-
PRECAUTIONS:
-
General: New first sentence - "Amicar Injection contains benzyl alcohol
as a preservative and is not recommended for use in newborns." (Change appears
in 1997 PDR)
- ADVERSE REACTIONS:
-
Labeling in 1997 PDR revised from the 1996 PDR
to read as follows -
"Amicar is generally well tolerated. The following adverse experiences
have been reported:
"General: Edema, fever, headache, hemorrhage, malaise.
"Hypersensitivity Reactions: Allergic and anaphylactoid reactions, anaphylaxis.
"Local Reactions: Injections site reactions, pain and necrosis.
"Cardiovascular: Bradycardia, hypotension, ischemia, thrombosis.
"Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting.
"Hematological Agranulocytosis, coagulation disorder,
leukopenia, thrombocytopenia.
"Musculoskeletal: CPK increased, muscle weakness, myalgia, myopathy (see WARNINGS),
myositis, rhabdomyolysis.
"Neurologic: Confusion, convulsions, delirium, dizziness, hallucinations, intracranial hypertension,
stroke, syncope.
"Respiratory: Dyspnea, nasal congestion, pulmonary embolism.
"Skin: Pruritus, rash.
"Special Senses: Deafness, glaucoma, tinnitus, vision decreased, watery eyes.
"Urogenital: BUN increased, ejaculatory disorder, renal failure."
Subsequent changes to the laabeling found in the 1997 PDR are as follows -
"fever", "hemorrhage", "deafness" and "glaucoma" deleted.
"ischemia" changed to peripheral ischemia.
Text added to Urogenital subsection- "There have been some reports of dry
ejaculation
during the period of Amicar treatment. These have been reported to date only
in hemophilia patients who received the drug after undergoing dental
surgical procedures. However, this symptom resolved in all patients within
24 to 48 hours of completion of therapy."
- OVERDOSAGE:
- First paragraph changed from "Signs, symptoms, laboratory findings,
and complications
have not been reported in association with acute overdosage of Amicar.
Concentrations of Amicar in biologic fluids related to toxicity
and/or death in humans are not known.
Further, the single dose of Amicar causing symptoms of overdosage or
considered to be life-threatening is unknown." to
"A few cases of acute overdosage with Amicar administered intravenously
have been reported.
The effects have ranged from no reaction to transient hypotension
to severe
acute renal failure leading to death. One patient with a history of
brain
tumor and seizures, experienced seizures after receiving an 8 gram
bolus injection
of Amicar. The single dose of Amicar causing syumptoms of overdosage or
considered
to be life-threatening is unknown. Patients have tolerated doses as
high as 100 grams
while acute renal failure has been reported following a dose of 12 grams."
(Change appears in 1997 PDR.)
New sentence added to end of section - "Pharmacokinetic studies have
shouwn that
total body clearance of Amicar is markedly decreased in patients with
severe renal failure." (Change appears in 1997 PDR.)
PRECAUTIONS:
-
Drug Interactions: Drugs metabolized by P450 2D6 (new subsection):
New subsection appears in the 1997 PDR.
- OVERDOSAGE:
-
Entire section revised as part of a tricyclic class labeling initiative.
New section appears in the 1997 PDR.
Return to quick reference
CEFZIL (cefprozil) Tablets
[April 23, 1997 – Bristol-Myers Squibb]
- PRECAUTIONS:
-
Pediatric Use: Subsection revised as follows (new text in italics)
– "The safety and effectiveness of cefprozil in the treatment of otitis
media have been established in the age groups 6 months to 12 years. Use of Cefzil for the
treatment of otitis media is supported by evidence from adequate and well-controlled studies
of cefprozil in pediatric patients. (See CLINICAL STUDIES section.)
"The safety and effectiveness of cefprozil in the treatment of
pharyngitis/tonsillitis or uncomplicated skin and skin structure infections have been
established in the age groups 2 to 12 years. Use of Cefzil for the treatment of these
infections is supported by evidence from adequate and well-controlled studies of cefprozil in
pediatric patients.
"The safety and effectiveness of cefprozil in the treatment of acute sinusitis
have been established in the age groups 6 months to 12 years. Use of Cefzil in these age
groups is supported by evidence from adequate and well-controlled studies of cefprozil in
adults.
"Safety and effectiveness in pediatric patients below the age of 6 months
have not been established for the treatment of otitis media or acute sinusitis, or below
the age of 2 years for the treatment of pharyngitis/tonsillitis or uncomplicated skin and
skin structure infections. However, accumulation of other cephalosporin antibiotics in
newborn infants (resulting from prolonged drug half-life in this age group)
has been reported."
- DOSAGE AND ADMINISTRATION:
-
In associated table, notation
"Not to exceed recommended adult doses" added with regard to dosage in children
(2 years - 12 years) and infants & children (6 months - 12 years).
Return to quick reference
CLIMARA (estradiol) Transdermal System
[April 11, 1997 - Berlex]
- INFORMATION ABOUT CLIMARA:
-
How and Where to Apply the Climara System: In second paragraph, fifth sentence revised (New text in italics.) - "Apply the adhesive side of the Climara system to a clean dry area of
the lower (replaces "the skin on the") abdomen or the upper
quadrant of the buttock."
Return to quick reference
CLOZARIL
(clozapine) Tablets
[April 25, 1997 - Novartis]
- CLINICAL PHARMACOLOGY:
-
Pharmacodynamics: Subsection revised - "…although Clozaril (clozapine) does
interfere with the binding of dopamine at D1, D2, D3,
and D5 receptors, and has a high affinity for the D4 receptor, it
does not induce catalepsy…" (Italicized words replacing "both D-1 and D-2 receptors").
- PRECAUTIONS:
-
Hepatitis (new subsection): "Caution is advised in patients using Clozaril
(clozapine) who have concurrent hepatic disease. Hepatitis has been reported in both
patients with normal and pre-existing liver function abnormalities. In patients who develop
nausea, vomiting, and/or anorexia during Clozaril (clozapine) treatment, liver function tests
should be performed immediately. If the elevation of these values is clinically relevant or if
symptoms of jaundice occur, treatment with Clozaril (clozapine) should be discontinued."
Use in Patients with Concomitant Illness: "…using Clozaril (clozapine) in patients
with ("hepatic," deleted) renal, or cardiac disease."
Drug Interactions: "Cimetidine and erythromycin may both increase plasma
levels of Clozaril (clozapine), potentially resulting in adverse effects."
(Italicized words are new.)
ADVERSE REACTIONS:
-
Gastrointestinal System: "hepatitis" and "jaundice" moved to the
new body system Hepatobiliary System (changed from "Hepatic System").
Return to quick reference
CUTIVATE (fluticasone propionate) Cream
[April 25, 1997 - Glaxo Wellcome]
-
CLINICAL PHARMACOLOGY:
-
New second paragraph - "Fluticasone propionate is lipophilic and has a strong affinity for the
glucocorticoid receptor. It has weak affinity for the progesterone receptor, and virtually no
affinity for the mineralocorticoid, estrogen, or androgen receptors. The therapeutic potency
of glucocorticoids is related to the half-life of the glucocorticoid-receptor complex.
Fluticasone propionate binding to the glucocorticoid receptor is rapid. The half-life of the
fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours."
Pharmacokinetics: First paragraph in section revised to read (New text in italics.) - "The extent of
percutaneous absorption of topical corticosteroids is determined by many factors, including
the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances
penetration. Topical corticosteroids can be absorbed from normal intact skin.
Inflammation and/or other disease processes in the skin increase percutaneous absorption.
Fluticasone propionate absorbed systemically is rapidly metabolized in the liver by
esterase-catalyzed hydrolysis to the 17-B-carboxylic acid, which has no significant
glucocorticoid or anti-inflammatory activity."
-
PRECAUTIONS:
-
General: Previous third paragraph "Fluticasone propionate cream, … with a dose of 30 g
per day." replaced with
" Fluticasone propionate cream, 0.05% caused depression of A.M. plasma cortisol levels in
one of six patients when used daily for 7 days in patients with psoriasis or eczema involving
at least 30% of the body surface. After 2 days of treatment, this patient developed a 60%
decrease from pretreatment values in the A.M. plasma cortisol level. There was some evidence
of corresponding decrease in 24- hour urinary free cortisol levels. The A.M. plasma cortisol
level remained slightly depressed for 48 hours before recovering by day 6 of treatment."
New first sentence in last paragraph - "Cutivate Cream should not be used in the treatment of
preexisting skin atrophy and should not be used where infection is present at the treatment
site."
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Prior first paragraph
"Long-term animal studies have not been performed to evaluate the carcinogenic potential of
fluticasone propionate." replaced by
"Two 18-month studies were performed in mice to evaluate the carcinogenic potential of
fluticasone propionate when given topically (as an 0.5% ointment) and orally. No evidence
of carcinogenicity was found in either study."
Pregnancy: Teratogenic Effects: Pregnancy Category C: Second sentence revised to
read (New text in italics.) - "Some (replaces "The more potent") corticosteroids have been shown to be
teratogenic after dermal application in laboratory animals."
-
ADVERSE REACTIONS:
-
New paragraph added to end of section - "In a clinical study which compared QD and BID
administration of Cutivate cream, the local adverse events which were considered to be drug
related were as follows." (See Table "Drug related adverse events - skin" in label/package
insert.)
-
DOSAGE AND ADMINISTRATION:
-
Section revised to read (New text in italics.) - "Eczema: Apply a thin film of
Cutivate Cream to the
affected skin areas once or twice daily. Rub in gently.
"
Other Corticosteroid-Responsive Dermatoses: Apply a thin film of Cutivate Cream
to the affected skin areas twice daily. Rub in gently.
"As with other corticosteroids, therapy should be discontinued when control is achieved.
If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary.
"Cutivate Cream should not be used with occlusive dressings."
-
CLINICAL STUDIES (new section):
-
Results of psoriasis and eczema studies provided. (see label/package insert.)
Return to quick reference
DESFERAL (deferoxamine mesylate) Injection
[April 2, 1997 - Novartis]
-
WARNINGS:
-
Text added to end of section - "High doses of Desferal and concomitant low ferritin levels
have also been associated with growth retardation. After reduction of Desferal dose, growth
velocity may partially resume to pretreatment rates.
"Acute respiratory distress syndrome has been described following treatment with excessively
high intravenous doses of Desferal in patients with acute iron intoxication or
thalassemia."
-
ADVERSE REACTIONS:
-
Digestive: Nausea and vomiting have been added.
Return to quick reference
E.E.S. (erythromycin ethylsuccinate)
Granules for Oral Suspension
and
ERY-PED (ethylsuccinate)
Chewable Tablets, Oral Suspension, and Drops
and
PCE (erythromycin particles) Dispertab Tablets
[April 14, 1997 - Abbott]
-
CONTRAINDICATIONS:
-
Paragraph added - "Erythromycin is contraindicated in patients taking terfenadine,
astemizole, or cisapride. (see PRECAUTIONS - Drug Interactions.)
-
WARNINGS:
-
Prior section "There have been reports of hepatic dysfunction with or without jaundice,
occurring in patients receiving oral erythromycin products" deleted and replaced with
"There have been reports of hepatic dysfunction, including increased liver enzymes, and
hepatocellular and/or cholestatic hepatitis, with or without jaundice, occurring in patients
receiving oral erythromycin products.
"There have been reports suggesting that erythromycin does not reach the fetus in adequate
concentration to prevent congenital syphilis. Infants born to women treated during pregnancy
with oral erythromycin for early syphilis should be treated with an appropriate penicillin
regimen.
"Pseudomembranous colitis has been reported with nearly all antibacterial agents,
including erythromycin, 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. (paragraph bolded.)
"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 a 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
discontinuation of the drug alone. In moderate to severe cases, consideration should be
given to management with fluids and electrolytes, protein supplementation, and treatment with
an antibacterial clinically effective against Clostridium difficile colitis.
"Rhabdomyolysis with or without renal impairment has been reported in seriously ill
patients receiving erythromycin concomitantly with lovastatin. Therefore, patients
receiving concomitant lovastatin and erythromycin should be carefully monitored for creatine
kinase (CK) and serum transaminase levels. (See package insert for lovastatin.)"
-
PRECAUTIONS:
-
General: New second paragraph added - "There have been reports that erythromycin may
aggravate the weakness of patients with myasthenia gravis."
Drug Interactions: Sentence added to paragraph on interactions with oral
anticoagulants - "Increased anticoagulation effects due to interactions of erythromycin with
various oral anticoagulants may be more pronounced in the elderly."
"Erythromycin has been reported to decrease the clearance of triazolam
and midazolam and thus, may increase the pharmacologic effect of these
benzodiazepines (replacing "of triazolam")" (New information in italics.)
The remainder of the subsection revised to read (New information in italics.) - "The use of erythromycin in patients
concurrently taking drugs metabolized by the cytochrome P450 system may be associated with
elevations in serum levels of these other drugs. There have been reports of interactions
of erythromycin with carbamazepine, cyclosporine, tacrolimus, hexobarbital, phenytoin,
alfentanil, cisapride, disopyramide, lovastatin, bromocriptine, valproate, terfenadine, and
astemizole. Serum concentrations of drugs metabolized by the cytochrome P450 system should
be monitored closely in patients concurrently receiving erythromycin.
"Erythromycin has been reported to significantly alter the metabolism of the nonsedating
antihistamines terfenadine and astemizole when taken concomitantly. Rare cases of serious
cardiovascular adverse events, including electrocardiographic QT/QTc interval
prolongation, cardiac arrest, torsades de pointes, and other ventricular arrhythmias have
been observed. (See CONTRAINDICATIONS.) In addition, deaths have been reported rarely with
concomitant administration of terfenadine and erythromycin.
"There have been postmarketing reports of drug interactions when erythromycin is coadministered with cisapride, resulting in QT prolongation, cardiac arrhythmias, ventricular tachycardia, ventricular fibrillation, and torsades de pointes, most likely due to inhibition of hepatic metabolism of cisapride by erythromycin. Fatalities have been reported. (See CONTRAINDICATIONS.)"
-
ADVERSE REACTIONS:
-
In third sentence - "Symptoms of hepatitis, hepatic dysfunction …" (new addition in italics.)
Paragraph on pseudomembranous colitis revised to read - "Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS.)"
Paragraph on transient central nervous system side effects deleted.
Paragraph on arrhythmias revised to read - "Rarely, erythromycin has been associated with the production of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, in individuals with prolonged QT intervals."
Paragraph on allergic reactions revised to read - "Allergic reactions ranging from urticaria to anaphylaxis have occurred. Skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely."
-
CLINICAL PHARMACOLOGY:
-
Pharmacokinetics: Deletion of the following text at end of
subsection - "In a trial in elderly
patients given 5 mg of alendronate (n=86) before breakfast, similar bone
mineral density changes were noted when compared to the pivotal triasl,
in which one fo the treatment arms was 5 mg alendronate administered
60 minutes before breakfast."
Sentence added as third to last in the subsection - "In studies of treatment and prevention
of osteoporosis, alendronate was effective when administered at least 30
minutes before breakfast.
Table "Summary of Pharmacokinetic Parameters in
the Normal Population" revised to include absolute bioavailability
information.
Pharmacodynamics: Osteoporosis in postmenopausal
women: Sentence added to end of second paragraph - "Alendronate is
not an estrogen and does not have the benefits and risks of estrogen replacement therapy."
Clinical Studies: Section revised to incorporate information supporting the new indication of "Prevention of osteoporosis in postmenopausal women", and the expansion of the current indications to include "Prevention of fractures in the treatment of postmenopausal osteoporosis". (See label/package insert.)
-
INDICATIONS AND USAGE:
-
Section revised to incorporate information on the new indications. (See label/package insert.)
-
WARNINGS:
-
First sentence in second paragraph revised to read (new text in italics) -
"Esophageal adverse experiences, such as esophagitis, esophageal ulcers
and esophageal erosions, occasionally with bleeding, have been
reported in patients receiving treatment with Fosamax."
Sentence added to end of third paragraph - "In patients who cannot comply
with dosing instructions due to mental disability, therapy with Fosamax
should be used under appropriate supervision."
-
PRECAUTIONS:
-
General: New first sentence added - "There have been rare (post-marketing) reports of gastric and duodenal ulcers, some severe and with complications, although no increased risk was observed in pre-marketing clinical trials."
Drug Interactions: Estrogen: Subsection revised to read - " The safety and effectiveness of the concomitant use of hormone replacement therapy and Fosamax in postmenopausal women has not been established."
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (new subsection): "Fosamax may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking Fosamax 5 or 10 mg compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with Fosamax."
Other: Entire subsection deleted.
Nursing Mothers: First sentence "Alendronate was secreted in the milk of rats after an IV dose." deleted.
Section now reads (New text in italics.) - "It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fosamax is administered to nursing women."
-
ADVERSE REACTIONS:
-
Clinical Studies: New paragraph added to end of subsection - "Fosamax has been evaluated for safety in approximately 3800 postmenopausal women in clinical studies."
Treatment of Osteoporosis (name changed from "Osteoporosis in Postmenopausal Women"): First sentence "Fosamax … patients." Deleted.
Text added to end of subsection - "In the Vertebral Fracture Study of the Fracture Intervention Trial, discontinuation of therapy due to any clinical adverse experience occurred in 7.6% of 1022 patients treated with Fosamax 5 mg/day for 2 years and 10mg/day for the third year and 9.4% of 1005 patients treated with placebo. Similarly, discontinuations due to upper gastrointestinal adverse experiences were comparable: Fosamax, 2.6%; placebo, 2.6%. The overall adverse experience profile was similar to that seen in other studies with Fosamax 5 or 10 mg/day."
Prevention of Osteoporosis (new subsection): "The safety of Fosamax in postmenopausal women 40-60 years of age has been evaluated in three double-blind, placebo-controlled studies involving over 1,400 patients randomized to receive Fosamax for either two or three years. In these studies the overall safety profiles of Fosamax 5 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 7.5% of 642 patients treated with Fosamax 5 mg/day and 5.7% of 648 patients treated with placebo. The adverse experiences reported by the investigators as possibly, probably or definitely drug related in > or = 1% of patients treated with either Fosamax 5 mg/day or placebo are presented in the following table.
|
Drug-Related ** Adverse Experiences
Reported in > or = 1% of Patients |
| |
Fosamax
5 mg/day
%
(n=642) |
Placebo
%
(n=648) |
|
Gastrointestinal |
|
|
|
Abdominal pain |
1.7 |
3.4 |
|
Acid regurgitation |
1.4 |
2.5 |
|
Diarrhea |
1.1 |
1.7 |
|
Dyspepsia |
1.9 |
1.7 |
|
Nausea |
1.4 |
1.4 |
**Considered possibly, probably, or definitely drug related as assessed by the investigators.
Post-Marketing Experience: Section revised as follows - "The following adverse reactions have been reported in post-marketing use:
"Body as a Whole (new subsection): hypersensitivity reactions including urticaria and rarely angioedema.
"Gastrointestinal (new subsection): 'esophagitis', 'esophageal erosions', 'esophageal ulcers', and oropharyngeal ulceration. Rarely, gastric or duodenal ulcers, some severe and with complications have been reported (see WARNINGS, PRECAUTIONS, General and Information for Patients, and DOSAGE AND ADMINISTRATION)." (Items in single quotes appeared in previous labeling.)
-
DOSAGE AND ADMINISTRATION::
-
Section revised to incorporate information on the new indications. (See label/package insert.)
- CLINICAL PHARMACOLOGY (new section):
-
Pharmacodynamics (new subsection): (New text in italics. Unitalicized text appeared in previous ACTIONS section.)
"The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures."
Pharmacokinetics (new subsection): "Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are reached within 1-4 hours after oral administration. Clonazepam is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. The derivative can be acetylated, hydroxylated, and glucuronidated. Cytochrome P-450, including CYP3A, may play an important role in clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range. There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans.
"Pharmacokinetics in Demographic Subpopulations and in Disease States: Controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Thus, caution should be exercised when administering clonazepam to these patients."
Clinical Trials (new subsection): Panic Disorder: See label/package insert.
-
INDICATIONS AND USAGE (changed from "INDICATIONS"):
-
Seizure Disorders (new subsection): Paragraph from previous INDICATION section moved here.
Panic Disorder (new subsection): See label/package insert.
-
WARNINGS:
-
Section revised as follows -
Interference with Cognitive and Motor Performance (new subsection): First paragraph from previous WARNINGS section moved here, with new notation to see Information for Patients under PRECAUTIONS.
Pregnancy Risks (changed from "Usage in Pregnancy"): "Data from several sources raise concerns about the use of Klonopin during pregnancy."
Animal Findings (new subsection): "In three studies in which Klonopin was administered orally to pregnant rabbits at doses of 0.2, 1.0, 5.0, or 10.0 mg/kg/day (low dose approximately 0.2 times the maximum recommended daily human dose of 20 mg/day for seizure disorder and equivalent to the maximum dose of 4 mg/day for panic disorder on a mg/m2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day, or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis)."
General Concerns and Considerations About Anticonvulsants (new subsection): Two paragraphs from previous "Usage in Pregnancy" section - Beginning with "Recent reports suggest an association between …" and ending with "…do not pose hazards to the developing embryo or fetus." moved here.
General Concerns About Benzodiazepines (new subsection): "An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several studies.
"There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period."
Advice Regarding the Use of Klonopin in Women of Childbearing Potential (new subsection): (New text in italics.)
"In general, the use of Klonopin in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus.
"The specific considerations addressed above regarding the use of anticonvulsants for epilepsy in women of childbearing potential should be weighed in treating or counseling these women.
"Because of experience with other members of the benzodiazepine class, Klonopin is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug."
Withdrawal Symptoms (new subsection): Previous sentence "Withdrawal…section)." about withdrawal symptoms moved here.
-
PRECAUTIONS:
-
General (new subsection): Previous PRECAUTIONS section, excluding "Information for Patients" subsection, split and put into five new subsections - Worsening of Seizures, Laboratory Testing During Long-Term Therapy, Risks of Abrupt Withdrawal, Caution in Renally Impaired Patients, and Hypersalivation.
Information for Patients: New first sentence added - "Physicians are advised to discuss the following issues with patients for whom they prescribe Klonopin:"
Doses Changes (new subsection): Previous "Information for Patients" paragraph moved here.
Interference With Cognitive and Motor Performance (new subsection): "Because benzodiazepines have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Klonopin therapy does not affect them adversely."
Pregnancy (new subsection): "Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with Klonopin (see WARNINGS.)"
Nursing (new subsection): "Patients should be advised not to breast-feed an infant if they are taking Klonopin."
Concomitant Medication (new subsection): "Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions."
Alcohol (new subsection): "Patients should be advised to avoid alcohol while taking Klonopin."
Drug Interactions (new subsection): Effect of Clonazepam on the Pharmacokinetics of Other Drugs (new subsection): "Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine, or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated."
Effect of Other Drugs on the Pharmacokinetics of Clonazepam (new subsection): "Ranitidine and propantheline, agents that decrease stomach acidity, do not greatly alter clonazepam pharmacokinetics. Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine, and phenobarbital induce clonazepam metabolism, causing an approximately 30% decrease in plasma clonazepam levels. Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents, should be used cautiously in patients receiving clonazepam."
Pharmacodynamic Interactions (new subsection): Previous "Drug Interactions" paragraph moved here.
Carcinogenesis, Mutagenesis, Impairment of Fertility (new subsection): "Carcinogenicity studies have not been conducted with clonazepam.
"The data currently available are not sufficient to determine the genotoxic potential of clonazepam.
"In a two generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day (low dose approximately 24 times and 5 times the maximum clinical dose of 4 mg/day for panic disorder and 20 mg/day for seizure disorder, respectively, on a mg/m2 basis), there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning."
Pregnancy: Teratogenic Effects - Pregnancy Category D (new subsection): "See WARNINGS."
Labor and Delivery (new subsection): "The effect of Klonopin on labor and delivery in humans has not been specifically studied, however, perinatal complications have been reported in children born to mothers who have been receiving benzodiazepines late in pregnancy, including findings suggestive of either excess benzodiazepine exposure or of withdrawal phenomena (see Pregnancy Risks, under WARNINGS)."
Nursing Mothers (new subsection): Statement about breast-feeding from previous WARNING section moved here.
Pediatric Use (new subsection): Previous "WARNINGS: Usage in Children" section moved here with "…being treated for seizure disorder (see INDICATIONS and DOSAGE AND ADMINISTRATIONS sections)." added to the end of the sentence.
"Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established." added to end of subsection.
-
ADVERSE REACTIONS:
-
New first sentence added - "The adverse experiences for Klonopin are provided separately for patients with seizure disorders and with panic disorders."
Seizure Disorders (new subsection): Previous ADVERSE REACTIONS section moved here.
Psychiatric: Sentence added - "The following paradoxical reactions have been observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams."
Panic Disorder (new subsection): "Adverse events during exposure to Klonopin were obtained by spontaneous report and recorded by clinical investigators using 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 smaller number of standardized event categories. In the tables and tabulations that follow, CIGY dictionary terminology has been used to classify reported adverse events, except in certain cases in which redundant terms were collapsed into more meaningful terms, as noted below.
"The stated frequencies of adverse events 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."
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials (new subsection): Adverse Events Associated with Discontinuation of Treatment (new subsection): "Overall, the incidence of discontinuation due to adverse events was 17% for Klonopin compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most common events (> or = 1%) associated with discontinuation and a dropout rate twice or greater for Klonopin than that of placebo included the following:
|
Adverse Event |
Klonopin (n=574) |
Placebo (n=294) |
|
Somnolence |
7% |
1% |
|
Depression |
4% |
1% |
|
Dizziness |
1% |
<1% |
|
Nervousness |
1% |
0% |
|
Ataxia |
1% |
0% |
|
Intellectual Ability Reduced |
1% |
0% |
Adverse Events Occurring at an Incidence of 1% or More Among Klonopin-Treated Patients (new subsection): "Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of panic disorder from a pool of two 6- to 9-week trials. Events reported in 1% or more of patients treated with Klonopin (doses ranging from 0.5 to 4mg/day) and for which the incidence was greater than that in placebo-treated patients are included.
"The prescriber should be aware that the figures in Table 1 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 in the population studied." (See Table 1 in the label/package insert.)
Commonly Observed Adverse Events (new subsection): (See Table 2 in the label/package insert.)
Treatment-Emergent Depressive Symptoms (new subsection): "In the pool of two short-term placebo-controlled trials, adverse events classified under the preferred term 'depression' were reported in 7% of Klonopin-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these same trials, adverse events classified under the preferred term 'depression' were reported as leading to discontinuation in 4% of Klonopin-treated patients compared to 1% of placebo-treated patients. While these findings are noteworthy, Hamilton Depression Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D scores in the clonazepam group than the placebo group, suggesting that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression."
Other Adverse Events Observed During the Premarketing Evaluation of Klonopin in Panic Disorder (new subsection): "Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with Klonopin at multiple doses during clinical trials. All reported events are included except those already listed in Table 1 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening. It is important to emphasize that, although the events occurred during treatment with Klonopin, they were not necessarily caused by it.
"Events are further categorized by body system and listed in order of decreasing frequency. These adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1000 patients." (See label/package insert.)
-
DRUG ABUSE AND DEPENDENCE:
-
Controlled Substance Class (new subsection): "Clonazepam is a Schedule IV controlled substance."
Physical and Psychological Dependence (new subsection): Previous DRUG ABUSE AND DEPENDENCE section moved here.
Paragraph added to end of subsection - "Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see Clinical Trials, under CLINICAL PHARMACOLOGY), patients were gradually withdrawn during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance period was associated with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon. However, there are not sufficient data from adequate and well controlled long-term clonazepam studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use."
-
OVERDOSAGE:
-
Human Experience (new subsection): First sentence from previous OVERDOSAGE section moved here with clonazepam replacing "Klonopin".
Overdose Management (new subsection): Text from previous OVERDOSAGE section "Treatment …value." except for statement "Methylphenidate or caffeine and sodium benzoate may be given to combat CNS depression." moved here followed by
"Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. (Sentence bolded.) The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, should be consulted prior to use.
"Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures. (Sentence bolded.)
"Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly."
-
DOSAGE AND ADMINISTRATION:
-
Seizure Disorders (new subsection): Previous DOSAGE AND ADMINISTRATION section moved here.
Panic Disorder (new subsection): (See label/package insert.)
Liver enzymes: New second paragraph added - "In the largest long-term placebo-controlled clinical trial with pravastatin (Pravastatin Primary Prevention Study; See CLINICAL PHARMACOLOGY), the overall incidence of AST and/or ALT elevations to greater than three times the upper limit of normal was 1.05% in the pravastatin group as compared to 0.75% in the placebo group. One (0.03%) pravastatin-treated patient and 2 (0.06%) placebo-treated patients were discontinued because of transaminase elevations. Of the patients with normal liver function at week 12, three of 2875 treated with pravastatin (0.10%) and one of the 2919 placebo patients (0.03%) had elevations of AST greater than three times the upper limit of normal on two consecutive measurements and/or discontinued due to elevations in transaminase levels during the 4.8 years (median treatment) of the study."
In next paragraph, first sentence "It is recommended that liver function tests be performed before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or elevation in dose, and periodically thereafter (e.g., semiannually)." Replaced with
"It is recommended that liver function tests be performed prior to and at 12 weeks following initiation of therapy or the elevation of dose."
In next sentence - "Patients who develop increased transaminase levels or signs and symptoms of liver disease should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal." (Italicized words are new addition.)
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PRELAY (troglitazone) Tablets
[April 8, 1997 - Sankyo U.S.A.]
and
REZULIN (troglitazone) Tablets
[April 4, 1997 - Parke Davis]
- CLINICAL PHARMACOLOGY:
-
Pharmacokinetics and Drug Metabolism: Metabolism: In second paragraph, the last sentence "Incubation of Metabolite 3 with human liver microsomes suggests that it is not subject to further metabolism." deleted and replaced with
"Studies in human microsomes suggest that Metabolite 3 is not subject to further metabolism by the major P450 isozymes. Troglitazone did not inhibit any of the major P450 enzymes at clinically relevant concentrations. The inhibitory characteristics of Metabolite 3 have not been investigated directly."
The third paragraph beginning "The inhibitory profile of …" deleted and replaced with
"The results of human in vivo drug interaction trials suggest that troglitazone induces cytochrome P450 3A4 at clinically relevant doses. (See Drug Interactions.)"
-
PRECAUTIONS:
-
Information for Patients: Text added to end of subsection - "Use of Prelay [Rezulin] can cause resumption of ovulation in women taking oral contraceptives and in patients with polycystic ovary disease. Therefore, a higher dose of an oral contraceptive or an alternative method of contraception should be considered."
"Prelay [Rezulin] may affect other medications used in diabetic patients. Patients started on Prelay [Rezulin] should ask their physician to review their other medications to make sure that they are not affected by Prelay [Rezulin]."
Drug Interactions: Oral contraceptives (new subsection): "Administration of Prelay [Rezulin] with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30%, which could result in loss of contraception. Therefore, a higher dose of oral contraceptive or an alternative method of contraception should be considered."
Terfenadine (new subsection): "Coadministration of Prelay [Rezulin] with terfenadine decreases the plasma concentration of both terfenadine and its active metabolite by 50-70% and may result in decreased efficacy of terfenadine."
Cholestryamine: The word "approximately" deleted before 70%.
Glyburide: Subsection name changed from "Sulfonylureas".
Digoxin (new subsection): "Coadministration of Prelay [Rezulin] with digoxin does not alter the steady-state pharmacokinetics of digoxin."
Text added to end of Drug Interactions section - "The above interactions with terfenadine and oral contraceptives suggest that troglitazone may induce drug metabolism by CYP3A4. Studies have not been performed with other drugs metabolized by this enzyme such as: astemizole, calcium channel blockers, cisapride, corticosteroids, cyclosporine, HMG-CoA reductase inhibitors, tacrolimus, triazolam, and trimetrexate. The possibility of altered safety and efficacy should be considered when Prelay [Rezulin] is used concomitantly with these drugs.
"Patients stable on one or more of these agents when Prelay [Rezulin] is started should be closely monitored and their therapy adjusted as necessary."
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PRILOSEC (omeprazole) Delayed-Release Capsules
[April 15, 1997 - Astra Merck]
-
CONTRAINDICATIONS:
-
Clarithromycin: Section revised as follows (new text in italics) - "Clarithromycin is contraindicated in patients with a known hypersensitivity to any macrolide antibiotic. ("and in patients receiving terfenadine therapy who have preexisting cardiac abnormalities or electrolyte disturbances" - deleted) Concomitant administration of clarithromycin with cisapride, pimozide, or terfenadine is contraindicated. There have been postmarketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with cisapride, pimozide, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of hepatic metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported. (Please refer to full prescribing information for clarithromycin before prescribing)."
Drug Interactions: Combination Therapy with Clarithromycin: Text added to the end of the subsection - "Concomitant administration of clarithromycin with cisapride, pimozide, or terfenadine is contraindicated."
"There have been reports of an interaction between erythromycin and astemizole resulting in QT prolongation and torsades de pointes. Concomitant administration of erythromycin and astemizole is contraindicated. Because clarithromycin is also metabolized by cytochrome P450, concomitant administration of clarithromycin with astemizole is not recommended. (See also CONTRAINDICATIONS, Clarithromycin, above. Please refer to full prescribing information for clarithromycin before prescribing.)"
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PROCARDIA (nifedipine) Capsules
and
PROCARDIA XL (nifedipine) Extended Release Tablets
[April 21, 1997 - Pfizer]
- PRECAUTIONS:
-
Pediatric Use (new subsection): "Safety and effectiveness in pediatric patients have not been established ."
"Use in pediatric population is not recommended." (Added to Procardia Capsules only.)
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PROGRAF (tacrolimus) Capsules and Injection
[April 22 - Fujisawa]
Labeling extensively revised. Contact company for a copy of label/package insert.
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PROVENTIL-HFA (albuterol sulfate) Inhalation Aerosol
[April 21, 1997 - 3M]
-
PRECAUTIONS:
-
Information for Patients:: Text added after "Patients should be given the following information:"
"Keeping the plastic mouthpiece clean is very important to prevent medication build-up and blockage. The mouthpiece should be washed, shaken to remove excess water and air dried thoroughly at least once a week. Inhaler may cease to deliver medication if not properly cleaned. (In caps.)
"The mouthpiece should be cleaned (with the canister removed) by running warm water through the top and bottom for 30 seconds at least once a week. The mouthpiece must be shaken to remove excess water, then air dried thoroughly (such as overnight). Blockage from medication build-up or improper medication delivery may result from failure to thoroughly air dry the mouthpiece.
"If the mouthpiece should become blocked (little or no medication coming out of the mouthpiece), the blockage may be removed by washing as described above.
"If it is necessary to use the inhaler before it is completely dry, shake off excess water, replace canister, test spray twice away from face and take the prescribed dose. After such use, the mouthpiece should be rewashed and allowed to air dry thoroughly."
-
DOSAGE AND ADMINISTRATION:
-
Section revised to include the cleaning instructions.
-
PATIENT'S INSTRUCTION FOR USE:
-
Section revised to include illustrations and instructions for cleaning.
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TRENTAL (pentoxifylline) Tablets
[April 29, 1997 - Hoechst Marion Roussel]
- CLINICAL PHARMACOLOGY:
-
Pharmacokinetics and Metabolism: Text added after the first sentence in the last paragraph - "Coadministration of Trental tablets with meals resulted in an increase in mean Cmax and AUC by about 28% and 13% for pentoxifylline, respectively. Cmax for metabolite M1 also increased by about 20%."
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VALTREX (valacyclovir HCl) Caplets
[April 30, 1997 - Glaxo Wellcome]
-
ADVERSE REACTIONS:
-
Observed During Clinical Practice (new subsection): "Based on clinical practice experience in patients treated with oral Valtrex, adverse events have been spontaneously reported from domestic and foreign sources during worldwide postmarketing surveillance. Data are insufficient to support an estimate of their incidence or to establish causation. These events may also occur as part of the underlying disease process. The following adverse events have been reported:
"General: Facial edema.
"Nervous: Confusion, hallucinations (auditory and visual).
"Hemic: Thrombocytopenia.
"Skin: Erythema multiforme, rash, urticaria."
-
OVERDOSAGE:
-
First sentence "There have been no reports of overdosage from the administration of Valtrex." deleted.
New first paragraph added - "Certain events have been reported in patients with acute or chronic renal impairment in whom recommended dose reduction was not utilized. The following adverse events have been reported in these patients: aggressive behavior, confusion, dizziness, dreams, formication, hallucinations, hypertension, mania, and tachycardia. Dose adjustment is recommended in this patient population."
"However, it is known that" deleted from before "Precipitation of acyclovir…"
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ZOFRAN (ondansetron HCl) Tablets, Solution, and Injection
[April 2 & 15, 1997 - Glaxo Wellcome]
-
WARNINGS (new section):
-
"Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists."
-
PRECAUTIONS:
-
Text added to beginning of section (Tablets and Solution only; text already in Injection labeling) - "Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension."
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