MedWatch - October 2005 Safety-Related Drug Labeling Changes

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Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) -- October 2005

The detailed view includes drug products with safety labeling changes to the CONTRAINDICATIONS, BOXED WARNING, WARNINGS, PRECAUTIONS, or ADVERSE REACTIONS sections. The prescribing information may be accessed by clicking on the drug name.

Summary View

Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Biaxin Filmtab (clarithromycin tablets) Biaxin XL Filmtab (clarithromycin extended-release tablets) Biaxin Granules (clarithromycin for oral suspension, USP) (click product name to read prescribing information)	CONTRAINDICATIONS PRECAUTIONS Drug Interactions Colchicine CYP3A Ergotamine/dihydroergotamine ADVERSE REACTIONS Post-marketing Experience Interstitial Nephritis	Concomitant administration of clarithromycin and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, and ergotamine or dihydroergotamine....

Diprolene (augmented betamethasone dipropionate lotion) Lotion (click product name to read prescribing information)	CONTRAINDICATIONS PRECAUTIONS Information for Patients Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy: Teratogenic Effects Pregnancy Category C Pediatric Use ADVERSE REACTIONS The following additional local adverse reactions have been reported with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids.....	Diprolene Lotion is contraindicated in patients who are hypersensitive to betamethasone dipropionate, to other corticosteroids, or to any ingredient in this preparation.

Diprolene (augmented betamethasone dipropionate ointment) Ointment (click product name to read prescribing information)	CONTRAINDICATIONS PRECAUTIONS General Information for Patients Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy: Teratogenic Effects Pregnancy Category C Pediatric Use ADVERSE REACTIONS Hypertrichosis Systemic absorption of topical corticosteroids.....	Diprolene Ointment is contraindicated in patients who are hypersensitive to betamethasone dipropionate, to other corticosteroids, or to any ingredient in this preparation.

Efudex (fluorouracil) Topical Solutions and Cream (click product name to read prescribing information)	CONTRAINDICATIONS WARNINGS Dihydropyrimidine Dehydrogenase (DPD) Enzyme Deficiency	CONTRAINDICATIONS Efudex should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities. WARNINGS Patients should discontinue therapy with Efudex if symptoms of DPD enzyme deficiency develop. Rarely, life-threatening toxicities such as stomatitis, diarrhea, neutropenia, and neurotoxicity have been reported with intravenous administration of fluorouracil in patients with DPD enzyme deficiency.....

Imodium (loperamide hydrochloride) Capsules (click product name to read prescribing information)	CONTRAINDICATIONS WARNINGS PRECAUTIONS General Information for Patients Drug Interactions Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy Teratogenic Effects Pregnancy Category C Non-teratogenic Effects Nursing Mothers ADVERSE REACTIONS Clinical Trial Data Post-marketing Experience Skin and Subcutaneous Tissue Disorders Immune System Disorders Gastrointestinal Disorders Renal and Urinary Disorders	CONTRAINDICATIONS (See prescribing information for contraindications) WARNINGS In general, Imodium should not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Imodium must be discontinued promptly when constipation, abdominal distention or ileus develop. Treatment of diarrhea with Imodium is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate (or when indicated).

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Brand (Generic) Name

Sections Modified

Summary of Changes to Contraindications and Warnings

Avinza (morphine sulfate extended-release capsules)

(click product name to read prescribing information)

BOXED WARNING

WARNINGS

Interactions with Alcohol and Drugs of Abuse

PRECAUTIONS

Information for Patients

BOXED WARNING & WARNINGS

Patients must not consume alcoholic beverages while on Avinza therapy. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on Avinza therapy. Consumption of alcohol while taking Avinza may result in the rapid release and absorption of a potentially fatal dose of morphine.

WARNINGS

In vitro studies performed by the FDA demonstrated that when Avinza 30 mg was mixed with 900 mL of buffer solutions containing ethanol (20% and 40%), the dose of morphine that was released was alcohol concentration-dependent, leading to a more rapid release of morphine. While the relevance of in vitro lab tests regarding Avinza to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine.

For additional details, see MedWatch 11/03/2005 Safety Alert.

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Epogen (epoetin alfa) for Injection (click product name to read prescribing information)	WARNINGS Pure Red Cell Aplasia PRECAUTIONS Lack or Loss of Response ADVERSE REACTIONS Immunogenicity	Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with Epogen. This has been reported predominantly in patients with CRF receiving Epogen by subcutaneous administration. Any patient who develops a sudden loss of response to Epogen, accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin. If anti-erythropoietin antibody-associated anemia is suspected, withhold Epogen and other erythropoietic proteins. For additional details, see MedWatch 12/01/2005 Safety Alert.

Humira (adalimumab) (click product name to read prescribing information)	WARNINGS Serious Infections Neurologic Events Malignancies ADVERSE REACTIONS Infections Tuberculosis Malignancies Autoantibodies Other Adverse Events Humira has been studied in 395 patients with psoriatic arthritis in two placebo-controlled studies and in an open-label extension study..... PATIENT PACKAGE INSERT	Serious Infections Serious infections, sepsis, tuberculosis and rare cases of opportunistic infections, including fatalities, have been reported with the use of TNF blocking agents including Humira. Neurologic Events Use of TNF blocking agents, including Humira, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Malignancies In the controlled portions of clinical trials of some TNF-blocking agents, including Humira, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients.....

Marcaine (bupivacaine hydrochloride injection, USP) Marcaine with Epinephrine 1:200,000 (as bitartrate) (bupivacaine hydrochloride and epinephrine injection, USP) (click product name to read prescribing information)	WARNINGS	The statement, "Warning: Contains Sulfites" has been added to the container labels and carton labeling as these products contain the antioxidant, sodium metatabisulfite.

Prinivil (lisinopril) Tablets (click product name to read prescribing information)	WARNINGS Head and Neck Angioedema Hepatic Failure	Head and Neck Angioedema .....Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery..... Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis, and (sometimes) death.....

Prinzide (lisinopril-hydrochlorothiazide) Tablets (click product name to read prescribing information)	WARNINGS Head and Neck Angioedema Hepatic Failure	Head and Neck Angioedema .....ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients..... .....Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery..... Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis, and (sometimes) death.....

Rapamune (sirolimus) Tablets and Oral Solution (click product name to read prescribing information)	WARNINGS PRECAUTIONS Renal Function ADVERSE REACTIONS Other Clinical Experience Angioedema Hypersensitivity Vasculitis Lymphedema Calcineurin Inhibitor-induced HUS/TTP/TMA	..... Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, and hypersensitivity vasculitis, have been associated with the administration of sirolimus.

Vytorin (ezetimibe/simvastatin tablets) (click product name to read prescribing information)	WARNINGS Myopathy/Rhabdomyolysis The safety and effectiveness of ezetimibe administered with fibrates have not been established. Therefore, the concomitant use of Vytorin and fibrates should be avoided. PRECAUTIONS Information for Patients Skeletal Muscle Other Drug Interactions Cyclosporine Warfarin ADVERSE REACTIONS Post-marketing Experience Ezetimibe	There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with gemfibrozil. Therefore, although not recommended, if Vytorin is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily.

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Brand (Generic) Name	Sections Modified
Allegra (fexofenadine hydrochloride) Tablets (click product name to read prescribing information)	PRECAUTIONS Information for Patients Drug Interaction with Erythromycin and Ketoconazole .....This observed increase in the bioavailability of fexofenadine may be due to transport-related effects, such as p-glycoprotein..... Interactions with Fruit Juices Carcinogenesis, Mutagenesis, Impairment of Fertility Nursing Mothers ADVERSE REACTIONS Chronic Idiopathic Urticaria Table 3

Aminosyn II (amino acid injection with electrolytes) with Electrolytes in Dextrose Injection with Calcium (click product name to read prescribing information)	PRECAUTIONS Geriatric Use

Aredia (pamidronate disodium for injection) for Intravenous Infusion (click product name to read prescribing information)	PRECAUTIONS Musculoskeletal Pain

Aromasin (exemestane tablets) (click product name to read prescribing information)	PRECAUTIONS Laboratory Tests ADVERSE REACTIONS Adjuvant Treatment of Early Breast Cancer Table 8 Table 9

CellCept (mycophenolate mofetil capsules and tablets ) CellCept Oral Suspension (mycophenolate mofetil for oral suspension) CellCept Intravenous (mycophenolate mofetil hydrochloride for injection) (click product name to read prescribing information)	PRECAUTIONS Drug Interactions Acyclovir Ganciclovir ADVERSE REACTIONS Pediatrics Leukopenia

Detrol (tolterodine tartrate tablets) (click product name to read prescribing information)	PRECAUTIONS Information for Patients Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy Pediatric Use

Detrol LA (tolterodine tartrate extended release capsules) (click product name to read prescribing information)	PRECAUTIONS Patients with Congenital or Acquired QT Prolongation Drug Interactions CYP3A4 Inhibitors Ketoconazole

Flomax (tamsulosin hydrochloride) Capsules (click product name to read prescribing information)	PRECAUTIONS General Intraoperative Floppy Iris Syndrome (IFIS) ADVERSE REACTIONS Postmarketing Experience Intraoperative Floppy Iris Syndrome (IFIS) For additional details, see MedWatch 11/22/2005 Safety Alert.

Gleevec (imatinib mesylate) Tablets (click product name to read prescribing information)	PRECAUTIONS Hepatic Impairment ADVERSE REACTIONS Chronic Myeloid Leukemia Hematologic Toxicity Hepatotoxicity Gastrointestinal Stromal Tumors Table 9 Table 10

Kaletra (lopinavir/ritonavir) Tablets and Oral Solution (click product name to read prescribing information)	PRECAUTIONS Information for Patients Table 10

Levemir (insulin detemir [rDNA origin] injection) (click product name to read prescribing information)	PRECAUTIONS Pediatric Use

Nor-QD (norethindrone tablets, USP) Tablets (click product name to read prescribing information)	PRECAUTIONS Drug Interactions Anti-infective Agents and Anticonvulsants Anti-HIV Protease Inhibitors Herbal Products PATIENT PACKAGE INSERT

Norvir (ritonavir capsules) Soft Gelatin and (ritonavir oral solution) (click product name to read prescribing information)	PRECAUTIONS Pediatric Use ADVERSE REACTIONS Pediatrics Treatment-Emergent Adverse Events Laboratory Abnormalities

Novolin R (regular, human insulin injection [recombinant DNA origin], USP) (click product name to read prescribing information)	PRECAUTIONS Hypoglycemia and Hypokalemia Laboratory Tests

NovoLog (insulin aspart [rDNA origin] injection) (click product name to read prescribing information)	PRECAUTIONS General Laboratory Tests

Trileptal (oxcarbazepine) Tablets and Oral Suspension (click product name to read prescribing information)	PRECAUTIONS Cognitive/Neuropsychiatric Adverse Events Pediatric Patients Pediatric Use ADVERSE REACTIONS Adjunctive Therapy/Monotherapy in Pediatric Patients 1 month to < 4 Years Old Previously Treated or Not Previously Treated with other AEDs

Truvada (emtricitabine and tenofovir disoproxil fumarate) Tablets (click product name to read prescribing information)	PRECAUTIONS Bone Effects Tenofovir Disoproxil Fumarate Immune Reconstitution Syndrome ADVERSE REACTIONS Clinical Trials Viread Lipodystrophy Anxiety Total Cholesterol (> 300 mg/dL) Post-marketing Experience Viread Gastrointestinal Disorders Increased Amylase Hepatobiliary Disorders Increased Liver Enzymes Hepatitis Renal and Urinary Disorders Nephrogenic Diabetes Insipidus

Venofer (iron sucrose injection, USP) (click product name to read prescribing information)	PRECAUTIONS Hypersensitivity Reactions Hypotension Geriatric Use ADVERSE REACTIONS Adverse Events Observed in All Treated Populations Table 2 Table 3 Table 4 Adverse Events Observed in Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) Patients Hypersensitivity Reactions

Zometa (zoledronic acid) Injection (click product name to read prescribing information)	PRECAUTIONS Musculoskeletal Pain ADVERSE REACTIONS Post-marketing Experience Uveitis Episcleritis

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Brand (Generic) Name	Sections Modified
Arava (leflunomide) Tablets (click product name to read prescribing information)	ADVERSE REACTIONS Post-marketing Skin and Appendages Vasculitis including Cutaneous Necrotizing Vasculitis

Beconase AQ (beclomethasone dipropionate monohydrate) Nasal Spray (click product name to read prescribing information)	ADVERSE REACTIONS Anaphylactoid/Anaphylactic Reactions

Cubicin (daptomycin for injection) (click product name to read prescribing information)	ADVERSE REACTIONS Post-Marketing Experience Immune System Disorders Anaphylaxis Musculoskeletal System Rhabdomyolysis

Emend (aprepitant) Capsules (click product name to read prescribing information)	ADVERSE REACTIONS Moderately Emetogenic Chemotherapy Highly and Moderately Emetogenic Chemotherapy

Invanz (ertapenem for injection) (click product name to read prescribing information)	ADVERSE REACTIONS Additional Adverse Experiences In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were treated with ertapenem, the adverse experience profile was generally similar to that seen in previous clinical trials. Adverse Laboratory Changes In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were treated with ertapenem, the laboratory adverse experience profile was generally similar to that seen in previous clinical trials.

Mylotarg (gemtuzumab ozogamicin for injection) (click product name to read prescribing information)	ADVERSE REACTIONS Other Clinical Experience Pulmonary Hemorrhage

Plavix (clopidogrel bisulfate tablets) (click product name to read prescribing information)	ADVERSE REACTIONS Post-marketing Experience Body as a Whole Serum Sickness Hepato-biliary Disorders Acute Liver Failure Respiratory, Thoracic and Mediastinal Disorders Interstitial Pneumonitis Skin and Subcutaneous Tissue Disorders Toxic Epidermal Necrolysis Gastrointestinal Disorders Stomatitis

Trelstar Depot 3.75 mg (triptorelin pamoate for injectable suspension) (click product name to read prescribing information)	ADVERSE REACTIONS Pituitary Apoplexy

Trelstar LA 11.25 mg (triptorelin pamoate for injectable suspension) (click product name to read prescribing information)	ADVERSE REACTIONS Pituitary Apoplexy

Zoladex (goserelin acetate implant) 3.6 mg Please contact AstraZeneca Pharmaceuticals at 1-800-236-9933 for prescribing information.	ADVERSE REACTIONS Post-marketing Pituitary Apoplexy During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed. Most of the pituitary apoplexy cases occurred within 2 weeks of the first dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Zoladex (goserelin acetate implant) 10.8 mg - 3 month Please contact AstraZeneca Pharmaceuticals at 1-800-236-9933 for prescribing information.	ADVERSE REACTIONS Post-marketing Pituitary Apoplexy During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed. Most of the pituitary apoplexy cases occurred within 2 weeks of the first dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

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