MedWatch - October 2006 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 2006

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.

Summary View

Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Avastin (bevacizumab) for Intravenous Use Prescribing Information	BOXED WARNING Gastrointestinal Perforations Hemorrhage WARNINGS Hemorrhage Neutropenia and Infection Proteinuria Congestive Heart Failure PRECAUTIONS Drug Interactions In Study 6, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin..... Geriatric Use n Study 5 patients age 65 and older receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. ADVERSE REACTIONS Initial Section Neutropenia and Infection Adverse Reactions in Clinical Trials The data described below reflect exposure to Avastin in 1529 patients, including 665 receiving Avastinfor at least 6 months and 199 receiving Avastin for at least one year. Avastinwas studied primarily in placebo- and active-controlled trials (n = 501, and n = 1028, respectively). Gastrointestinal Perforation Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy..... Hemorrhage Arterial Thromboembolic Events Venous Thromboembolic Events The incidence of NCI-CTC Grade 3-4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone..... Hypertension Neutropenia and Infection Metastatic Carcinoma of the Colon and Rectum Initial Section .....Only NCI-CTC Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events related to treatment were reported. The median age was a 61 years, 40% were female, 87% were Caucasian, 99% received prior chemotherapy for metastatic colorectal cancer, 26% had received prior radiation therapy, and the 49% had an ECOG performance status of 0..... Non-Squamous, Non-Small Cell Lung Cancer Table 7: NCI‑CTC Grade 3-5 Non‑Hematologic and Grade 4 and 5 Hematologic Adverse Events in Study 5.....	BOXED WARNING/Gastrointestinal Perforations .....The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra‑abdominal abscess) in patients with colorectal cancer and in patients with non-small cell lung cancer (NSCLC) receiving Avastin was 2.4% and 0.9%, respectively..... BOXED WARNING/Hemorrhage Fatal pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and Avastin. The incidence of severe or fatal hemoptysis was 31% in patients with squamous histology and 2.3% in patients with NSCLC excluding predominant squamous histology. Patients with recent hemoptysis (≥1/2 tsp of red blood) should not receive Avastin..... WARNINGS/Hemorrhage In Study 6, four of 13 (31%) Avastin‑treated patients with squamous cell histology and two of 53 (4%) Avastin‑treated patients with histology other than squamous cell, experienced serious or fatal pulmonary hemorrhage as compared to none of the 32 (0%) patients receiving chemotherapy alone..... .....In Study 5, the rate of pulmonary hemorrhage requiring medical intervention for the PC plus Avastin arm was 2.3% (10 of 427) compared to 0.5% (2 of 441) for the PC alone arm. There were seven deaths due to pulmonary hemorrhage reported by investigators in the PC plus Avastin arm as compared to one in the PC alone arm. Generally, these serious hemorrhagic events presented as major or massive hemoptysis without an antecedent history of minor hemoptysis during Avastin therapy. Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 tsp of red blood..... WARNINGS/Neutropenia and Infection Increased rates of severe neutropenia, febrile neutropenia, and infection with severe neutropenia (including some fatalities) have been observed in patients treated with myelosuppressive chemotherapy plus Avastin. WARNINGS/Proteinuria .....In Studies 1, 3 and 5 the incidence of NCI‑CTC Grade 3 and 4 proteinuria, characterized as >3.5 gm/24 hours, ranged up to 3.0% in Avastin‑treated patients. Nephrotic syndrome occurred in seven of 1459 (0.5%) patients receiving Avastin in clinical studies..... WARNINGS/Congestive Heart Failure Congestive heart failure (CHF), defined as NCI‑CTC Grade 2-4 left ventricular dysfunction, was reported in 25 of 1459 (1.7%) patients receiving Avastin in clinical studies....

ChloraPrep with Tint (2% chlorhexidine gluconate (w/v) topical solution) 26-mL Applicator Please contact Medi-Flex, Inc. at 1-800-523-0502 for prescribing information.	BOXED WARNING WARNINGS	BOXED WARNING Avoid getting solution into hairy areas. Solution may take much longer to dry or may not dry completely. WARNINGS Do not use with electrocautery procedures until dry.

Coumadin Tablets (warfarin sodium tablets, USP) Crystalline Coumadin for Injection (warfarin sodium for injection, USP) Prescribing Information Medication Guide See MedWatch Safety Alert posted 10/6/2006 for additional information on Coumadin labeling revisions.	BOXED WARNING (new) WARNING: Bleeding Risk PRECAUTIONS Drug-Drug and Drug-Disease Interactions The following factors, alone or in combination, may be responsible for increased PT/INR response..... Exogenous Factors Potential drug interactions with Coumadin are listed below by drug class and by specific drugs. Specific Drugs Reported Argatroban Atenolol Bivalirudin Ezetimibe Lepirudin Miconazole (intravaginal, oral, systemic) Valdecoxib Information for Patients ADVERSE REACTIONS Adverse reactions reported infrequently include: Hypotension Anemia Pallor Angina Syndrome Chest Pain Loss of Consciousness Syncope Coma MEDICATION GUIDE (new)	BOXED WARNING/WARNING: Bleeding Risk Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs, and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding.

Remicade (infliximab) for IV Injection Prescribing Information Medication Guide	BOXED WARNING Risk of Infections CONTRAINDICATIONS WARNINGS Risk of Infections Hypersensitivity Malignancies PRECAUTIONS Information for Patients Pediatric Use Safety and effectiveness of Remicade in patients with juvenile rheumatoid arthritis and pediatric patients with ulcerative colitis and plaque psoriasis have not been established. Geriatric Use In rheumatoid arthritis and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis..... ADVERSE REACTIONS Initial Paragraph Infusion-related Reactions Infusion Reactions The infusion reaction rates remained stable in psoriasis..... Delayed Reactions/Reactions Following Readministration Plaque Psoriasis Infections In Remicade clinical studies in patients with ulcerative colitis, infections treated with antimicrobials..... Immunogenicity In the psoriasis Study II,..... Hepatotoxicity Table 11: Proportion of patients with elevated ALT in Clinical Trials Adverse Reactions in Psoriasis Studies Other Adverse Reactions Safety data are available from 4779 Remicade-treated adult patients, including 1304 with 1326 rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthrtis, 1373 with plaque psoriasis and 17 with other conditions..... MEDICATION GUIDE (new)	BOXED WARNING/Risk of Infections Patients treated with Remicade are at increased risk for infections, including progression to serious infections leading to hospitalization or death. These infections have included bacterial sepsis, tuberculosis, invasive fungal and other opportunistic infections. Patients should be educated about the symptoms of infection, closely monitored for signs and symptoms of infection during and after treatment with Remicade, and should have access to appropriate medical care. Patients who develop an infection should be evaluated for appropriate antimicrobial therapy and for serious infections Remicade should be discontinued. Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) has been observed in patients receiving Remicade. Patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection prior to initiating Remicade and during therapy. Treatment of latent tuberculosis infection should be initiated prior to therapy with Remicade. Treatment of latent tuberculosis in patients with a reactive tuberculin test reduces the risk of tuberculosis reactivation in patients receiving Remicade. Some patients who tested negative for latent tuberculosis prior to receiving Remicade have developed active tuberculosis. Physicians should monitor patients receiving Remicade for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection. CONTRAINDICATIONS Remicade should not be re-administered to patients who have experienced a severe hypersensitivity reaction to Remicade. Additionally, Remicade should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins. WARNINGS/Risk of Infections See highlighted prescribing information for revised/new text. WARNINGS/Hypersensitivity .....However, in some cases, serum sickness-like reactions have been observed in patients after initial Remicade therapy (i.e., as early as after the second dose), and when Remicade therapy was reinstituted following an extended period without Remicade treatment..... WARNINGS/Malignancies In the controlled portions of clinical trials of some TNF-blocking agents including Remicade, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients..... .....In controlled and open-label portions of Remicade clinical trials, 5 patients developed lymphomas among 5707 patients treated with Remicade..... Psoriasis patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for Remicade, NMSCs were more common in patients with previous phototherapy.....

Seroquel (quetiapine fumarate) Tablets Prescribing Information Medication Guide	BOXED WARNING Suicidality in Children and Adolescents WARNINGS Clinical Worsening and Suicide Risk PRECAUTIONS Cholesterol and Triglyceride Elevations Transaminase Elevations Suicide Geriatric Use ADVERSE REACTIONS Initial Section Adverse Findings Observed in Short-Term, Controlled Trials Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo- Controlled Trials Bipolar Disorder Depression Table 3: Treatment-Emergent Adverse Experience Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials Extrapyramidal Symptoms In two placebo-controlled clinical trials for the treatment of bipolar depression..... Vital Signs and Laboratory Studies Weight Gain In bipolar depression trials..... ECG Changes In bipolar depression trials..... MEDICATION GUIDE (new)	BOXED WARNINGS/Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Seroquel or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Seroquel is not approved for use in pediatric patients..... WARNINGS/Clinical Worsening and Suicide Risk See section for new prescribing information.

Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Allegra (fexofenadine hydrochloride) Tablets and Oral Suspension Prescribing Information	CONTRAINDICATIONS PRECAUTIONS Information for Patients Interactions with Fruit Juices Pediatric Use ADVERSE REACTIONS Table 3: Adverse experiences reported in placebo-controlled studies in pediatric subjects with allergic rhinitis aged 6 months to 5 years of age at rates greater than 2% Chronic Idiopathic Urticaria The safety of fexofenadine hydrochloride in the treatment of chronic idiopathic urticaria in pediatric patients 6 months to 11 years of age is based on the safety profile of fexofenadine hydrochloride in adults and pediatric patients.....	CONTRAINDICATIONS Allegra Tablets and Allegra Oral Suspension are contraindicated in patients with known hypersensitivity to any of the ingredients.

Opana (oxymorphone hydrochloride) Injection Prescribing Information	CONTRAINDICATIONS WARNINGS Respiratory Depression Misuse, Abuse and Diversion of Opioids Interactions with Alcohol and Drugs of Abuse Drug Abuse and Addiction Controlled Substance Interactions with Other Central Nervous System Depressants Head Injury and Increased Intracranial Pressure Hypotensive Effect Hepatic Impairment PRECAUTIONS General Interactions with Mixed Agonist/Antagonist Opioid Analgesics Ambulatory Surgery and Post-Operative Use Use in Pancreatic/Biliary Tract Disease Physical Dependence and Tolerance Information for Patients/Caregivers Use in Drug and Alcohol Addiction Drug-Drug Interactions Use with CNS Depressants Use with Mixed Agonist/Antagonist Opioid Analgesics Other Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy Initial Section Teratogenic Effects Non-teratogenic Effects Labor and Delivery Nursing Mothers Geriatric Use Hepatic Impairment Renal Impairment Gender Differences ADVERSE REACTIONS Cardiac Disorders Eye Disorders Gastrointestinal Disorders General Disorders and Administration Site Conditions Hepatobilliary Disorders Immune System Disorders Metabolism and Nutrition Disorders Nervous System Disorders Psychiatric Disorders Renal and Urinary Disorders Respiratory, Thoracic, and Mediastinal Disorders Skin and Subcutaneous Tissue Disorders Social Circumstances Vascular Disorders	CONTRAINDICATIONS AND WARNINGS See prescribing information for revised/new text.

0.9% Sodium Chloride Irrigation, USP Prescribing Information	CONTRAINDICATIONS WARNINGS PRECAUTIONS General Laboratory Tests Drug Interactions Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy - Teratogenic Effects - Pregnancy Category C Labor and Delivery Nursing Mothers Pediatric Use Geriatric Use ADVERSE REACTIONS	CONTRAINDICATIONS 0.9% Sodium Chloride Irrigation, USP is not for injection by usual parenteral routes. An electrolyte solution should not be used for irrigation during electrosurgical procedures. WARNINGS FOR IRRIGATION ONLY. NOT FOR INJECTION. Irrigating fluids have been demonstrated to enter the systemic circulation in relatively large volumes; thus, irrigation solutions must be regarded as systemic drugs. Absorption of large amounts can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the administered parenteral solutions. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentration. Do not warm above 150°F (66°C). After opening container, its contents should be used promptly to minimize the possibility of bacterial growth or pyrogen formation. Discard unused portion of irrigating solution since it contains no preservatives.

Vicoprofen (hydrocodone bitartrate and ibuprofen tablets Prescribing Information Medication Guide	CONTRAINDICATIONS WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Hypertension Congestive Heart Failure and Edema Misuse Abuse and Diversion of Opioids Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding and Perforation Renal Effects Advanced Renal Disease Anaphylactoid Reactions Skin Reactions PRECAUTIONS General Hepatic Effects Hematological Effects Information for Patients Laboratory Tests Drug Interactions Antidepressants Aspirin Diuretics Lithium Mixed Agonist/Antagonist Opioid Analgesics Neuromuscular Blocking Agents Pregnancy Teratogenic Effects Labor and Delivery Nursing Mothers MEDICATION GUIDE (new)	CONTRAINDICATIONS Vicoprofen is contraindicated in patients with known hypersensitivity to hydrocodone or ibuprofen. Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone. Vicoprofen should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Vicoprofen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. WARNINGS See WARNINGS section for revised/new prescribing information.

Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Depacon (valproate sodium injection) Prescribing Information	WARNINGS Usage in Pregnancy Human Data Congenital Malformations Neural Tube Defects Other Adverse Pregnancy Effects	See WARNINGS/Usage in Pregnancy section for revised prescribing information.

Depakene (valproic acid capsules and oral solution, USP) Prescribing Information	WARNINGS Usage in Pregnancy Human Data Congenital Malformations Neural Tube Defects Other Adverse Pregnancy Effects	See WARNINGS/Usage in Pregnancy section for revised prescribing information.

Depakote (divalproex sodium) Delayed-Release Tablets Prescribing Information	WARNINGS Usage in Pregnancy Human Data Congenital Malformations Neural Tube Defects Other Adverse Pregnancy Effects	See WARNINGS/Usage in Pregnancy section for revised prescribing information.

Depakote ER (divalproex sodium) Extended-Release Tablets Prescribing Information	WARNINGS Usage in Pregnancy Human Data Congenital Malformations Neural Tube Defects Other Adverse Pregnancy Effects	See WARNINGS/Usage in Pregnancy section for revised prescribing information.

Depakote (divalproex sodium coated particles in capsules) Sprinkle Capsules Prescribing Information	WARNINGS Usage in Pregnancy Human Data Congenital Malformations Neural Tube Defects Other Adverse Pregnancy Effects	See WARNINGS/Usage in Pregnancy section for revised prescribing information.

Heparin Sodium Injection, USP Prescribing Information See MedWatch Safety Alert posted 12/08/2006 for additional information on Heparin labeling revisions.	WARNINGS Thrombocytopenia Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia Thrombosis (HITT) Delayed Onset of HIT and HITT PRECAUTIONS General Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) ADVERSE REACTIONS Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT	WARNINGS/Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence up to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm³) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm³ or if recurrent thrombosis develops (see Heparin induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered. WARNINGS/Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia Thrombosis (HITT) Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. WARNINGS/Delayed Onset of HIT and HITT Heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

Hep-Lock (heparin lock flush solution, USP) Prescribing Information See MedWatch Safety Alert posted 12/08/2006 for additional information on Heparin labeling revisions.	WARNINGS Thrombocytopenia Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) Delayed Onset of HIT and HITT PRECAUTIONS General Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) ADVERSE REACTIONS Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT	WARNINGS/Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm³) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm³or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued and, if necessary, an alternative anticoagulant administered. WARNINGS/Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm³ or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation. WARNINGS/Delayed Onset of HIT and HITT Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

Hep-Lock U/P Preservative-Free (heparin lock flush solution, USP) Prescribing Information See MedWatch Safety Alert posted 12/08/2006 for additional information on Heparin labeling revisions.	WARNINGS Thrombocytopenia Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) Delayed Onset of HIT and HITT PRECAUTIONS General Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) ADVERSE REACTIONS Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT	WARNINGS/Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm³) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm³or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued and, if necessary, an alternative anticoagulant administered. WARNINGS/Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm³ or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation. WARNINGS/Delayed Onset of HIT and HITT Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

Strattera (atomoxetine HCl) Capsules Prescribing Information Medication Guide	WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Assessing Cardiovascular Status in Patients Being Treated with Atomoxetine Emergence of New Psychotic or Manic Symptoms MEDICATION GUIDE What should I tell my doctor before taking Strattera? Other important safety information about Strattera	WARNINGS See highlighted prescribing information for new WARNINGS information as a result of a class labeling initiative for all central nervous system (CNS) stimulant medications that include safety language for cardiac and psychiatric events.

Taxotere (docetaxel) Injection Concentrate Prescribing Information Patient Package Insert	WARNINGS Hematologic Effects PRECAUTIONS Geriatric Use Among the 221 patients treated with Taxotere in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years..... Of the 174 patients who received the induction treatment with Taxotere in combination with cisplatin and fluorouracil for SCCHN (TAX323)..... The clinical study of Taxotere in combination with cisplatin and fluorouracil in patients with SCCHN (TAX323)..... ADVERSE REACTIONS Initial Section Combination therapy with Taxotere in Gastric Adenocarcinoma Table 17: Clinically Important Treatment Emergent Adverse Events Regardless of Relationship to Treatment in the Gastric Cancer Study Combination Therapy with Taxotere in Head and Neck Cancer Table 18: Clinically Important Treatment Emergent Adverse Events (Regardless of Relationship) in Patients with SCCHN Receiving Taxotere in Combination with Cisplatin and fluorouracil (TAX 323) PATIENT PACKAGE INSERT	WARNINGS/Hematologic Effects In gastric cancer patients treated with Taxotere in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection.

Vytorin (ezetimibe/simvastatin tablets) Prescribing Information Patient Package Insert	WARNINGS Myopathy/Rhabdomyolysis Table 7: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis PRECAUTIONS Drug Interactions Other Drug Interactions Cyclosporine or Danazol ADVERSE REACTIONS Post-marketing Experience Ezetimibe Myalgia PATIENT PACKAGE INSERT What are the possible side effects of Vytorin? Muscle Pain	WARNINGS/Myopathy/Rhabdomyolysis See highlighted WARNINGS section for new text.

Brand (Generic) Name	Sections Modified
Abilify (aripiprazole) Tablets and Oral Solution Abilify Discmelt (aripiprazole) Orally Disintegrating Tablets Prescribing Information	PRECAUTIONS Drug-Drug Interactions Potential for Abilify to Affect Other Drugs No effect of aripiprazole was seen on the pharmacokinetics of lithium or valproate.

Avandaryl (rosiglitazone maleate and glimepiride) Tablets Prescribing Information Patient Package Insert	PRECAUTIONS Weight Gain Table 5: Weight Changes (kg) From Baseline at Endpoint During Clinical Trials..... ADVERSE REACTIONS Initial Section Table 9: Adverse Events (≥5% in Any Treatment Group) Reported by Drug-Naïve Patients in a 28-Week Double-Blind Clinical Trial of Avandaryl Pediatric Use PATIENT PACKAGE INSERT What is Avandaryl? What are possible side effects of Avandaryl?

Byetta (exenatide injection) Prescribing Information Patient Package Insert	PRECAUTIONS Information for Patients Each dose of Byetta should be administered as a SC injection in the thigh, abdomen, or upper arm at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart)..... ADVERSE REACTIONS Spontaneous Data PATIENT PACKAGE INSERT How should I use Byetta?

Cubicin (daptomycin for injection) Prescribing Information	PRECAUTIONS Drug Laboratory Test Interactions

Factive (gemifloxacin mesylate) Tablets Prescribing Information Patient Package Insert	PRECAUTIONS Information for Patients Patients should be counseled: .....that increases of the International Normalized Ratio (INR), or prothrombin time (PT), and/or clinical episodes of bleeding have been noted with concurrent administration of warfarin or its derivatives, and Factive..... Drug Interactions .....However, post-marketing reports of increases in the INR, and/or PT, and/or clinical episodes of bleeding in patients have been noted with the use of quinolones, including Factive, and warfarin, or its derivatives. In addition, infectious disease and its accompanying inflammatory process, age and general status of the patient are risk factors for increased anticoagulation activity..... PATIENT PACKAGE INSERT What about other medicines I am taking?

Ferrlecit (sodium ferric gluconate complex in sucrose injection) Prescribing Information	PRECAUTIONS Hypersensitivity Reactions ADVERSE REACTIONS Hypersensitivity Reactions Postmarketing Surveillance

Flovent HFA (fluticasone propionate) Inhalation Aerosol Prescribing Information Patient Package Insert	PRECAUTIONS Information for Patients Use Flovent HFA only with the actuator supplied with the product. When the counter reads 020, contact the pharmacist for a refill of medication or consult the physician to determine whether a prescription refill is needed. Discard the inhaler when the counter reads 000. Never try to alter the numbers or remove the counter from the metal canister. PATIENT PACKAGE INSERT

Gleevec (imatinib mesylate) Tablets Prescribing Information The labeling revisions provide for the treatment of the following conditions: adult dermafibrosarcoma protuberans (DFSP), adult myelodysplastic syndrome/myeloproliferative diseases (MDS/MPD), adult Ph+ acute lymphoblastic leukemia (ALL) monotherapy, adult aggressive systemic mastocytosis (ASM), and adult hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL).	PRECAUTIONS Hypereosinophilic Cardiac Toxicity Severe Congestive Heart Failure and Left Ventricular Dysfunction ADVERSE REACTIONS Acute Lymphoblastic Leukemia Myelodyplastic/Myeloproliferative Diseases Table 14: Adverse Experiences Reported (more than one patient) in MPD Patients..... Aggressive Systemic Mastocytosis Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia Dermatofibrosarcoma Protuberans Table 15: Adverse Experiences Reported in DFSP Patients..... Table 16: Laboratory Abnormalities Reported in DFSP Patients.....

Gleevec (imatinib mesylate) Tablets Prescribing Information The labeling revisions provide for updated text to the package insert to include the results of the final 2 year rat carcinogenicity study.	PRECAUTIONS Carcinogenesis, Mutagenesis, Impairment of Fertility In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day..... The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure..... The relevance of these findings in the rat carcinogenicity study for humans is not known.

Namenda (memantine hydrochloride) Tablets and Oral Solution Please contact Forest Pharmaceuticals, Inc. at 1-800-678-1605 for prescribing information.	PRECAUTIONS Special Populations Hepatic Impairment - Namenda undergoes partial hepatic metabolism, with about 48% of administered dose excreted in urine as unchanged drug or as the sum of parent drug and the N-glucuronide conjugate (74%). No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Namenda should be administered with caution to patients with severe hepatic impairment.

Neulasta (pegfilgrastim) Prescribing Information Patient Package Insert	PRECAUTIONS Drug Interaction Increased hematopoetic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imagine results. PATIENT PACKAGE INSERT What are the ingredients in Neulasta? The needle cover on the single-use prefilled syringe contains dry natural rubber (laxex), which should not be handled by persons sensitive to this substance.

Neupogen (filgrastim) Prescribing Information Patient Package Insert	PRECAUTIONS Drug Interaction Increased hematopoetic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imagine results. PATIENT PACKAGE INSERT What are the ingredients in Neupogen? The needle cover on the single-use prefilled syringe contains dry natural rubber (laxex), which should not be handled by persons sensitive to this substance.

Nexium (esomeprazole magnesium) Delayed-Release Capsules Nexium (esomeprazole magnesium) for Delayed-Release Oral Suspension Prescribing Information	PRECAUTIONS Information for Patients Administration Options Nexium Delayed-Release Capsules Nexium For Delayed-Release Oral Suspension

Prinivil (lisinopril) Tablets Prescribing Information	PRECAUTIONS Drug Interactions Gold Nitritoid Reactions

Prinzide (lisinopril/hydrochlorothiazide) Tablets Prescribing Information	PRECAUTIONS Drug Interactions Lisinopril Gold Nitritoid Reactions

Risperdal Consta (risperidone) Long Acting Injection Please contact Janssen, L.P. at 1-800-526-7736 for prescribing information.	PRECAUTIONS Use in Patients With Concomitant Illness .....Patients with Parkinson's Disease or Dementia with Lewy Bodies who receive antipsychotics, including Risperdal, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

Risperdal (risperidone) Tablets and Oral Solution Risperdal M-TAB (risperidone) Orally Disintegrating Tablets Prescribing Information	PRECAUTIONS Use in Patients with Concomitant Illnesses Clinical experience with Risperdal in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy Bodies who receive antipsychotics, including Risperdal, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome. Pediatric Use The efficacy and safety of Risperdal in the treatment of irritability associated with autistic disorder were established in two 8-week, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years..... The safety and effectiveness of Risperdal in pediatric patients with autistic disorder less than 5 years of age have not been established. ADVERSE REACTIONS Initial Paragraph Adverse Events and Other Safety Measures in Pediatric Patients With Autistic Disorder Table 4: Incidence of Treatment-Emergent Adverse Events in Two 8-Week, Placebo-Controlled Trials in Pediatric Patients with Autistic Disorder

Viagra (sildenafil citrate) Tablets Prescribing Information	PRECAUTIONS Information for Patients Sildenafil is also marketed as Revatio for pulmonary arterial hypertension. Drug Interactions Effects of Other Drugs on Viagra In a study of healthy male volunteers, co-administration of sildenafil at steady state (80mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly cytochrome P4502C19) at steady state (125 mg b.i.d.) resulted in 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax..... Effects of Viagra on Other Drugs Sildenafil at steady state (80mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in Cmax of bosentan (125 b.i.d.)

Brand (Generic) Name	Sections Modified
Aricept (donepezil hydrochloride) Oral Solution Prescribing Information	ADVERSE REACTIONS Severe Alzheimer's Disease Adverse Events Leading to Discontinuation Most Frequent Adverse Clinical Events Seen in Association with the Use of Aricept Adverse Events Reported in Controlled Trials Table 4: Adverse Events Reported in Controlled Clinical Trials in Severe Alzheimer's Disease in at Least 2% of Patients Receiving Aricept..... Other Adverse Events Observed During Clinical Trials

Aricept (donepezil hydrochloride tablets) Aricept ODT (donepezil hydrochloride) Orally Disintegrating Tablets Prescribing Information	ADVERSE REACTIONS Severe Alzheimer's Disease Adverse Events Leading to Discontinuation Most Frequent Adverse Clinical Events Seen in Association with the Use of Aricept Adverse Events Reported in Controlled Trials Table 4: Adverse Events Reported in Controlled Clinical Trials in Severe Alzheimer's Disease in at Least 2% of Patients Receiving Aricept..... Other Adverse Events Observed During Clinical Trials

Cialis (tadalafil) Tablets Prescribing Information	ADVERSE REACTIONS Postmarketing Surveillance Other Adverse Events Nervous Migraine

Hepsera (adefovir dipivoxil) Tablets Prescribing Information Patient Package Insert	ADVERSE REACTIONS Initial Section Patients who received Hepsera for up to 240 weeks in Study 438 reported adverse reactions similar in nature..... Laboratory Abnormalities No patients with adequate renal function treated with Hepsera developed a serum creatinine increase ≥0.5 mg/dL from baseline by week 48..... .....For patients who chose to continue Hepsera for up to 240 weeks in Study 438, 4 of 125 patients (3%) had a confirmed increase of 0.5 mg/dL from baseline. The creatinine elevation resolved in 1 patient who permanently discontinued treatment and remained stable in 3 patients who continued treatment..... PATIENT PACKAGE INSERT You may be more likely to get lactic acidosis or serious liver problems if you are very overweight (obese) or have been taking nucleoside analog medicines.....

Rapamune (sirolimus) Oral Solution and Tablets Prescribing Information	ADVERSE REACTIONS Other Clinical Experience The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population has not been established. In an ongoing study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (target concentrations of 12 - 20 ng/mL, by chromatographic assay).....

Yaz (drospirenone and ethinyl estradiol) Tablets Prescribing Information Patient Package Insert	ADVERSE REACTIONS The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: Possible diminution in lactation when given immediately postpartum Mood changes, including depression Vaginitis, including candidiasis Decrease in serum folate levels Exacerbation of systemic lupus erythematosus Exacerbation of porphyria Exacerbation of chorea Aggravation of varicose veins Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted: Dysmenorrhea Optic neuritis, which may lead to partial or complete loss of vision Pancreatitis The most frequent (>1%) treatment-emergent adverse events, listed in descending order, reported with the use of Yaz in the PMDD clinical trials, which may or not be drug related, included..... PATIENT PACKAGE INSERT Yaz may also be taken to treat premenstrual dysphoric disorder (PMDD) if you choose to use the Pill for birth control..... You should only use Yaz for treatment of PMDD if you..... Yaz has not been shown to be effective for the treatment of premenstrual syndrome (PMS).....

Brand (Generic) Name	Sections Modified
Humatrope (somatropin [rDNA origin] for Injection) Patient Package Insert	PATIENT PACKAGE INSERT

Intron A (interferon alfa-2b, recombinant) for Injection Medication Guide	MEDICATION GUIDE Instructions for Preparing and Giving a Dose of Intron A Multidose Pen Storing Intron A Solution Multidose Pen for Injection Discard any unused Intron A pen remaining after 4 weeks.

Topamax (topiramate) Tablets Topamax (topiramate capsules) Sprinkle Capsules Patient Package Insert	PATIENT PACKAGE INSERT (new)