Summary Of Safety-Related Drug Labeling
Changes Approved By FDA Center for Drug
Evaluation and Research (CDER)
February 2002

(Posted: 4/01/2002)

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ACCUTANE (isotretinoin) Capsules

[February 15, 2002: Hoffman-La Roche]

[Other safety related information: http://www.fda.gov/medwatch/safety/2001/safety01.htm#accuta]

The new labeling references the brochure in the WARNINGS section of the package insert, with the statement: Prescribers should read the brochure "Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Accutane (isotretinoin)".

[February 12, 2002: Eisai Inc]

Pediatric Use: Safety and efficacy in pediatric patients below the age of 3 12 years have not been established.

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AGENERASE (amprenavir) Capsules & Oral Solution

Labeling provides for the inclusion of pharmacokinetic, safety, and dosing information on the co-administration of AGENERASE Capsules/AGENERASE Oral Solution with NORVIR (ritonavir) in the AGENERASE Capsules and AGENERASE Oral Solution package inserts.

Also, labeling for AGENERASE CAPSULES and AGENERASE Oral Solution provides for the inclusion of wording outlining the potential for redistribution/accumulation of body fat concurrent with the use of nucleoside analogues in the PRECAUTIONS and Patient Information tear off of the AGENERASE CAPSULES and AGENERASE Oral Solution package insert and patient package insert.

AKINETON (biperiden) Tablet

[February 4, 2002: Abbott]

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[Labeling not found in 2001 PDR]

Carcinogenesis: Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet at doses of 0.6, 5.5, and 56 mg/kg/day for 27 months in rats. These doses were approximately equivalent to 5.7, 52 and 534 times the recommended human dose (1.2 mg) on a mg/m 2 body surface area basis. Statistically significant dose-related increases in testicular interstitial (Leydig’s) cell tumors occurred, according to the trend test adjusted for survival. Pair-wise comparison of the high dose against control failed to show statistical significance. In the mouse study, buprenorphine was administered in the diet at doses of 8, 50, and 100 mg/kg/day for 86 weeks. The high dose was approximately equivalent to 477 times the recommended human dose (1.2 mg) on a mg/m ² basis. Buprenorphine was not carcinogenic in mice.

Mutagenesis: Buprenorphine was studied in a series of tests. Results were negative in Chinese hamster bone marrow and spematogonia cells, and negative in mouse lymphoma L5178Y assay. Results were equivocal in the Ames test: negative in studies in two laboratories, but positive in frame shift mutation at high dose (5 mg/plate) in a third study.

Impairment of Fertility: Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80 mg/kg (approximately 763 times the recommended human daily dose of 1.2 mg on a mg/m ² basis ) or up to 5 mg/kg I.M. or S.C. (approximately 48 times the recommended human daily dose of 1.2 mg on a mg/m ² basis).

Teratogenic effects: Buprenorphine was not teratogenic in rats or rabbits after I.M. or S.C. doses up to 5 mg/kg/day (approximately 48 and 95 times the recommended human daily dose of 1.2 mg on a mg/m ² basis), I.V. doses up to 0.8 mg/kg/day (approximately 8 and 15 times the recommended human daily dose of 1.2 mg on a mg/m 2 basis), or oral doses up to 160 mg/kg/day in rats (approximately 1525 times the recommended human daily dose of 1.2 mg on a mg/m 2 basis) and 25 mg/kg/day in rabbits (approximately 475 times the recommended human daily dose of 1.2 mg on a mg/m ² basis). Significant increases in skeletal abnormalities (e.g. extra thoracic vertebra or thoracolumbar ribs) were noted in rats after S.C. administration of 1 mg/kg/day and up (approximately 9.5 times the recommended human daily dose of 1.2 mg on a mg/m ² basis) and in rabbits after I.M. administration of 5 mg/kg/day (approximately 95 times the recommended human daily dose of 1.2 mg on a mg/m ² basis), but these increases were not statistically significant. Increases in skeletal abnormalities after oral administration were not observed in rats, and increases in rabbits (1-25 mg.kg/day) were not statistically significant.

Nursing Mothers: An apparent lack of milk production during general reproduction studies with buprenorphine in rats caused decreased viability and lactation indices. Use of high doses of sublingual buprenorphine in pregnant women showed that buprenorphine passes into the mother’s milk. Breast-feeding is therefore not advised in nursing mothers treated with Buprenex.

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CENESTIN (synthetic conjugated estrogens, A) Tablets

b. Breast cancer

Hematologic: rare blood dyscrasia (e.g., Cases of thrombocytopenia and/or leukopenia have been reported. A causal relationship has not been clearly established).

administration/rapid intravenous infusion may be associated with hypotension, tachycardia and gastrointestinal disturbances; acute but transient loss of vision, aphasia, agitation, headache, nausea, pallor, CNS depression including coma, bradycardia and acute renal failure have been reported.

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If hypotension occurs, patients should be placed in the Trendelburg position and be given an infusion of normal saline using a separate i.v. line. During and after Ethyol infusion, care should be taken to monitor the blood pressure of patients whose antihypertensive medication has been interrupted since hypertension may be exacerbated by discontinuation of antihypertensive medication and other causes such as IV hydration. Guidelines for interrupting...

Allergic reactions have been reported with the use of Ethyol characterized by one or more of the following manifestations have been observed during or after Ethyol administration: the majority of cases presents with the following symptoms: hypotension, fever, chills/rigors, dyspnea, hypoxia, chest tightness, skin rashes, urticaria and laryngeal edema. Other Skin reactions including erythema multiforme, and in rare cases, Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported occurred. Rare anaphylactoid reactions and cardiac arrest have been reported. There have been rare reports of anaphylactoid reactions including hypoxia, laryngeal edema, chest tightness, and possible arrest.

There have been rare reports of seizures in patients receiving Ethyol. Seizures and syncope have been reported rarely. (See WARNINGS and PRECAUTIONS).

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After intravenous administration of ¹⁴ C-etoposide (100-124 mg/m ² ), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide: fecal recovery of radioactivity was 44% of the dose at 120 hours.

6th paragraph deleted - Biliary excretion appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism accounts for most of the nonrenal clearance of etoposide. The major urinary metabolite of etoposide in adults and children is the hydroxyacid [4’-demethylepipodophyllic acid-9-(4,6-0-(R)-ethylidene- b -D-glucopyranoside)], formed by opening of the lactone ring. It is also present in human plasma, presumably as the transisomer. Glucuronide and/or sulfate conjugates of etoposide are excretedin human urine and represent 5 to 22% of the dose. In addition, 0-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.

CONTRAINDICATIONS

WARNINGS

Added to following subsection:

PATIENT SUMMARY OF INFORMATION ABOUT

GEODON (ziprasidone HCl)

• You are currently taking medications that should not be taken in combination with ziprasidone, for example, dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, or tacrolimus.

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Labeling provides for the use of Gleevec (imatinib mesylate) for the treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). (See CLINICAL STUDIES : Gastrointestinal Stromal Tumors) The effectiveness of Gleevec is based on overall hematologic and cytogenetic response rates in CML and objective response rates in GIST (see CLINICAL STUDIES). There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. Contact the company for a copy of the labeling/package insert.

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WARNINGS/Diabetes and Hypoglycemia
Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in
patients on propranolol.

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INNOHEP (tinzaparin sodium) Injection

Bleeding can occur at any site in any tissue or organ of the body during therapy with INNOHEP.

Because of increased risk of bleeding, INNOHEP should be used with caution in patients receiving oral anticoagulants, platelet inhibitors (e.g., salicylates, dipyridamole, sulfinpyrazone, dextran, NSAIDs including ketorolac tromethamine, ticlopidine, and clopidogrel), and thrombolytics. If coadministration is essential, close clinical and laboratory monitoring of these patients is advised (see PRECAUTIONS, Laboratory Tests).

There have been four reports of fetal death/miscarriage in pregnant women receiving INNOHEP who had high risk pregnancies and/or a prior history of spontaneous abortion.

Bleeding:

Fatal or nonfatal hemorrhage from any tissue or organ can occur. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as, but are not limited to, paralysis; dizziness; shortness of breath, difficult breathing or swallowing; swelling; weakness; hypoptension, shock, or coma. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis (see WARNINGS, Hemorrhage).

Bleeding-related - Hematoma

Cutaneous reactions - Stevens-Johnson syndrome

Allergic reactions - Allergic purpura

Fetal/neonatal- Cutis aplasia of the scalp

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3.Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug Interactions.)

In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%).

As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m ² /week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range 0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m ² ), or for JRA (3.75 to 26.2 mg/m ² ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively.

Third paragraph, first sentence, after "advanced mycosis fungoides", "(cutaneous T cell lymphoma)" is added.

Hematologic: aplastic anemia was added.

Neurologic: transient blindness was added.

Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, leukopenia and/or thrombocytopenia. Hypogammaglobulinemia has been reported rarely.

Transient blindness, speech impairment including dysarthria were added.

Sepsis added.

Musculoskeletal System: stress fracture added.

Respiratory fibrosis, respiratory failure added.

Skin ulceration added.

Virtually all of these patients were on concomitant non-steroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. (See PRECAUTIONS.)

Mycosis Fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical remissions in one half of the cases responses in up to 50% of patients treated. Dosage in early stages is usually 2.5 to 10 mg daily by mouth for weeks or months 5 to 50 mg once weekly. Dose levels of drug and adjustment of dose regimen by reduction or cessation of drug are is guided by patient response and hematologic monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg 2 times weekly. administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered

Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules

Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m 2 given once weekly.

For either adult RA of polyarticular-course JRA dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m ² /wk in children, there are too few published data to assess how doses over 20 mg/m ² /wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m ² /wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

Clinical Studies in Adolescent Patients

Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia

In a double-blind, placebo-controlled study, 132 boys 10-17 years of age (mean age 12.7 yrs) with heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo (n=65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The mean baseline LDL-C value was 253.1 mg/dL (range: 171-379 mg/dL) in the MEVACOR group compared to 248.2 mg/dL (range: 158.5-413.5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.

MEVACOR significantly decreased plasma levels of total-C, LDL-C and apolipoprotein B (see Table IV).

*data presented as median percent changes

The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in the MEVACOR group compared to 244.8 mg/dL (range: 135-404 mg/dL) in the placebo group.

Efficacy of Lovastatin in Post-menarchal Girls with Heterozygous Familial Hypercholesterolemia

In a double-blind, placebo-controlled study, 54 girls 10-17 years of age who were at least 1 year post-menarche with heFH were randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks. Inclusion in the study required a baseline LDL-C level of 160-400 mg/dL and a parental history of familial hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3-363.7 mg/dL) in the MEVACOR group compared to 198.8 mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter.

MEVACOR significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see Table V).

The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in the MEVACOR group compared to 203.5 mg/dL (range: 135-304 mg/dL) in the placebo group.

The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

INDICATIONS AND USAGE

Hypercholesterolemia

Adolescent Patients with Heterozygous Familial Hypercholesterolemia

MEVACOR is indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if after an adequate trial of diet therapy the following findings are present:

1. LDL-C remains >189 mg/dL or

2. LDL-C remains >160 mg/dL and:

· there is a positive family history of premature cardiovascular disease or

The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:

Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.

PRECAUTIONS

Pediatric Use

Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In these limited controlled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than 10 years of age.

ADVERSE REACTIONS

Adolescent Patients (ages 10-17 years),

In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the groups treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the groups treated with placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS, Pediatric Use).

Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia

The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP Pediatric Panel Guidelines †† , CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of MEVACOR. A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

†† National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in

Added as the last sentence:

Added as the last three sentences:

The following information added in parentheses after "aspirin triad":

(bronchial asthma, rhinitis, aspirin intolerance).

strengthen the language in

Fatal asthmatic and anaphylactoid reactions have been reported in such patients.

The following added as the initial phrase in this subsection:

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NARCAN (naloxone HCl) Injection

[February 11, 2002: Endo]

[To view the complete label, go to the following link:
http://www.fda.gov/cder/foi/label/2002/16636slr054lbl.pdf]

CLINICAL PHARMACOLOGY

Complete or Partial Reversal of Opioid Depression

NARCAN is an essentially pure opioid antagonist, i.e., it does not possess the "agonistic"or morphine-like properties characteristic of other opioid antagonists. NARCAN does not produce respiratory depression, psychotomimetic effects or pupillary constriction. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.

NARCAN has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids NARCAN will produce withdrawal symptoms. However, in the presence of opioid dependence, withdrawal symptoms will appear within minutes of NARCAN administration and will subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of NARCAN and to the degree and type of dependence.

While the mechanism of action of NARCAN is not fully understood, in vitro evidence suggests that NARCAN antagonizes opioid effects by competing for the same receptor sites the µ, κ and σ opiate receptor sites in the CNS, with the greatest affinity for the µ receptor.

Adjunctive Use in Septic Shock

Although the mechanism of action is not completely understood, NARCAN appears to block endorphine-medicated hypotension in septic shock patients.

NARCAN has been shown in some cases of septic shock to produce a rise in blood pressure that may last up to several hours; however, this pressor response has not been demonstrated to improve patient survival. In some studies, treatment with NARCAN in the setting of septic shock has been associated with adverse effects, including agitation, nausea and vomiting, pulmonary edema, hypotension, cardiac arrhythmias, and seizures. The decision to use NARCAN in septic shock should be exercised with caution, particularly in patients who may have underlying pain or have previously received opioid therapy and may have developed opioid tolerance.

Patients who have responded to NARCAN received the drug early in the course of treatment of septic shock. Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established. Published reports demonstrating a pressor effect have evaluated single bolus injections of 0.4 mg over three (3) to five (5) minutes, which have been repeated for 3-5 doses depending on the response. Bolus infusion doses ranging from 0.03 mg/kg to 0.2 mg/kg over five (5) minutes have also been reported. If a response was elicited, treatment was continued by intravenous infusion of concentrations of 0.03 mg/kg/hour to 0.3 mg/kg/hour for 1-24 hours or more depending upon the clinical response.

PHARMACOKINETICS

Distribution

Following parenteral administration NARCAN is rapidly distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk.

Metabolism and Elimination

NARCAN is metabolized in the liver, primarily by glucuronide conjugation with naloxone-3-glucoronide as the major metabolite. In one study the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study the mean plasma half-life was observed to be 3.1 ± 0.5 hours. After an oral or intravenous dose, about 25-40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.

INDICATIONS AND USAGE

NARCAN is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids, including propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol and cyclazocine. NARCAN is also indicated for diagnosis of suspected or known acute opioid overdosage.

WARNINGS

Drug Dependence, Repeat Administration Respiratory and Depression due to Other Drugs added as new headings.

Respiratory Depression due to Other Drugs

NARCAN is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of buprenorphine-induced respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.

PRECAUTIONS

Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of NARCAN in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION: Usage in Adults-Postoperative Opioid Depression).

Drug Interactions

Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antag-onism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals to assess the carcinogenic potential of NARCAN have not been conducted. NARCAN was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses as high as 50 times the usual human dose (10 mg/day) demonstrated no impairment of fertility. Reproduction studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10mg/day (when based on surface area or mg/m ² ), demonstrated no embryotoxic or teratogenic effects due to NARCAN.

Use in Pregnancy

Teratogenic Effects Pregnancy Category B C: : Reproduction studies performed in mice and rats at doses as high as 50 times the usual human dose (10 mg/day), revealed no evidence of impaired fertility or harm to the fetus due to NARCAN.

Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m ² ), demonstrated no embryotoxic or teratogenic effects due to NARCAN. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, NARCAN should be used during pregnancy only if clearly needed.

Non-teratogenic Effects: Risk-benefit must be considered before NARCAN is

administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur.

Use in Labor and Delivery

It is not known if NARCAN (naloxone hydrochloride injection, USP) affects the duration of labor and/or delivery. However, published reports indicated that administration of naloxone during labor did not adversely affect maternal or neonatal status.

Pediatric Use

NARCAN may be administered intravenously, intramuscularly or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to NARCAN, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.

When NARCAN is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer NARCAN directly to the neonate if needed after delivery. NARCAN has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia which is not related to opioid use.

Usage in Pediatric Patients and Neonates for Septic Shock: The safety and effectiveness of NARCAN in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures.

Geriatric Use

Clinical studies of NARCAN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Liver Disease

The safety and effectiveness of NARCAN in patients with liver disease have not been established in well-controlled clinical trials. In one small study in patients with liver cirrhosis, plasma naloxone concentrations were approximately six times higher than in patients without liver disease. NARCAN was well tolerated and no adverse events were reported. Caution should be exercised when NARCAN is administered to patients with liver disease.

ADVERSE REACTIONS

Postoperative

The following adverse events have been associated with the use of NARCAN in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of NARCAN in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults-Postoperative Opioid Depression).

Opioid Depression

Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death (see PRECAUTIONS).

Opioid Dependence

Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome which may include, but not limited to, the following signs and symptoms: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In the neonate, opioid withdrawal may also include: convulsions; excessive crying; hyperactive reflexes. (see WARNINGS).

Agitation and paresthesias have been infrequently reported with the use of NARCAN.

Adverse events associated with the postoperative use of NARCAN are listed by organ system and in decreasing order of frequency as follows:

Cardiac Disorders: pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these events.

Gastrointestinal Disorders: vomiting, nausea

Nervous System Disorders: convulsions, paraesthesia, grand mal convulsion

Psychiatric Disorders: agitation, hallucination, tremulousness

Respiratory, Thoracic and Mediastinal Disorders: dyspnea, respiratory depression, hypoxia

Skin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweating

Vascular Disorders: hypertension, hypotension, hot flushes or flushing.

See also PRECAUTIONS and DOSAGE AND ADMINISTRATION;

Usage in Adults; Postoperative Opioid Depression.

OVERDOSAGE

Adult Patients

In one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity.

In another study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m ² /min) of NARCAN followed immediately by 2 mg/kg/hr for 24 hours. Twenty-three patients experienced adverse events associated with naloxone use, and naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3).

At doses of 2 mg/kg in normal subjects, cognitive impairment and behavioral symptoms, including irritability, anxiety, tension, suspiciousness, sadness, difficulty concentrating, and lack of appetite have been reported. In addition, somatic symptoms, including dizziness, heaviness, sweating, nausea, and stomachaches were also reported. Although complete information is not available, behavioral symptoms were reported to often persist for 2-3 days.

Pediatric Patients

Previous labeling:

Up to 11 doses of 0.2 mg of naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2-1/2 year-old child who inadvertently received a dose of 20 mg of naloxone and a 4-1/2 year-old child who received 11 doses during a 12-hour period, both of whom had no adverse sequelae.

Revised labeling:

Up to 11 doses of 0.2 mg of naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2-1/2 year-old child who inadvertently received a dose of 20 mg of naloxone for treatment of respiratory depression following overdose with diphenoxylate hydrochloride with atropine sulfate. The child responded well and recovered without adverse sequelae There is also a report of a 4-1/2 year-old child who received 11 doses during a 12-hour period, with no adverse sequelae.

Animal Data

The intravenous single-dose LD50 (95% confidence limits) in rats and mice is 150 (135-165) mg/kg and 109 (97-121) mg/kg, respectively. In newborn rats, the subcutaneous single-dose LD50 (95% confidence limits) is 260 (228-296) mg/kg. Subcutaneous injection in rats at 100 mg/kg/day for three weeks produced only transiently increased salivation and partial ptosis; no drug-related effects were seen at 10 mg/kg/day for three weeks.

Some chemical impurities in naloxone, i.e., noroxymorphone and bisnaloxone, have been shown to produce emesis in dogs when administered alone at I.V. at doses equivalent to impurity levels present in naloxone at 60 times 50x the recommended maximum naloxone dose the usual human dose (10 mg/day) or less.

DOSAGE AND ADMINISTRATION

NARCAN Challenge Test: Used for the diagnosis of suspected opioid tolerance or acute opioid overdosage.

The NARCAN challenge test should not be performed in a patient showing clinical signs or symptoms of opioid withdrawal, or in a patient whose urine contains opioids. The NARCAN challenge test may be administered by either the intravenous or subcutaneous routes.

Intravenous:

Inject 0.2 mg NARCAN. Observe for 30 seconds for signs or symptoms of withdrawal. If no evidence of withdrawal, inject 0.6 mg NARCAN. Observe for an additional 20 minutes.

Subcutaneous:

Administer 0.8 mg NARCAN. Observe for 20 minutes for signs or symptoms of withdrawal. Note: Individual patients, especially those with opioid dependence, may respond to lower doses of NARCAN. In some cases, 0.1 mg IV NARCAN has produced a diagnostic response.

Interpretation of the Challenge: Monitor vital signs and observe the patient for signs and symptoms of opioid withdrawal. These may include, but are limited to: nausea, vomiting, dysphoria, yawning, sweating, tearing, rhinorrhea, stuffy nose, craving for opioid,poor appetite, abdominal cramps, sense of fear, skin erythema, disrupted sleep patterns, fidgeting, uneasiness, poor ability to focus, mental lapses, muscles aches or cramps, pupillary dilation, piloerection, fever, changes in blood pressure, pulse or temperature, anxiety, depression, irritability, back aches, bone ot joint pains, tremors, sensations of skin crawling or fasciculations. If signs or symptoms of withdrawal appear, the test is positive and no addiitonal NARCAN should be administered.

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The cumulative risk of developing treatment-related AML, in 1774 patients with breast cancer who received NOVANTRONE concomitantly with other cytotoxic agents and radiotherapy, was estimated as 1.1% and 1.6% at 5 and 10 years, respectively (see WARNINGS section).

Secondary leukemia has been reported in cancer patients treated with NOVANTRONE concomitantly with other cytotoxic agents and/or radiotherapy. The largest published report 5 involved 1774 patients with breast cancer treated with NOVANTRONE in combination with methotrexate with or without mitomycin. In this study, the cumulative probability of developing secondary leukemia was estimated to be 1.1% and 1.5% at 5 and 10 years, respectively. The second largest report 6 involved 449 patients with breast cancer treated with NOVANTRONE, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years. There are insufficient long-term follow-up data to estimate the risk of leukemia or myelodysplasia in patients with multiple sclerosis treated with NOVANTRONE.

PARAPLATIN (carboplatin) Injection

Labeling provides for a patient package insert for PARAPLATIN.

(generic name = carboplatin for injection)

Who should not take PARAPLATIN?

How is PARAPLATIN used?

What should you tell your doctor before starting treatment with PARAPLATIN?

What should I avoid while taking PARAPLATIN?

You should avoid contact with adults and children who have infections, and tell your doctor right away if you show signs of infection such as cough, fever, and/or chills. Also, while you are being treated with PARAPLATIN or after you stop treatment, first check with your doctor before getting any immunizations

What are the possible side effects of PARAPLATIN?

•bleeding and reduced blood cells, including reduced red blood cells (anemia) and platelets (needed for proper blood clotting), which may be severe enough to require blood transfusion. You should tell your doctor right away if you notice any unusual bruising or bleeding, including black tarry stools or blood in the urine.

•infection - PARAPLATIN can temporarily lower the number of white blood cells in your blood, increasing the risk of infection;

•life-threatening allergic reaction - during and after treatment the doctor or nurse will observe you carefully for signs of allergic reaction;

•kidney and liver problems;

•loss of hearing or ringing in the ears;

Contact your doctor right away if you experience any of these effects, or notice effects that worry you or are troublesome.

Of the less serious side effects associated with PARAPLATIN treatment, the most common are nausea, vomiting, diarrhea, loss of appetite, hair loss and numbness, tingling, burning, or pain in the hands or feet.

[Other labeling changes not found in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#plavix ]

section of the package insert to include safety information from Study 016, "A Double-Blind Study to Evaluate the Effects of Omeprazole and an H2 Antagonist in the Treatment of Barrett’s Esophagus." Contact the company for a copy of the new labeling/package insert.

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PROCARDIA (nifedipine) Capsules

[February 22, 2002: Pfizer]

[labeling not found in 2001 PDR]

Grapefruit Juice: Co-administration of nifedipine with grapefruit juice resulted in approximately a 2-fold increase in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations are most likely due to inhibition of CYP 3A4 related first-pass metabolism. Co-administration of nifedipine with grapefruit juice is to be avoided.

Geriatric Use: Although small pharmacokinetic studies have identified an increase half-life and increased Cmax and AUC (see CLINICAL PHARMACOLGY: Pharmacokinetics and Metabolism), clinical studies of nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Co-administration of nifedipine with grapefruit juice is to be avoided (see CLINICAL PHARMACOLOGY AND PRECAUTIONS: Other Interactions).

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Endocrine: Gynecomastia

Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Add the full contents (25 mL) of the SPORANOX Injection ampule into the infusion bag

provided, which contains 50 mL of 0.9% Sodium Chloride Injection, USP (normal saline). Mix gently after the solution is completely transferred. Withdraw and discard 15 mL of the solution before administering to the patient. Using a flow control device, infuse 60 mL of the dilute solution (3.33 mg/mL = 200 mg itraconazole, pH apx. 4.8) intravenously over 60 minutes, using an extension line and the infusion set provided. After administration, flush the infusion set with 15-20 mL of 0.9% Sodium Chloride Injection, USP, over 30 seconds-15 minutes, via the two-way stopcock. Do not use Bacteriostatic Sodium Chloride Injection, USP. The compatibility of SPORANOX Injection with flush solutions other than 0.9% Sodium Chloride Injection, USP (normal saline) is not known. Discard the entire infusion line.

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Adults: Once mixed with food or dissolved in water, the entire contents must be consumed within 6 hours in order to obtain the full dose. If it is not consumed immediately, the mixture must be stored under refrigeration for up to 6 hours.

Pediatric Patients (2-13 years): The recommended use period for storage of the product in these media is 6 hours under refrigeration.

"How should VIRACEPT Oral Powder be prepared?"

Once the powder is mixed, it may be stored at room temperature or refrigerated if it is not consumed immediately, it must be stored under refrigeration for up to 6 hours. Do not heat the mixed dose once it has been prepared.

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Geriatric Use: No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.

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ZERIT (stavudine) Capsules

Fatal lactic acidosis has occurred in patients treated with ZERIT in combination with other antiretroviral agents. Patients with suspected lactic acidosis should immediately suspend therapy with ZERIT. Permanent discontinuation of ZERIT should be considered for patients with confirmed lactic acidosis.

Body as a Whole: redistribution/accumulation of body fat (see PRECAUTIONS, Fat Redistribution).

Nervous System—insomnia, severe motor weakness (most often reported in the setting of lactic acidosis, see WARNINGS).

ZOLADEX (goserelin acetate) Implant

[February 5 & 28, 2002: AstraZeneca]

[3.6 mg Depot, 3-Month 10.8 mg Depot]

[3.6 mg Depot, 3-Month 10.8 mg Depot]

5. Change the direction of the needle so it parallels the abdominal wall. Push the needle in until the barrel hub touches the patient’s skin. Withdraw the needle one centimeter to create a space to discharge ZOLADEX. Fully depress the plunger to discharge ZOLADEX.

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