SUMMARY OF SAFETY-RELATED DRUG LABELING CHANGES APPROVED BY FDA
November 1996
(Posted: 1/29/97)
(Prozac, Adverse Reactions, Postintroduction Reports - Added: 3/18/97)
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 1996 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
(Click on name of the product to go
directly to the summary.)
BECONASE AQ (beclomethasone dipropionate, monohydrate) -
CIPRO (ciprofloxacin) -
CORTISPORIN OTIC SOLUTION (polymyxin B sulfate-neomycin sulfate-hydrocortisone) -
LUVOX (fluvoxamine maleate) -
NOLVADEX (tamoxifen citrate) -
NORMODYNE (labetalol HCl) -
PROZAC (fluoxetine HCl) -
REDUX (dexfenfluramine HCl)-
RESERPINE -
RHINOCORT (budesonide) -
VISTIDE (cidofovir)
BECONASE AQ
(beclomethasone dipropionate, monohydrate)
Nasal Spray
[November 26, 1996: Glaxo-Wellcome]
-
PRECAUTIONS:
- General: Beconase AQ:
Cataracts added to list of rare instances of adverse reactions
that have been reported following the use of intranasal beclomethasone
dipropionate (previously, "intranasal application of aerosolized
corticosteroids");
The next sentence "Although these have not been observed in clinical
trials with Beconase AQ Nasal Spray, vigilance should be maintained" has been
deleted.
-
ADVERSE REACTIONS:
-
Beconase AQ: Statement added that reports of dryness and irritation of the nose
and throat, and unpleasant taste and smell have been received.
-
PATIENTS INSTRUCTIONS FOR USE:
-
The following instruction has been added:
"8. The correct amount of medication in each spray cannot be assured
after a specified number of sprays even though the bottle is not
completely empty. Before the discard date you should consult your doctor
to determine whether a refill is needed. Just as you should not take extra
doses without consulting your doctor, you should also not stop Beconase AQ
Nasal Spray without consulting your doctor."
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CIPRO
(ciprofloxacin)
[November 22, 1996: Bayer]
-
ADVERSE REACTIONS:
-
Post-Marketing Adverse Events: Agitation, delirium, and
myoclonus added to Central Nervous System category, and methemoglobinemia
added to Hemic/Lymphatic category.
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CORTISPORIN
OTIC SOLUTION
(polymyxin B sulfate-neomycin sulfate-hydrocortisone)
[November 21, 1996: Glaxo-Wellcome]
-
CONTRAINDICATIONS:
- Revised to indicate that Cortisporin
should not be used if the external auditory canal
disorder is suspected or known to be due to cutaneous viral infection
(for example, herpes simplex virus or varicella zoster virus).
-
WARNINGS:
-
First two paragraphs of section replaced by the following three
paragraphs:
"Neomycin can induce permanent sensorineural hearing loss due to
cochlear damage, mainly destruction of hair cells in the organ of Corti.
The risk of ototoxicity is greater with prolonged use; therefore, duration
of therapy should be limited to 10 consecutive days. (See PRECAUTIONS -
General.)
"Patients being treated with eardrops containing neomycin
should be under close clinical observation. Due to its acidity which
may cause burning and stinging, Cortisporin Otic Solution should not be
used in any patient with a perforated tympanic membrane.
"Neomycin sulfate may cause cutaneous sensitization. A precise
incidence of hypersensitivity reactions (primarily skin rash) due
to topical neomycin is not known. Discontinue this product promptly
if sensitization or irritation occurs."
-
DOSAGE AND ADMINISTRATION:
-
Recommendation added that
therapy with this product should be limited to 10 consecutive days.
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LUVOX
(fluvoxamine maleate)
[November 13, 1996: Solvay]
-
PRECAUTIONS:
-
Potential Interactions with Drugs that Inhibit or are
Metabolized by Cytochrome P450 Isozymes: Subsection revised to include
information concerning extensive and poor metabolizers [see complete
subsection in package insert].
- Tricyclic Antidepressants (TCAs): Revised to note
that plasma TCA concentrations may need to be monitored, and TCA dose
may need to be reduced, during co-administration with fluvoxamine.
-
ADVERSE REACTIONS:
-
Non-US Postmarketing Reports: Hepatitis added.
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NOLVADEX
(tamoxifen citrate)
[November 15, 1996: Zeneca]
-
ADVERSE REACTIONS:
-
The second sentence of section
"If adverse reactions are severe, it is sometimes possible to control
them by a simple reduction of dosage without loss of control
of the disease." has been deleted.
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NORMODYNE
(labetalol HCl) Injection
[November 25, 1996: Schering]
-
WARNINGS:
-
Statement added that several deaths have occurred when
Normodyne Injection was used during surgery
(including when used in cases to control bleeding).
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PROZAC
(fluoxetine HCl)
[November 21, 1996: Lilly]
-
WARNINGS:
-
Rash and Possibly Allergic Events: First sentence revised
to indicate that in U.S. fluoxetine clinical trials, 7% of
10,782 patients developed various types of rashes and/or urticaria.
-
PRECAUTIONS:
-
General: Based on data from U.S. placebo-controlled clinical trials,
incidence rates of specific events
revised in the
following subsections [see complete package insert for specifics]:
Anxiety and Insomnia, Altered Appetite and Weight,
Activation of Mania/Hypomania, and
Seizures.
- Suicide: Second paragraph revised to include notation of the
well-established comorbidity between bulimia and depression, and that the
same precautions observed when treating patients with depression should be
observed when treating patients with bulimia.
- Drug Interactions:
Drugs Metabolized by Cytochrome P450IIIA4 (new subsection):
In an in vivo interaction study involving co-administration of fluoxetine
with single doses of terfenadine (a cytochrome P450IIIA4 substrate), no
increase in plasma terfenadine concentrations occurred with concomitant
fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent
inhibitor of P450IIIA4 activity, to be at least 100 times more potent than
fluoxetine or norfluoxetine as an inhibitor of the metabolism of several
substrates for this enzyme, including astemizole, cisapride, and midazolam.
These data indicate that fluoxetine's extent of inhibition of cytochrome
P450IIIA4 activity is not likely to be of clinical significance.
- CNS Active Drugs: Statement added that in evaluating
individual cases, consideration should be given to using lower initial
doses of the concomitantly administered drugs, using conservative titration
schedules, and monitoring of clinical status (See Accumulation and
Slow Elimination under CLINICAL PHARMACOLOGY).
- Anticonvulsants (new subsection): Patients on stable
doses of phenytoin and carbamazepine have developed elevated plasma
anticonvulsant concentrations and clinical anticonvulsant toxicity
following initiation of concomitant fluoxetine treatment.
-
Antipsychotics (new subsection): Some clinical data suggests
a possible pharmacodynamic and/or pharmacokinetic interaction between
serotonin specific reuptake inhibitors (SSRIs) and antipsychotics.
Elevation of blood levels of haloperidol and clozapine has been observed
in patients receiving concomitant fluoxetine. A single case report has
suggested possible additive effects of pimozide and fluoxetine leading to
bradycardia.
- Benzodiazepines (new subsection): The half-life of
concurrently administered diazepam may be prolonged in some patients
(see Accumulation and Slow Elimination under CLINICAL PHARMACOLOGY).
Co-administration of alprazolam and fluoxetine has resulted in increased
alprazolam plasma concentrations and in further psychomotor performance
decrement due to increased alprazolam levels.
- Lithium: That there have been reported cases of increased
serotonergic effects when lithium was used concomitantly with fluoxetine
has been added.
- Warfarin (new subsection): Altered anti-coagulant effects,
including increased bleeding, have been reported when fluoxetine is
co-administered with warfarin. Patients receiving warfarin therapy should
receive careful coagulation monitoring when fluoxetine is initiated or
stopped.
-
ADVERSE REACTIONS:
-
Section has undergone marked revision [see complete section in
package insert] and now contains the following introductory information:
- "Multiple doses of Prozac had been administered to 10,782 patients
with various diagnoses in US clinical trials as of May 8, 1995. Adverse
events were recorded by clinical investigators using descriptive terminology
of their own choosing. Consequently, it is not possible to provide a
meaningful estimate of the proportion of individuals experiencing adverse
events without first grouping similar types of events into a limited
(i.e., reduced) number of standardized event categories.
"In the tables and tabulations that follow, COSTART Dictionary
terminology has been used to classify reported adverse events. The stated
frequencies represent the proportion of individuals who experienced, at
least once, a treatment-emergent adverse event of the type listed. An event
was considered treatment-emergent if it occurred for the first time or
worsened while receiving therapy following baseline evaluation. It is
important to emphasize that events reported during therapy were not
necessarily caused by it.
"The prescriber should be aware that the figures in the tables
and tabulations cannot be used to predict the incidence of side effects in
the course of usual medical practice where patient characteristics and other
factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other
clinical investigations involving different treatments, uses, and
investigators. The cited figures, however, do provide the prescribing
physician with some basis for estimating the relative contribution of drug
and nondrug factors to the side effect incidence rate in the population
studied."
- Incidence in US Placebo-Controlled Clinical Trials
(excluding data from extensions of trials) (new subsection):
Contains two tables:
TABLE 1: Enumerates the most common treatment-emergent
adverse events associated with Prozac use (incidence of less than or equal to
5% for Prozac
and at least twice that for placebo within at least one of the indications)
for treatment of depression, OCD, and bulimia in U.S. controlled clinical
trials;
TABLE 2: Enumerates treatment-emergent adverse events
that occurred in greater than or equal to 2% of patients treated with Prozac and with
incidence greater than
placebo who participated in U.S. controlled clinical trials comparing
Prozac with placebo in treatment of depression, OCD, or bulimia.
(TABLE 2 provides combined data for the pool of studies that
are provided separately by indication in TABLE 1).
-
Associated with Discontinuation in US Placebo-Controlled Clinical
Trials (excluding data from extensions of trials) (new subsection):
Contains one table:
TABLE 3: Lists the adverse events associated with
discontinuation of Prozac treatment (incidence at least twice that for
placebo and greater than or equal to 1% for Prozac in clinical trials)
in depression, OCD, and
bulimia.
- Other Events Observed In All US Clinical Trials [replaces previous
subsection Other Events Observed During Premarketing Evaluation of
Prozac (fluoxetine hydrochloride)]: Lists all treatment-emergent adverse
events reported at any time by individuals taking fluoxetine in U.S.
clinical trials (10,782 patients) except (1) those listed in the body or
footnotes of TABLES 1 or 2, or elsewhere in labeling; (2) those for which
the COSTART terms were uninformative or misleading; (3) those events for
which a causal relationship to Prozac use was considered remote; and (4)
events occurring in only one patient treated with Prozac and which did not
have a substantial probability of being acutely life threatening.
Postintroduction Reports: Stevens-Johnson syndrome added.
DOSAGE AND ADMINISTRATION:
Bulimia Nervosa (new subsection): Initial Treatment information
contains same cautions as in Depression and Obsessive-Compulsive
Disorder
subsections, namely that 1) a lower or less frequent dosage of Prozac
should be used in patients with renal and/or hepatic impairment, and 2) a
lower or less frequent dosage should also be considered for patients,
such as the elderly (see Usage in the Elderly under PRECAUTIONS),
with concurrent disease or on multiple medications.
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REDUX
(dexfenfluramine HCl)
[November 4, 1996: Interneuron]
-
WARNINGS:
-
Introductory sentence added (bolded and in capital letters):
"Dexfenfluramine is an appetite suppressant, and appetite suppressants
increase the risk of developing primary pulmonary hypertension, an often
fatal disorder."
In the paragraph detailing the results of the case-control
epidemiology study, the following changes have been made:
The odds ratio has been changed from 9.1 to 23.1, and
the
95% confidence interval from 2.6 - 31.5 to 6.9 - 77.7;
The sentence regarding increased risk of primary
pulmonary hypertension
and time course of usage hs been changed to include only the previous notation that there
was no significant
increase in risk for persons who had used appetite suppressants for 3
months or less.;
The sentence regarding the estimated risk associated with long-term use
of appetite suppressants has been changed to indicate the estimated risk is about 23-46
[increased from 18, as previous]
cases per million persons exposed per year, based upon a background estimate
of 1-2 cases per million persons.
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RESERPINE, USP
[November 6, 1996: Eon Labs]
-
CLINICAL PHARMACOLOGY:
-
The paragraph regarding specific pharmacokinetics parameters revised to:
"Mean maximum plasma levels of plasma
concentrations after a single dose of 0.5 mg of reserpine, administered as
two 0.25 mg tablets or as an aqueous solution, peaked after 2.5 hours. The
mean peak level was approximately 1.1 ng/ml. The two formulations were found
to be bioequivalent. Absolute bioavailability of reserpine, as established
by comparison to an intravenous dose, has been reported to be approximately
50%.
Reserpine is extensively bound (95%) to plasma proteins.
Reserpine is almost completely metabolized in the body, and only about 1%
is excreted as unchanged drug in the urine. No definitive studies on the
human metabolism of reserpine have been made. After oral administration, an
initial half-life of approximately 5 hours is followed by a terminal
half-life of the order of 200 hours. Plasma levels may be measurable 14
days after a single dose. The clinical significance of the long terminal
half-life is unknown."
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RHINOCORT
(budesonide) Nasal Inhaler
[November 15, 1996: Astra USA]
-
PATIENT'S INSTRUCTIONS FOR USE:
-
- Instruction 2 (addition of new sentence): Instruction to press straight down on the
canister to actuate a dose, and notation that Rhinocort Nasal Inhaler
must be sprayed into the air 4 times before using for the first time.
- Instruction 5 (new): If Rhinocort Nasal Inhaler is not used for
a period of 8 weeks, test spray the unit by spraying into the air 4
times before reuse.
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VISTIDE
(cidofovir)
[November 14, 1996: Gilead Sciences]
-
BOXED WARNING:
-
Renal function (serum creatinine and
urine protein) must [rather than "should", as previous] be monitored
within 48 hours prior to each
dose of Vistide;
New statement added that Vistide is contraindicated in patients
who are receiving other nephrotoxic agents.
-
CONTRAINDICATIONS:
-
New statement added that initiation of therapy with Vistide is
contraindicated in patients with a serum creatinine greater than 1.5 mg/dL,
a calculated creatinine clearance less than or equal to 55 mL/min, or a
urine protein greater than or equal to 100 mg/dL (equivalent to greater than or equal
to 2+ proteinuria);
-
New statement added that Vistide is contraindicated in patients
receiving agents with nephrotoxic potential. Such agents must be
discontinued at least seven days prior to starting therapy with Vistide;
-
Prior notation regarding contraindication against direct intraocular injection
of Vistide revised to note that direct injections of cidofovir has been associated with
iritis, ocular hypotony, and
permanent impairment of vision.
-
WARNINGS:
-
Nephrotoxicity: Revised to include the following:
-
New statement that renal function (serum creatinine and urine protein) must be
monitored within 48 hours prior to each dose of vistide;
-
Acute renal failure, in some cases, resulting in the need for
dialysis, added to list of possible results of additional proximal
tubular cell injury to which continued administration of Vistide may lead;
Intravenous aminoglycosides (e.g., tobramycin, gentamicin, and
amikacin), vancomycin, and non-steroidal anti-inflammatory agents added
to list of other known potentially nephrotoxic agents for which the safety
of Vistide has not been evaluated in patients receiving these agents (see
DOSAGE AND ADMINISTRATION);
- Preexisting Renal Impairment: Revised to note that
initiation of therapy with Vistide is contraindicated in patients with a
baseline serum creatinine greater than 1.5 mg/dL, a creatinine clearance less than or equal
to 55 mL/min,
or a urine protein greater than or equal to 100 mg/dL
(equivalent to greater than or equal to 2+ proteinuria).
-
PRECAUTIONS:
-
General: Revised to note that due to the potential for increased
nephrotoxicity, doses greater than the recommended dose must
[rather than "should", as previous]
not be
administered and the frequency or rate of administration must [rather than "should", as previous]
not be
exceeded (see DOSAGE AND ADMINISTRATION);
- Drug Interactions, Nephrotoxic Agents: Intravenous amiknoglycosides (e.g.,
tobramycin, gentamicin, and
amikacin), vancomycin, and non-steroidal anti-inflammatory agents added to
list of other known potentially nephrotoxic agents, all of which are now contraindicated.
In addition, there is a new statemnt that such agents must be discontinued at least
seven days prior to
starting therapy with Vistide.
-
ADVERSE REACTIONS:
-
Nephrotoxicity: Revised to indicate that as prior foscarnet
use has been associated with an increased risk of nephrotoxicity,
such patients must [rather than should, as previous] be monitored closely.
-
OVERDOSAGE:
-
Previous overdosage information deleted; new section information
as follows:
"Two cases of cidofovir overdosage have been reported.
These patients received single doses of Vistide at 16.3 mg/kg and
17.4 mg/kg, respectively, with comcomitant oral probenecid and intravenous
hydration. In both cases the patients were hospitalized and received oral
probenecid (one gran three times daily) and vigorous intravenous hydration
with normal saline for 3 to 5 days. Significant changes in renal function
were not observed in either patient."
-
DOSAGE AND ADMINISTRATION:
-
Revisions made in several subsections
[Induction Treatment; Dose Adjustment (Changes in Renal Function During
Vistide Therapy; Preexisting Renal Impairment); Hydration] [see complete
section in package insert].
- Patient Monitoring: Revised to indicate that serum
creatinine and urine protein must be monitored within 48 hours prior to
each dose.
- Previous section Dose Adjustment, Changes in Renal Function
During Vistide Therapy removed.
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