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

(Posted: 10/31/2002)

MedWatch Home | What's New | About Medwatch | How to Report | Submit Report | Safety Info
Continuing Education | Download PDF | Comments | Privacy Statement

ALDARA (imiquimod) Cream

[September 3, 2002]

INDICATIONS AND USAGE

Aldara 5% cream is indicated for the treatment of external genital and perianal warts/condyloma acuminata in adults in individuals 12 years old and above.

PRECAUTIONS

Information for Patients

Pediatric Use

Safety and efficacy in patients below the age of 12 years have not been established.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

ALTOCOR (lovastatin) Extended-Release Tablets

[September 11, 2002: Andrx]

Labeling provides for the use of Altocor (lovastatin) Extended-Release Tablets in the primary prevention of coronary heart disease in patients who have average to moderately elevated Total-C and LDL-C and below average HDL-C. Contact the company for a copy of the new labeling/package insert.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

ARIMIDEX (anastrozole) Tablets

[September 5, 2002: AstraZeneca]

This supplemental new drug application provides for the use of ARIMIDEX (anastrozole) Tablets for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. Contact the company for a copy of the new labeling/package insert.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

ATACAND (candesartan cilexetil)

[September 13, 2002: AstraZeneca]

CLINICAL PHARMACOLOGY

Special Populations

Hepatic Insufficiency:

Replaces previous subsection -

The pharmacokinetics of candesartan were compared in patients with mild and moderate hepatic impairment to matched healthy volunteers following a single oral dose of 16 mg candesartan cilexetil. The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. The pharmacokinetics after candesartan cilexetil administration have not been investigated in patients with severe hepatic impairment. No initial dosage adjustment is necessary in patients with mild hepatic impairment. In patients with moderate hepatic impairment, consideration should be given to initiation of ATACAND at a lower dose. (See DOSAGE AND ADMINISTRATION).

Clinical Trials

Second paragraph added -

The antihypertensive effects of candesartan cilexetil and losartan potassium at their highest recommended doses administered once-daily were compared in two randomized, double-blind trials. In a total of 1268 patients with mild to moderate hypertension who were not receiving other antihypertensive therapy, candesartan cilexetil 32 mg lowered systolic and diastolic blood pressure by 2 to 3 mm Hg on average more than losartan potassium 100 mg, when measured at the time of either peak or trough effect. The antihypertensive effects of twice daily dosing of either candesartan cilexetil or losartan potassium were not studied.

PRECAUTIONS

General

Impaired Hepatic Function

Based on pharmacokinetic data which demonstrate significant increases in candesartan AUC and Cmax in patients with moderate hepatic impairment, a lower initiating dose should be considered for patients with moderate hepatic impairment. (See DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY, Special Populations.)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Second paragraph revised -

Candesartan and its O-deethyl metabolite tested positive for genotoxicty in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candesartan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay.

Geriatric Use

First sentence -

Of the total number of subjects in clinical studies of ATACAND, 21% (683/3260) were 65 and over, while 3% (87/3260) were 75 and over.

OVERDOSAGE

Second paragraph -

Limited data are available in regard to overdosage in humans. In one recorded case of an intentional overdose, a 43 year old female patient (Body Mass Index of 31 kg/m ² ) ingested an estimated 160 mg of candesartan cilexetil, in conjunction with multiple other pharmaceutical agents (ibuprofen, naproxen sodium, diphenhydramine hydrochloride and ketoprofen). Gastric lavage was performed, the patient was monitored in hospital for several days and was discharged without sequelae.

DOSAGE AND ADMINSTRATION

Added to second paragraph -

In patients with moderate hepatic impairment, consideration should be given to initiation of ATACAND at a lower dose (See CLINICAL PHARMACOLOGY, Special Populations)

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

AVAPRO (irbesartan) Tablets

[September 17, 2002: Sanofi-Synthelabo]

Labeling provides for the use of Avapro (irbesartan) Tablets, 75, 150 and 300 mg for the treatment of type 2 diabetic nephropathy. Contact the company for a copy of the new labeling/package insert.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

CANCIDAS (caspofungin acetate) Injection

[September 20, 2002: Merck]

Labeling provides for the use of Cancidas (caspofungin acetate) for the treatment of esophageal candidiasis.

Labeling to some sections extensively revised, e.g., Clinical Studies, Precautions, Dosage and Administration, plus some revisions to the Warnings section.

Contact the company for a copy of the new label/package insert.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

COZAAR (losartan potassium) Tablets

[September 17, 2002: Merck]

Labeling provides for the use of Cozaar (losartan potassium) 25, 50 and 100 mg Tablets for the treatment of type 2 diabetic nephropathy. Contact the company for a copy of the new labeling/package insert.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

CRIXIVAN (indinavir sulfate) Capsules

[September 19, 2002: Merck]

[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jun02.htm#crixiv

http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#crixiv ]

MICROBIOLOGY

Mechanism of Action: HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1 . Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles.

Antiretroviral Activity In Vitro: The relationship between in vitro susceptibility of HIV to indinavir and inhibition of HIV replication in humans has not been established. The in vitro activity of indinavir was assessed in cell lines of lymphoblastic and monocytic origin and in peripheral blood lymphocytes. HIV-1 variants used to infect the different cell types include laboratory-adapted variants, primary clinical isolates and clinical isolates resistant to nucleoside analogue and nonnucleoside inhibitors of the HIV-1 reverse transcriptase. The IC95 (95% inhibitory concentration) of indinavir in these test systems was in the range of 25 to 1 00 nM. In drug combination studies with the nucleoside analogues zidovudine and didanosine, as well as with an investigational nonnucleoside (L-697,66 1 ), indinavir showed synergistic activity in cell culture. The relationship between in vitro susceptibility of HIV-1 to indinavir and inhibition of HIV-1 replication in humans has not been established.

Drug Resistance: Isolates of HIV-1 with reduced susceptibility to the drug have been recovered from some patients treated with indinavir. Viral resistance was correlated with the accumulation of mutations that resulted in the expression of amino acid substitutions in the viral protease. Eleven amino acid residue positions, (L 1 0l/V/R, K20l/M/R, L24l, M46l/L, l54A/V, L63P, l64V, A7 1 T/V, V82A/F/T, l84V, and L90M), at which substitutions are associated with resistance, have been identified. Resistance was mediated by the co-expression of multiple and variable substitutions at these positions. No single substitution was either necessary or sufficient for measurable resistance (≥ 4-fold increase in IC95). In general, higher levels of resistance were associated with the co-expression of greater numbers of substitutions, although their individual effects varied and were not additive. At least 3 amino acid substitutions must be present for phenotypic resistance to indinavir to reach measurable levels. In addition, mutations in the p7/ p 1 and p 1 / p6 gag cleavage sites were observed in some indinavir resistant HIV-1 isolates.

In vitro phenotypic susceptibilities to indinavir were determined for 38 viral isolates from 1 3 patients who experienced virologic rebounds during indinavir monotherapy. Pre-treatment isolates from five patients exhibited indinavir IC₉₅ values of 50-1 00 nM. At or following viral RNA rebound (after 1 2-76 weeks of therapy), IC₉₅ values ranged from 25 to >3000 nM, and the viruses carried 2 to 1 0 mutations in the protease gene relative to baseline.

Cross-Resistance to Other Antiviral Agents: Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of HIV-1 indinavir and other HIV-protease inhibitors. In studies with ritonavir, saquinavir, and amprenavir, the extent and spectrum of cross-resistance varied with the specific mutational patterns observed. In general, the degree of cross-resistance increased with the accumulation of resistance-associated amino acid substitutions. Within a panel of 29 viral isolates from indinavir-treated patients that exhibited measurable (≥ 4-fold) phenotypic resistance to indinavir, all were resistant to ritonavir. Of the indinavir resistant HIV-1 isolates, 63% showed resistance to saquinavir and 81 % to amprenavir.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

GLUCOVANCE (Glyburide and Metformin HCL) Tablets

[September 30, 2002: Bristol-Myers Squibb]

Labeling provides for the use of Glucovance (Glyburide and Metformin HCl) tablets with a thiazolidinedione when glycemic control is not obtained with Glucovance alone. Contact the company for a copy of the new labeling/package insert.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Glycine Irrigation

[September 3, 2002: Baxter Healthcare]

Description

The plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million into solutions in contact with the plastic, however, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissues culture toxicity studies.

WARNINGS

Revisions to previous labeling contained in the following:

Careful cardiovascular monitoring should be maintained due to the possibility of fluid overload. Should fluid overload occur, intensive fluid and electrolyte management is necessary. Monitoring of fluid and electrolyte levels beyond the acute phase may be considered due to the possibility of delayed fluid absorption. (See ADVERSE REACTIONS, Post-Marketing Experience.)

PRECAUTIONS

Geriatric Use

Clinical studies of Irrigation Solutions did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from other younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

ADVERSE REACTIONS

Post-Marketing Experience

Following off-label use of 1.5% Glycine Irrigation, USP for hysteroscopic procedures in women, life threatening adverse events related to fluid overload have been reported.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

GoLYTELY (PEG-3350 and Electrolytes) Oral Solution

[September 19, 2002: Braintree Laboratories]

ADVERSE REACTIONS

Published literature contains isolated reports of serious adverse reactions following the administration of PEG-ELS products in patients over 60 years of age. These adverse events include upper GI bleeding from Mallory-Weiss Tear, esophageal perforation, asystole, sudden dyspnea with pulmonary edema, and "butterfly-like" infiltrate on chest X-ray after vomiting and aspirating PEG.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

HIVID (zalcitabine) Tablets

[September 12, 2002: Hoffman-La Roche]

[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/aug02.htm#hivid, http://www.fda.gov/medwatch/SAFETY/2002/jul02.htm#hivid ]

PRECAUTIONS

Drug Interactions: Zidovudine: There is no significant pharmacokinetic interaction between ZDV and zalcitabine which has been confirmed clinically. Zalcitabine also has no significant effect on the intracellular phosphorylation of ZDV, as shown in vitro in peripheral blood mononuclear cells or in two other cell lines (U937 and Molt-4). In the same study it was shown that didanosine and stavudine had no significant effect on the intracellular phosphorylation of zalcitabine in peripheral blood mononuclear cells.

Lamivudine: In vitro studies^{2, 3, 4} in peripheral blood mononuclear cells, U937 and Molt-4 cells revealed that lamivudine significantly inhibited zalcitabine phosphorylation in a dose dependent manner. Effects were already seen with doses corresponding to relevant plasma levels in humans, and the intracellular phosphorylation of zalcitabine to its three metabolites (including the active zalcitabine triphosphate metabolite) was significantly inhibited. Zalcitabine inhibited lamivudine phosphorylation at high concentration ratios (10 and 100); however, it is considered to be unlikely that this decrease of phosphorylated lamivudine concentration is of clinical significance, as lamivudine is a more efficient substrate for deoxycytidine kinase than zalcitabine. These in vitro studies suggest that concomitant administration of zalcitabine and lamivudine in humans may result in sub-therapeutic concentrations of active phosphorylated zalcitabine, which may lead to a decreased antiretroviral effect of zalcitabine. It is unknown how the effect seen in these in vitro studies translates into clinical consequences. Concomitant use of zalcitabine and lamivudine is not recommended.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

INDIUM OXINE (INDIUM In 111 Oxyquinoline Solution)

[September 19, 2002: Amersham Health]

PRECAUTIONS

Geriatrics Use

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.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

LESCOL & LESCOL XL (fluvastatin sodium) Capsules & Extended-Release Tablets

[September 6, 2002: Novartis]

Revision of the Elimination subsection of the CLINICAL PHARMACOLOGY section of the approved package insert, incorporating results of a study evaluating steady state pharmacokinetics of fluvastatin sodium following administration of Lescol XL 80 mg Tablets. Contact the company for a copy of the new labeling/package insert.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

MEVACOR (lovastatin) Tablets

[September 20, 2002: Merck]

[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#mevaco ]

CLINICAL PHARMACOLOGY

Pharmacokinetics

Seventh paragraph added:

The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).

WARNINGS

Skeletal Muscle

Myopathy/Rhabdomyolysis

Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

• The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:

Potent inhibitors of CYP3A4: Cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily), particularly with higher doses of lovastatin (see below; CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, CYP3A4 Interactions).

Lipid-lowering drugs that can cause myopathy when given alone: Gemfibrozil, other fibrates, or lipid-lowering doses (≥1 g/day) of niacin, particularly with higher doses of lovastatin (see below; CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone).

Other drugs: The risk of myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class (see PRECAUTIONS, Drug Interactions, Other drug interactions).

•The risk of myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.

CONSEQUENTLY:

1. Use of lovastatin concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, or clarithromycin is unavoidable, therapy with lovastatin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.

2. The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin. The combined use of lovastatin with fibrates or niacin should be avoided unless the benefit of further alteration in lipid levels is likely to outweigh the increased risk of this drug combination. Addition of these drugs to lovastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained.

3. The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.

4. All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level >10 times the ULN indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

5. Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with lovastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

PRECAUTIONS

Information for Patients

Patients should be advised about substances they should not take concomitantly with lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking MEVACOR.

Drug Interactions

CYP3A4 Interactions

Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin.

See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics.

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

HIV protease inhibitors

Nefazodone

Cyclosporine

Large quantities of grapefruit juice (>1 quart daily)

Interactions with lipid-lowering drugs that can cause myopathy when given alone

The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent CYP3A4 inhibitors, but which can cause myopathy when given alone.

See WARNINGS, Myopathy/Rhabdomyolysis.

Gemfibrozil

Other fibrates

Niacin (nicotinic acid) (≥1 g/day)

Other drug interactions

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class (see WARNINGS, Myopathy/Rhabdomyolysis).

ADVERSE REACTIONS

Concomitant Therapy

The combined use of lovastatin at doses exceeding 20 mg/day with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin should be avoided (see WARNINGS, Myopathy/Rhabdomyolysis).

DOSAGE AND ADMINISTRATION

Dosage in Patients taking Cyclosporine

In patients taking cyclosporine concomitantly with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of MEVACOR and should not exceed 20 mg/day.

Dosage in Patients taking Amiodarone or Verapamil

In patients taking amiodarone or verapamil concomitantly with MEVACOR, the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other drug interactions).

Concomitant Lipid-Lowering Therapy

MEVACOR is effective alone or when used concomitantly with bile-acid sequestrants. If MEVACOR is used in combination with gemfibrozil, other fibrates or lipid-lowering doses (³ 1g/day) of niacin, the dose of MEVACOR should not exceed 20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

NEXIUM (esomeprazole magnesium) Delayed-Release Capsules

[September 19, 2002: AstraZeneca]

ADVERSE REACTIONS

Postmarketing Reports – There have been spontaneous reports of adverse events with postmarketing use of esomeprazole. These reports have included rare cases of anaphylactic reaction.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

PROTOPAM (pralidoxime chloride) for Injection

[September 27, 2002: Wyeth]

Precautions

GERIATRIC USE

Clinical studies of Protopam 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.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

REBETOL (ribavirin) Capsules

[September 3, 2002: Schering]

OVERDOSAGE

There is limited experience with overdosage. Acute ingestion of up to 20 grams of REBETOL Capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse events related to the therapeutic use of INTRON A and REBETOL. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.

There is no specific antidote for INTRON A or REBETOL, and hemodialysis and peritoneal dialysis are not effective treatment of overdose of either agent.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

REMERON (mirtazapine)Tablets

[September 30, 2002: Organon]

[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/apr02.htm#remero ]

PRECAUTIONS

Increased Appetite/Weight Gain

In US controlled studies, appetite increase was reported in 17% of patients treated with Remeron, compared to 2% for placebo and 6% for amitriptyline. In these same trials, weight gain of > 7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open label treatment, 8% of patients receiving Remeron discontinued for weight gain. In an 8-week long pediatric clinical trial of doses between 15- 45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo treated patients (see PRECAUTIONS-Pediatric Use).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. In an 8-week long pediatric clinical trial of doses between 15- 45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo treated patients. The mean increase in weight was 4 kg (2 kg SD) for Remeron-treated patients versus 1 kg (2 kg SD) for placebo-treated patients (see Precautions-Increased Appetite/Weight Gain).

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

SORBITOL (Urologic Irrigating Solution)

[September 3, 2002: Baxter Healthcare]

WARNINGS

Appropriate patient monitoring should be maintained due to the possibility of fluid overload. Should fluid overload occur, intensive fluid and electrolyte management is necessary. Monitoring of fluid and electrolyte levels beyond the acute phase may be considered due to the possibility of delayed fluid absorption. (See ADVERSE REACTIONS, Post-Marketing Experience.)

ADVERSE REACTIONS

Following off-label use of 3% Sorbitol Urologic Irrigating Solution for hysteroscopic procedures in women, life threatening adverse events related to fluid overload have been reported.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

SPORANOX (itraconazole) Oral Solution

[September 11, 2002: Johnson and Johnson]

[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jul02.htm# sporan, http://www.fda.gov/medwatch/SAFETY/2002/apr02.htm#sporan, http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#sporan]

CLINICAL PHARMACOLOGY

Special Populations

Cystic Fibrosis: Seventeen cystic fibrosis patients, ages 7 to 28 years old, were administered itraconazole oral solution 2.5 mg/kg bid for 14 days in a pharmacokinetic study. Steady state trough concentrations > 250 ng/mL were achieved in 7 out of 12 patients greater than 16 years of age but in none of the 5 patients less than 16 years of age. Large variability was observed in the pharmacokinetic data (%CV = 88% and 65% for > 16 and < 16 years, respectively for trough concentrations). If a patient does not respond to SPORANOX oral solution, consideration should be given to switching to alternative therapy.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Sulfur Colloid Kit

[September 13, 2002: CIS-US]

PRECAUTIONS

Geriatric Use

Clinical studies of Sulfur Colloid did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger patients. 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.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

SUSTIVA (efavirenz) Tablets Capsules

[September 20, 2002: Bristol-Meyers Squibb]

ADVERSE REACTIONS

Laboratory Abnormalities

Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving SUSTIVA when the Microgenics CEDIA . DAU Multi-Level THC assay was used for screening. Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry.

Of the three assays analyzed (Microgenics CEDIA DAU Multi-Level THC assay, Cannabinoid Enzyme Immunoassay [Diagnostic Reagents, Inc], and AxSYM Cannabinoid Assay [Abbott Laboratories]), only the Microgenics CEDIA DAU Multi-Level

THC assay showed false-positive results. The other two assays provided true-negative results.The effects of SUSTIVA on cannabinoid screening tests other than these three are unknown. The manufacturers of cannabinoid assays should be contacted for additional information regarding the use of their assays with patients receiving efavirenz.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

VALTREX (valacyclovir HCl) Caplets

[September 9, 2002: GlaxoSmithKline]

Labeling provides for the use of Valtrex (valacyclovir hydrochloride) for the treatment of cold sores (herpes labialis) in adult and adolescent patients 12 years of age and older. Contact the company for a copy of the new labeling/packaging insert.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

VIAGRA (sildenafil citrate) Tablets

(September 19, 2002: Pfizer)

[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#viagra ]

CLINICAL PHARMACOLOGY

Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, > 80-fold for PDE1, > 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels (see Pharmacodynamics).

Effects of VIAGRA on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.4/5.5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates (see CONTRAINDICATIONS).

Effects of VIAGRA on Cardiac Parameters:

Fourth paragraph -

In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively. These results demonstrated that the effect of VIAGRA on the primary endpoint was statistically non-inferior to placebo.

WARNINGS

Third paragraph -

Patients with the following underlying conditions can be particularly sensitive to the actions of vasodilators including Viagra – those with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure.

PRECAUTIONS

General

Fourth paragraph -

When the alpha blocker doxazosin (4 mg) and VIAGRA (25 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH), mean additional reductions of supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic were observed. When higher doses of VIAGRA and doxazosin (4mg) were administered simultaneously, there were infrequent reports of patients who experienced symptomatic postural hypotension within 1 to 4 hours of dosing. Simultaneous administration of VIAGRA to patients taking alpha-blocker therapy may lead to symptomatic hypotension in some patients. Therefore, Viagra doses above 25 mg should not be taken within 4 hours of taking an alpha-blocker.

Information for Patients

Second paragraph-

Physicians should advise patients that simultaneous administration of Viagra doses above 25 mg and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, Viagra doses above 25 mg should not be taken within four hours of taking an alpha-blocker.

ADVERSE REACTIONS

POST-MARKETING EXPERIENCE:

First sentence -

Cardiovascular and cerebrovascular

Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, and hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of VIAGRA.

Ocular OcularSpecial Senses: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal vascular disease or bleeding, vitreous detachment/traction, and paramacular edema and epistaxis.

DOSAGE AND ADMINISTRATION

Simultaneous administration of Viagra doses above 25 mg and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, Viagra doses above 25 mg should not be administered within four hours of administering an alpha-blocker.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

VIDEX (didanosine) Buffered Tablets, Buffered Powder for Oral Solution, and Pediatric Powder
VIDEX EC (didanosine) Delayed Release Capsules

[September 25 & 26, 2002: Bristol-Myers Squibb]

[Other labeling changes not in 2002 PDR:

http://www.fda.gov/medwatch/SAFETY/2002/aug02.htm#videx ,
http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#videx ,
http://www.fda.gov/medwatch/SAFETY/2002/apr02.htm#videx ]

[For a copy of the complete tables, contact the company]

VIDEX (didanosine) Chewable/Dispersible Buffered Tablets, Buffered Powder for Oral Solution and Pediatric Powder for Oral Solution

CLINICAL PHARMACOLOGY

[For a copy of the complete tables, contact the company]

Table 3: Results of Drug Interaction Studies: Effects of Coadministered Drug on Didanosine Plasma AUC and C_MAX Values

Addition of tenofovir

Table 4: Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and C_MAX Values

Addition of tenofovir

WARNINGS

Treatment with VIDEX should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

PRECAUTIONS

Drug Interactions

Table 7: Established Drug Interactions with VIDEX

Addition of tenofovir

Table 8: Predicted Drug Interactions with VIDEX

Addition of Ribavirin

Tenofovir disoproxil fumarate or ribavirin. Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with either tenofovir (see Tables 3 and 7) or ribavirin (see Table 8). Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir or ribavirin with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS).

ADVERSE REACTIONS

Observed during Clinical Practice

Liver - lactic acidosis symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure.

VIDEX (didanosine) Delayed-Release Capsules Enteric-Coated

CLINICAL PHARMACOLOGY

Drug Interactions

VIDEX EC

First paragraph revised -

Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval (CI) when available, following coadministration of VIDEX EC with a variety of drugs. The only clinically significant pharmacokinetic interaction noted was between VIDEX EC and tenofovir disoproxil fumarate. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions.

Insertion of a new table with tenofovir. Contact the company for a copy of the new table.

Table 3: Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered Drug on Didanosine Plasma AUC and C_MAX Values^a

Table 4: Results of Drug Interaction Studies with VIDEX EC: Effects of Didanosine on Coadministered Drug Plasma AUC and C_MAX Values^a

Addition of tenofovir

Table 5 Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and C_MAX Values

Addition of tenofovir

A change in the values under the "methadone" category, from 41% to 57% and 58% to 66%, respectively.

Table 6: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and C_MAX Values

Addition of tenovofir

WARNINGS

2. Lactic Acidosis/Sever Hepatomegaly with Steatosis

Addition of symptomatic hyperlactatemia .

Table 8: Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX EC

Addition of tenofovir

Table 9: Predicted Drug Interactions with VIDEX EC

Addition of Ribavirin

PRECAUTIONS

Drug Interactions

Last paragraph -

Tenofovir disoproxil fumarate or ribavirin. Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with either tenofovir (see Tables 3, 5, and 8) or ribavirin (see Table 9). Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir or ribavirin with VIDEX EC should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX EC should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS).

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

WESTCORT (hydrocortisone valerate) Ointment

[September 3, 2002: Bristol-Myers Squibb]

PRECAUTIONS

Geriatric Use

Clinical studies of Westcort Ointment, 0.2% 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.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

ZOLOFT (sertraline HCl) Tablets and Oral Concentrate

[September 18 & 20, 2002: Pfizer]

[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/may02.htm#zoloft ]

New package insert provides for labeling revisions to include prevention of relapse following long-term treatment of obsessive compulsive disorder and prevention of relapse following long-term treatment of panic disorder. Contact the company for a copy of the new labeling/package insert.

CONTRAINDICATIONS

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

PRECAUTIONS

Drug Interactions

CNS Active Drugs

Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose. In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in EKG. Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of Zoloft and pimozide should be contraindicated (see CONTRAINDICATIONS).

Drug Interactions-Drugs Metabolized by P450 3A4

In two separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine or carbamazepine, under steady-state conditions. The results of these studies demonstrated that sertraline co-administration did not increase plasma concentrations of terfenadine or carbamazepine. These data suggest that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and C_max were reduced by about 35%).

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

 

HTML by JLW