MedWatch - MONTH 2007 Safety-Related Drug Labeling Changes

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Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) -- April 2007

The detailed view includes drug products with safety labeling changes to the BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, or PATIENT PACKAGE INSERT/MEDICATION GUIDE sections. Deletions or editorial revisions made to these sections are not included in this summary. Read about the new physician labeling format

Summary View

Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Enjuvia (synthetic conjugated estrogens, B) Tablets Prescribing Information Patient Package Insert	BOXED WARNING Cardiovascular and Other Risks WARNINGS Cardiovascular Disorders Stroke Coronary Heart Disease Venous Thromboembolism Malignant Neoplasms Breast Cancer Dementia PRECAUTIONS General Addition of a progestin when a woman has not had a hysterectomy Ovarian Cancer Geriatric Use ADVERSE REACTIONS Table 8 In a second 12-week clinical trial, 310 women with symptoms of vulvar and vagular atrophy were treated... PATIENT PACKAGE INSERT What is the most important information I should know about Enjuva (an estrogen hormone mixture)? What is Enjuvia? What is Enjuvia used for? How should I take Enjuva? What can I do to lower my chances of a serious side effect with Enjuva?	BOXED WARNING & WARNINGS See highlighted labeling for revised text.

Fentora (fentanyl buccal tablet) Prescribing Information Medication Guide	BOXED WARNING PRECAUTIONS Information for Patients and Caregivers Patients and caregivers should be advised that if they have been receiving treatment with Fentora and the medicine is no longer needed they should flush any remaining product down the toilet... Drug Interactions ...strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazadone) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug effects including fatal respiratory depression... Grapefruit and grapefruit juice decrease CYP3A4 activity, increasing blood concentrations of fentanyl... Drugs that induce cytochrome P450 3A4 activity may have the opposite effects. Concomitant use of Fentora with an MAO inhibitor, or within 14 days of discontinuation, is not recommended. MEDICATION GUIDE What is Fentora? How should I use Fentora? How should I store Fentora?	BOXED WARNING Fentora is indicated only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. The concomitant use of Fentora with strong and moderate cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression.

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Ativan (lorazepam) Tablets Prescribing Information	CONTRAINDICATIONS WARNINGS Initial Section Physical and Psychological Dependence PRECAUTIONS Initial Section Clinically Significant Drug Interactions Pregnancy Nursing Mothers Geriatric Use ADVERSE REACTIONS	CONTRAINDICATIONS Ativan (lorazepam) is contraindicated in patients with hypersensitivity to benzodiazepines or to any components of the formulation... WARNINGS: Initial Section Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam... Use of benzodiazepines, including lorazepam, both used alone and in combination with other CNS depressants, may lead to potentially fatal respiratory depression. Use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence. WARNINGS: Physical and Psychological Dependence See highlighted labeling for revised text.

Femara (letrozole tablets) Prescribing Information	CONTRAINDICATIONS WARNINGS Pregnancy ADVERSE REACTIONS First-Line and Second-Line Breast Cancer	CONTRAINDICATIONS Femara is contraindicated in women of premenopausal endocrine status. WARNINGS: Pregnancy The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who recently became postmenopausal, until their postmenopausal status is fully established.

Invirase (saquinavir mesylate) Capsules and Tablets Prescribing Information Patient Package Insert	CONTRAINDICATIONS Initial Paragraph WARNINGS Interaction with Fluticasone PRECAUTIONS General Invirase must be used in combination with ritonavir. Immune Reconstitution Syndrome Drug Interactions Table 5 Garlic Capsules Table 6 HIV Protease Inhibitor Tipranavir/ritonavir Antifungal Ketoconazole Intraconazole Inhaled/Nasal Steroid Fluticasone Antidepressant Trazodone Proton Pump Inhibitors Omeprazole ADVERSE REACTIONS Initial Statement Invirase must be used in combination with ritonavir, which significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels. Additional Adverse Reactions Reported with Saquinavir PATIENT PACKAGE INSERT Are there other medications that I should not take with Invirase/Norvir (ritonavir)?	CONTRAINDICATIONS: Initial Paragraph Invirase must be used in combination with ritonavir, which significantly inhibits saquinavir's metabolism and provides increased plasma saquinavir levels. WARNINGS: Interaction with Fluticasone A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of Invirase with ritonavir and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and Invirase/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Advicor (niacin extended-release/lovastatin tablets) Prescribing Information	WARNINGS Skeletal Muscle Lovastatin Potent Inhibitors of CYP3A4 Ketolide antibiotic telithromycin added Use of Advicor with other Drugs Gemfibrozil, particularly with higher doses of lovastatin Cyclosporine or danazol, with higher doses of lovastatin PRECAUTIONS Lovastatin Endocrine Function ...The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown... Information for Patients ...flushing is a common side effect of niacin therapy that usually subsides... Drug Interactions Lovastatin Serious skeletal muscle disorders, e.g., rhabdomyolysis, have been reported during concomitant therapy of lovastatin or other HMG-CoA reductase inhibitors with cyclosporine, danazol, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, telithromycin, nefazodone or HIV protease inhibitors...	WARNINGS: Skeletal Muscle/Lovastatin Potent inhibitors of CYP3A4: The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Lovastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which share this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily). WARNINGS: Use of Advicor with other DrugsGemfibrozil, particularly with higher doses of lovastatin ... The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with gemfibrozil... Cyclosporine or danzaol, with higher doses of lovastatin: In patients taking concomitant cyclosporine, danazol or fibrates, the dose of Advicor should generally not exceed 1000 mg/20 mg, as the risk of myopathy may increase at higher doses. Interruption of Advicor therapy during a course of treatment with a systemic antifungal azole a macrolide antibiotic, or a ketolide antibiotic should be considered.

Baraclude (entecavir) Tablets and Oral Solution Contact Bristol-Myers Squibb Company at 1-800-321-1335 for prescribing information and patient package insert.	WARNINGS Exacerbations of Hepatitis After Discontinuation of Treatment PATIENT PACKAGE INSERT General Information How Should I Store Baraclude? Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Baraclude for a condition for which it was not prescribed. Do not give Baraclude to other people, even if they have the same symptoms you have. It may harm them. The leaflet summarizes the most important information about Baraclude. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Baraclude that is written for healthcare professionals. You can also call 1-800-321-1335 or visit the Baraclude website at www.Baraclude.com.	WARNINGS: Exacerbations of Hepatitis After Discontinuation of Treatment Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy.

Exjade (deferasirox) Tablets for Oral Suspension Prescribing Information See MedWatch Safety Alert posted 5/22/2007 for additional information on Exjade labeling revisions.	WARNINGS Renal Cytopenias ADVERSE REACTIONS Post-marketing Experience	WARNINGS: Renal Cases of acute renal failure, some with a fatal outcome, have been reported following the postmarketing use of Exjade. Most of the fatalities occurred in patients with multiple co-morbidities and who were in advanced stages of their hematological disorders. Particular attention should be given to monitoring serum creatinine in patients who: are at increased risk of complications, have preexisting renal conditions, are elderly, have co-morbid conditions, or are receiving medicinal products that depress renal function... WARNINGS: Cytopenias There have been postmarketing reports (both spontaneous and from clinical trials) of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia, in patients treated with Exjade. Some of these patients died. The relationship of these episodes to treatment with Exjade is uncertain. Most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure. In line with the standard clinical management of such hematological disorders, blood counts should be monitored regularly. Interruption of treatment with Exjade should be considered in patients who develop unexplained cytopenia. Reintroduction of therapy with Exjade may be considered, once the cause of the cytopenia has been elucidated.

Levitra (vardenafil HCl) Tablets Prescribing Information Patient Package Insert	WARNINGS Effect of Co-administration of Potent CYP3A4 Inhibitors PRECAUTIONS Congenital or Acquired QT Prolongation Drug Interactions Other CYP3A4 Inhibitors PATIENT PACKAGE INSERT Can Other Medications Affect Levitra?	WARNINGS: Effect of Co-administration of Potent CYP3A4 Inhibitors ...Patients taking indinavir, saquinavir, atazanavir or other potent CYP3A4 inhibitors such as clarithromycin, ketoconazole 400 mg daily, or itraconazole 400 mg daily, should not exceed a dose of Levitra 2.5 mg once daily. For patients taking ketoconazole 200 mg daily or itraconazole 200 mg daily, a single dose of 5 mg Levitra should not be exceeded in a 24-hour period...

Minocin (minocycline hydrochloride) Pellet-Filled Capsules Prescribing Information	WARNINGS Clostridium difficile associated diarrhea (CDAD) PRECAUTIONS Information for Patients Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.	WARNINGS: Clostridium difficile associated diarrhea (CDAD) Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Minocin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile... ...If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Sarafem (fluoxetine hydrochloride tablets) Prescribing Information See MedWatch Safety Alert posted on 7/19/2006 which discusses SSRIs and Treatment Challenges of Depression in Pregnancy.	WARNINGS Serotonin Syndrome PRECAUTIONS Information for Patients Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Sarafem and triptans, tramadol or other serotonergic agents. Drug Interactions Drugs metabolized by CYP2D6 Serotonergic Drugs Triptans Pregnancy Nonteratogenic Effects Pulmonary hypertension of the newborn (PPHN) ...Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.	WARNINGS: Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur with SNRIs and SSRIs, including Sarafem treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Sarafem with MAOIs intended to treat depression is contraindicated... If concomitant treatment of Sarafem with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases... The concomitant use of Sarafem with serotonin precursors (such as tryptophan) is not recommended...

Zerit (stavudine) Capsules Zerit (stavudine) for Oral Solution Prescribing Information and Patient Package Insert	WARNINGS Hepatic Impairment and Toxicity Use with Didanosine and Hydroxyurea-Based Regimens PRECAUTIONS Patient Information An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with Zerit in combination with didanosine and hydroxyurea. This combination should be avoided. PATIENT PACKAGE INSERT What are the possible side effects of Zerit? The combination of Zerit, didanosine, and hydroxyurea may increase your risk for liver damage, which may cause death. This combination should be avoided.	WARNINGS: Hepatic Impairment and Toxicity/ Use with Didanosine and Hydroxyurea Based Regimens An increased risk of hepatotoxicity may occur in patients treated with Zerit in combination with didanosine and hydroxyurea compared to when Zerit is used alone. Deaths attributed to hepatotoxicity have occurred in patients receiving this combination. This combination should be avoided.

Zyvox (linezolid) Injection and Tablets Zyvox (Iinezolid) for Oral Suspension Prescribing Information	WARNINGS Clostridium difficile associated diarhea (CDAD)... PRECAUTIONS Convulsions In some of these cases, a history of seizures or risk factors for seizures was reported. Information for Patients Diarrhea is a common problem caused by antibiotics, which usually ends wihen the antibiotic is discontinued... Pregnancy Teratogenic Effects, Pregnancy Category C Non-teratogenic Effects Animal Pharmacology	WARNINGS: Clostridium difficile associated diarhea (CDAD) Clostridium difficile associated diarhea (CDAD) has been reported with use of nearly all antibacterial agents, including Zyvox, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difcile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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Brand (Generic) Name

Sections Modified

Actonel (risedronate sodium tablets)