MedWatch - July 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) -- July 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
Arthrotec (diclofenac sodium/misoprostol) Tablets (click product name to read prescribing information)	CONTRAINDICATIONS PRECAUTIONS Information for Patients Special Note for Women Pregnancy Non-teratogenic Effects Nursing Mothers	Arthrotec should not be taken by pregnant women.

Celebrex (celecoxib capsules) (click product name to read prescribing information)	CONTRAINDICATIONS BOXED WARNING Cardiovascular Risk Gastrointestinal Risk WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Hypertension Congestive Heart Failure and Edema Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation Renal Effects Advanced Renal Disease Skin Reactions PRECAUTIONS Information for Patients Laboratory Tests Drug Interactions Aspirin ADVERSE REACTIONS Adverse Events from Celebrex Premarketing Controlled Arthritis Trials Other Serious Adverse Reactions which occur Rarely (estimated <0.1%), Regardless of Causality Cardiovascular Deep Venous Thrombosis Adverse Events from Ankylosing Spondylitis Studies MEDICATION GUIDE	CONTRAINDICATIONS Celebrex is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. BOXED WARNING Cardiovascular Risk Celebrex may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk..... Gastrointestinal Risk NSAIDs, including Celebrex, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Chronic use of Celebrex may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal..... There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and Celebrex does increase the risk of serious GI events..... Hypertension As with all NSAIDS, Celebrex can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events..... Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs, including Celebrex..... Celebrex should be used with caution in patients with fluid retention or heart failure. Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation .....NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors..... Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury..... Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Celebrex in patients with advanced renal disease. Therefore, treatment with Celebrex is not recommended in these patients with advanced renal disease. If Celebrex therapy must be initiated, close monitoring of the patient's renal function is advisable. Skin Reactions Celebrex is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens Johnson syndrome (SJS), and toxic epidermal necrolysis (TENS), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy.....

NuvaRing (etonogestrel/ethinyl estradiol vaginal ring) (click product name to read prescribing information)	CONTRAINDICATIONS WARNINGS Bleeding Irregularities Bleeding Patterns PRECAUTIONS Tampon Use Toxic Shock Syndrome (TSS) Drug Interactions Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Drugs Increase in Plasma Hormone Levels Associated with Co-Administered Drugs Expulsion Disconnected Ring PATIENT PACKAGE INSERT	CONTRAINDICATIONS NuvaRing should not be used in women who currently have the following conditions: Valvular heart disease with thrombogenic complications. WARNINGS Bleeding patterns were evaluated in three large clinical studies. In the US-Canadian study (N = 1177), the percentages of subjects with breakthrough bleeding/spotting ranged from 7.2 to 11.7% during cycles 1-13.....

Pipracil (piperacillin sodium) Please contact Wyeth Pharmaceuticals at 1-800-934-5556 for prescribing information.	CONTRAINDICATIONS PRECAUTIONS General Leukopenia or Neutropenia Drug Interactions Methotrexate Drug/Laboratory Test Interactions Bio-Rad Test ADVERSE REACTIONS Dermatologic Adverse Events Urticaria Toxic Epidermal Necrolysis Renal Adverse Events Renal Failure Hemic and Lymphatic Adverse Events Hemolytic Anemia Agranulocytosis Pancytopenia Prolonged Bleeding Time Serum Electrolytes Adverse Events Hypokalemia Other Adverse Events Fever	CONTRAINDICATIONS Pipracil is contraindicated in patients with a history of allergic reactions to any of the betalactams, including penicillins and/or cephalosporins. PRECAUTIONS General Leukopenia or neutropenia may occur during therapy. Drug Interactions Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored. Drug/Laboratory Test Interactions There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin/tazobactam injection who were subsequently found to be free of Aspergillus infection. Crossreactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin should be interpreted cautiously and confirmed by other diagnostic methods. ADVERSE REACTIONS Anaphylactic/anaphylactoid reactions (some leading to shock and fatalities have been reported. Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Pravachol (pravastatin sodium) Tablets (click product name to read prescribing information)	CONTRAINDICATIONS WARNINGS Skeletal Muscle ADVERSE REACTIONS Postmarketing Experience Hypersensitivity Angioedema Laboratory Abnormalities Liver Function Test Abnormalities	CONTRAINDICATIONS Active liver disease or unexplained, persistent elevations of serum transaminases. WARNINGS Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, was rare (<0.1%) in pravastatin clinical trials.

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Brand (Generic) Name

Sections Modified

Summary of Changes to Contraindications and Warnings

Mifeprex (mifepristone) Tablets

(click product name to read prescribing information)

BOXED WARNING

Atypical Presentation of Infection

WARNINGS

Infection and Sepsis

MEDICATION GUIDE

BOXED WARNING

Serious and sometimes fatal infections and bleeding occur very rarely following spontaneous, surgical, and medical abortions, including following Mifeprex use.....

Patients with serious bacterial infections (e.g. Clostridium sordellii) and sepsis can present without fever, bacteremia or significant findings on pelvic examination following an abortion. Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise.....

WARNINGS

As with other types of abortion, cases of serious bacterial infection, including very rare cases of fatal septic shock, have been reported following the use of Mifeprex. No causal relationship between these events and the use of Mifeprex and misoprostol has been established. Physicians evaluating a patient who is undergoing a medical abortion should be alert to the possibility of this rare event. In particular, a sustained fever of 100.4°F or higher, severe abdominal pain, or pelvic tenderness in the days after a medical abortion may be an indication of infection.

A high index of suspicion is needed to rule out sepsis (from e.g. Clostridium sordellii) if a patient reports abdominal pain or discomfort or general malaise (including weakness, nausea, vomiting or diarrhea) more than 24 hours after taking misoprostol.....

For additional details, see MedWatch 07/19/2005 Safety Alert.

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Enbrel (etanercept) For Subcutaneous Injection (click product name to read prescribing information)	WARNINGS Malignancies PRECAUTIONS Drug Interactions Wegener's Granulomatosis ADVERSE REACTIONS Malignancies PATIENT PACKAGE INSERT	The use of Enbrel in patients with Wegener’s granulomatosis receiving immunosuppressive agents is not recommended. The use of Enbrel in patients receiving concurrent cyclophosphamide therapy is not recommended.

Flovent Diskus (fluticasone propionate inhalation powder) (click product name to read prescribing information)	WARNINGS Ritonavir Drug Interaction Study PRECAUTIONS Information for Patients Drug Interactions Inhibitors of Cytochrome P450 Ritonavir Pregnancy: Teratogenic Effects Pediatric Use ADVERSE REACTIONS Observed During Clinical Practice Ear, Nose, and Throat Facial and Oropharyngeal Edema Non-Site Specific Very Rare Anaphylactic Reaction Very Rare Anaphylactic Reaction in Patients with Severe Milk Protein Allergy	A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate concentration, resulting in significantly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) Modified Neoral Oral Solution (cyclosporine oral solution, USP) Modified (click product name to read prescribing information)	WARNINGS: ALL PATIENTS Kidney, Liver and Heart Transplant PRECAUTIONS Drugs That May Potentiate Renal Dysfunction Antibiotics Ciprofloxacin Other Drugs Fibric Acid Derivatives (e.g., bezafibrate, fenofibrate) Drugs That Increase Cyclosporine Concentrations Antibiotics Azithromycin Other Drugs Oral Contraceptives Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations Other Drugs/Dietary Supplements Sulfinpyrazone Terbinafine Other Drug Interactions Potassium-sparing Diuretics Sirolimus	Another rare manifestation of cyclosporine-induced neurotoxicity, occurring in transplant patients more frequently than in other indications, is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension.

Norplant System (levonorgestrel implants) (click product name to read prescribing information)	WARNINGS Warnings Based on Experience with Combination (Progestin plus Estrogen) Oral Contraceptives Carcinoma of the Breast and Reproductive Organs	Numerous epidemiological studies have examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears.....

Reytaz (atazanavir sulfate) Capsules (click product name to read prescribing information)	WARNINGS Drug Interactions PRECAUTIONS Drug Interactions Table 11 Trazodone Inhaled Nasal Steriod 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 Reyataz with ritonavir and fluticasone propionate is expected to produce the same effects. ....

Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) Sandimmune Oral Solution (cyclosporine oral solution, USP) Sandimmune Injection (cyclosporine injection, USP) FOR INFUSION ONLY (click product name to read prescribing information)	WARNINGS PRECAUTIONS Drugs That May Potentiate Renal Dysfunction Antibiotics Ciprofloxacin Other Drugs Fibric Acid Derivatives (e.g., Bezafibrate, Fenofibrate) Drugs That Increase Cyclosporine Concentrations Antibiotics Azithromycin Other Drugs Imatinib Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations Other Drugs/Dietary Supplements Sulfinpyrazone Terbinafine Other Drug Interactions Potassium Sparing Drugs Potassium Containing Drugs Potassium Rich Diet Sirolimus	Another rare manifestation of cyclosporine-induced neurotoxicity is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension. Rarely (approximately 1 in 1000), patients receiving Sandimmune Injection (cyclosporine injection, USP) have experienced anaphylactic reactions. Although the exact cause of these reactions is unknown, it is believed to be due to the Cremophor EL (polyoxyethylated castor oil) used as the vehicle for the I.V. formulation. These reactions can consist of flushing of the face and upper thorax, and non-cardiogenic pulmonary edema, with acute respiratory distress, dyspnea, wheezing, blood pressure changes, and tachycardia. One patient died after respiratory arrest and aspiration pneumonia. In some cases, the reaction subsided after the infusion was stopped.

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Brand (Generic) Name	Sections Modified
Adderall XR (mixed salts of a single-entity amphetamine product) Extended-Release Capsules (click product name to read prescribing information)	PRECAUTIONS Hypertension Effects on Weight ADVERSE REACTIONS Initial Paragraph Adverse Events Occurring in a Controlled Trial Table 2

Avandia (rosiglitazone maleate) Tablets (click product name to read prescribing information)	PRECAUTIONS Pediatric Use Table 8 ADVERSE REACTIONS Pediatric

Camptosar (irinotecan hydrochloride injection) (click product name to read prescribing information)	PRECAUTIONS General Patients at Particular Risk Information for Patients Laboratory Tests ADVERSE REACTIONS Post-Marketing Experience Rare Cases of Symptomatic Pancreatitis Asymptomatic Elevated Pancreatic Enzymes

Cialis (tadalafil) Tablets (click product name to read prescribing information)	PRECAUTIONS Information for Patients Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) ADVERSE REACTIONS Postmarketing Surveillance Ophthalmologic Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) PATIENT PACKAGE INSERT For additional details, see MedWatch 07/08/2005 Safety Alert.

Levitra (vardenafil hydrochloride) Tablets (click product name to read prescribing information)	PRECAUTIONS Information for Patients Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) ADVERSE REACTIONS Post-Marketing Experience Ophthalmologic Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) PATIENT PACKAGE INSERT For additional details, see MedWatch 07/08/2005 Safety Alert.

Meridia (sibutramine hydrochloride monohydrate) Capsules (click product name to read prescribing information)	PRECAUTIONS Renal Impairment

Norvasc (amlodipine besylate) Tablets (click product name to read prescribing information	PRECAUTIONS General Drug Interactions Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy Category C

Paxil (paroxetine hydrochloride) Tablets and Oral Suspension (click product name to read prescribing information)	PRECAUTIONS Drugs Metabolized by CYP2D6 Risperidone or Atomoxetine

Paxil (paroxetine hydrochloride) Controlled-Release Tablets (click product name to read prescribing information)	PRECAUTIONS Drugs Metabolized by CYP2D6 Risperidone or Atomoxetine

Precose (acarbose tablets) (click product name to read prescribing information)	PRECAUTIONS Drug Interactions Patients Receiving Sulfonylureas or Insulin ADVERSE REACTIONS Digestive Tract Post Marketing Adverse Event Reports

Renagel (sevelamer hydrochloride) Tablets (click product name to read prescribing information)	PRECAUTIONS Drug Interactions Ciprofloxacin

Septra (trimethoprim/sulfamethoxazole) Tablets Septra (trimethoprim/sulfamethoxazole) DS Tablets Septra (trimethoprim/sulfamethoxazole) Suspension Septra (trimethoprim/sulfamethoxazole) Grape Suspension (click product name to read prescribing information)	PRECAUTIONS Drug Interactions Hyperkalemia in Elderly Patients Geriatric Use

Singulair (montelukast sodium) Tablets, Chewable Tablets, and Oral Granules (click product name to read prescribing information)	PRECAUTIONS Carcinogenesis, Mutagenesis, Impairment of Fertility Pediatric Use ADVERSE REACTIONS Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis Pediatric Patients 6 Months to 14 Years of Age with Perennial Allergic Rhinitis

Viagra (sildenafil citrate) Tablets (click product name to read prescribing information)	PRECAUTIONS Information for Patients Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) ADVERSE REACTIONS Post-marketing Experience Special Senses Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) PATIENT PACKAGE INSERT For additional details, see MedWatch 07/08/2005 Safety Alert.

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Brand (Generic) Name	Sections Modified
Adenocard IV (adenosine injection) (click product name to read prescribing information)	ADVERSE REACTIONS Post Marketing Experience CardiovascularRespiratory Central Nervous System

Adenoscan (adenosine injection) (click product name to read prescribing information)	ADVERSE REACTIONS Post Marketing Experience Body as a WholeCentral Nervous SystemDigestive Respiratory

Benicar (olmesartan medoxomil) Tablets(click product name to read prescribing information)	ADVERSE REACTIONS Post-Marketing Experience Body as a Whole Asthenia Gastrointestinal Vomiting Urogenital System Acute Renal Failure Increased Blood Creatinine Levels Skin and Appendages AlopeciaPruritus Urticaria
Benicar HCT (olmesartan medoxomil-hydrochlorothiazide) Tablets (click product name to read prescribing information)	ADVERSE REACTIONS Post-Marketing Experience Body as a Whole Asthenia Gastrointestinal Vomiting Urogenital System Acute Renal Failure Increased Blood Creatinine Levels Skin and Appendages AlopeciaPruritus Urticaria

Omnicef (cefdinir) Capsules Omnicef (cefdinir) Powder for Oral Suspension (click product name to read prescribing information)	ADVERSE REACTIONS Post Marketing Experience Serum Sickness-Like Reactions

Vfend (voriconazole) TabletsVfend I.V. (voriconazole) for Injection Vfend (voriconazole) for Oral Suspension (click product name to read prescribing information)	ADVERSE REACTIONS Table 11 Visual Disturbances Abnormal Vision

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