglycemia have been reported during post-marketing surveillance in
HIV-infected patients receiving protease inhibitor therapy. Some
patients required either initiation or dose adjustments of insulin or oral
hyperglycemic agents for treatment of these events. In some cases diabetic
ketoacidosis has occurred. In those patients who discontinued protease inhibitor
therapy, hyperglycemia persisted in some cases. Because these events have been
reported voluntarily during clinical practice, estimates of frequency cannot be
made and a causal relationship between protease inhibitor therapy and these
events
has not been established."
PRECAUTIONS:
Ritonavir: Subsection has
been revised (new text in italics):
"Coadministration of ritonavir with Viracept resulted in a 152%
increase in nelfinavir plasma AUC and very little change in ritonavir plasma AUC.
["The safety of this combination has not been established." deleted] Currently, there
are no safety and efficacy data available from the use of this
combination."
Saquinavir: Subsection has
been revised (new text in italics)- "Coadministration of saquinavir (using an
experimental soft-gelatin capsule formulation of saquinavir 1200 mg) with
Viracept resulted in an 18% increase in nelfinavir plasma AUC and a ["392%" deleted]
4-fold
increase in saquinavir plasma AUC. If used in combination with saquinavir
hard gelatin capsules at the recommended dose of 600 mg tid, no adjustments
are needed. Currently, there are no safety and efficacy data available from the
use of this combination."
DOSAGE AND ADMINISTRATION:
"Wytensin is contraindicated in patients with a known sensitivity to the drug or
any of the
tablet ingredients."
PRECAUTIONS:
"No evidence of carcinogenic potential emerged in rats during a two-year oral study with
Wytensin at doses up to 9.5 mg/kg/day, i.e., about 10 times the maximum recommended
human dose."
New paragraph added at beginning of section -
"Two-year studies were conducted with oral Wytensin administered in the diet to
mice and rats. No evidence of carcinogenic potential was seen in mice given
doses of up to 11.5 mg/kg/day (41.4 mg/m2/day) or in rats given doses of up to
9.5 mg/kg/day (83.8 mg/m2/day). On a body-weight basis, these doses are 9X and
7X, respectively, the maximum recommended human daily dose (MRHDD) of 64
mg (based on a 50 kg individual). On a body-surface-area basis, these doses are
1X (mice) and 2X (rats) the MRHDD."
Nursing Mothers: Entire subsection deleted -
"Because no information is available on the excretion of Wytensin in human milk,
it should not be administered to nursing mothers."
Replaced with the following text -
"It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when Wytensin is
administered to a nursing woman."
Pediatric Use: Subsection revised (new text in italics) -
"The safey and effectiveness of Wytensin in ["children less than 12 years of age" deleted]
pediatric patients have not been established." ["demonstrated. Therefore its
use in this age
group cannot be recommended at this time." - deleted]
GARAMYCIN (gentamicin sulfate) Ophthalmic Solution & Ophthalmic Ointment
[July 29, 1997: Schering]
INTAL
[July 23, 1997: Rhone-Poulenc Rorer]
KADIAN
[July 29, 1997: F.H. Faulding]
LEUCOVORIN CALCIUM
[July 21, 1997: Immunex ]
MAVIK
[July 2, 1997: Knoll]
Contact
the company for a copy of the labeling/package insert.
MIACALCIN
[July 14, 1997: Novartis]
OXYCONTIN
[July 25, 1997: Purdue Pharma L.P.]
PERSANTINE
[July 3, 1997: Boehringer-Ingelheim]
RITALIN
and
RITALIN-SR (methylphenidate HCl) Sustained-Release Tablets
[July 9, 1997: Novartis]
ULTRAVIST
[July 23, 1997: Berlex]
Contact the company for a copy of the
labeling/package insert.
VERELAN
[July 29, 1997: Lederle]
VIRACEPT
[July 31, 1997: Agouron]
VOSOL
and
VOSOL HC (hydrocortisone and acetic acid) Otic Solution
[July 29, 1997: Wallace]
WYTENSIN
[July 23, 1997: Wyeth-Ayerst]
ZOLOFT
[July 8, 1997: Pfizer]
Contact the company for a copy of the labeling/package insert.