MedWatch - March 2008 Safety-Related Drug Labeling Changes

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Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) -- March 2008

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
Aranesp (darbepoetin alfa) for Injection Prescribing Information See MedWatch Safety Alert posted 03/12/2008 for additional information on Erythropoiesis Stimulating Agents.	BOXED WARNING Cancer WARNINGS Decreased progression-free survival and overall survival...	BOXED WARNING Cancer ...ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers when dosed to target a hemoglobin of > 12 g/dL. WARNINGS Decreased progression-free survival and overall survival: Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which Aranesp was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. An interim analysis was performed after a median follow-up of approximately 3 years at which time the survival rate was lower (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate was lower (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) in the Aranesp-treated arm compared to the control arm. Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%)...

Epogen (epoetin alfa) for Injection Prescribing Information See MedWatch Safety Alert posted 03/12/2008 for additional information on Erythropoiesis Stimulating Agents.	BOXED WARNING Cancer WARNINGS Decreased progression-free survival and overall survival...	BOXED WARNING Cancer ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers when dosed to target a hemoglobin of > 12 g/dL. WARNINGS Decreased progression-free survival and overall survival: Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. An interim analysis was performed after a median follow-up of approximately 3 years at which time the survival rate was lower (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate was lower (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm. Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%)...

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Avodart (dutasteride) Soft Gelatin Capsules Prescribing Information Patient Package Insert	CONTRAINDICATIONS ADVERSE REACTIONS Postmarketing Experience Immune System Disorders Serious Skin Reactions Angioedema PATIENT PACKAGE INSERT How should I take Avodart? Swallow the capsule whole because the contents of the capsule may irritate your lips, mouth, or throat.	CONTRAINDICATIONS ...Avodart is contraindicated for patients with known hypersensitivity (e.g., angioedema) to dutasteride, other 5α-reductase inhibitors, or any component of the preparation.

Reyataz (atazanavir sulfate) Capsules Prescribing Information (in new labeling format) Patient Package Insert	CONTRAINDICATIONS Table 3: Drugs That Are Contraindicated with Reyataz WARNINGS AND PRECAUTIONS Drug Interactions Cardiac Conduction Abnormalities Rash ...Toxic skin eruptions (added) Hepatotoxicity ADVERSE REACTIONS Initial Section Clinical Trial Experience in Adults Treatment-Emergent Adverse Reactions in Treatment-Naive Patients Treatment-Emergent Adverse Reactions in Treatment-Experienced Patients Clinical Trial Experience in Pediatric Patients Postmarketing Experience DRUG INTERACTIONS Potential for Reyataz to Affect Other Drugs Potential for Other Drugs to Affect Atazanavir Established and Other Potentially Significant Drug Interactions Table 10 Drugs with No Observed or Predicted Interactions with Reyataz USE IN SPECIFIC POPULATIONS Pregnancy Pediatric Use Impaired Renal Function Impaired Hepatic Function PATIENT COUNSELING INFORMATION Initial Section Rash PATIENT PACKAGE INSERT Can children take Reyataz? What are the possible side effects of Reyataz? The following side effects have been reported with Reyataz...	CONTRAINDICATIONS Reyataz (atazanavir sulfate) is contraindicated: in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product or to atazanavir. when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance... See highlighted text, Table 3: Drugs That Are Contraindicated with Reyataz. WARNINGS AND PRECAUTIONS Cardiac Conduction Abnormalities ...Atazanavir in combination with diltiazem increased diltiazem plasma concentration by 2-fold with an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one half should be considered and ECG monitoring is recommended... Rash ...Reyataz should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions have been reported in patients receiving Reyataz... Hepatotoxicity ...In these patients, appropriate laboratory testing should be conducted prior to initiating therapy with Reyataz and these patients should be monitored during treatment...

Tussionex Pennkinetic (hydrocodone polistirex and chlorpheniramine polistirex) Extended-Release Suspension Prescribing Information See MedWatch Safety Alert posted 03/11/2008 for additional information on Long-Acting Hydrocodone-Containing Cough Product	CONTRAINDICATIONS WARNINGS Pediatric Use PRECAUTIONS Information for Patients Patients should be advised to measure Tussionex Pennkinetic Extended-Release Suspension with an accurate measuring device... Shake well before using. Pediatric Use ADVERSE REACTIONS General Disorders and Administration Site Conditions (added) Respiratory, Thoracic and Mediastinal Disorders Dryness of the pharynx, occasional tightness of the chest, and respiratory depression... ...Use of Tussionex Pennkinetic Extended-Release Suspension in children less than 6 years of age has been associated with fatal respiratory depression...	CONTRAINDICATIONS The use of Tussionex Pennkinetic Extended-Release Suspension is contraindicated in children less than 6 years of age due to the risk of fatal respiratory depression. WARNINGS Pediatric Use The use of Tussionex Pennkinetic Extended-Release Suspension is contraindicated in children less than 6 years of age... In pediatric patients, as well as adults, the respiratory center is sensitive to the depressant action of narcotic cough suppressants in a dose-dependent manner. Caution should be exercised when administering Tussionex Pennkinetic Extended-Release Suspension to pediatric patients 6 years of age and older. Overdose or concomitant administration of Tussionex Pennkinetic Extended-Release Suspension with other respiratory depressants may increase the risk of respiratory depression in pediatric patients. Benefit to risk ratio should be carefully considered, especially in pediatric patients with respiratory embarrassment (e.g., croup)...

Vfend I.V. (voriconazole) for Injection Vfend Tablets (voriconazole) Vfend (voriconazole) for Oral Suspension Prescribing Information Patient Package Insert	CONTRAINDICATIONS PRECAUTIONS Drug Interactions Table 11: Effect of Other Drugs on Voriconazole Pharmacokinetics St. John's Wort Monitoring of Pancreatic Function Pediatric Use There have been postmarketing reports of pancreatitis in pediatric patients PATIENT PACKAGE INSERT Who should not take Vfend? St. John's Wort (herbal supplement)	CONTRAINDICATIONS Coadministration of Vfend with St. John's Wort is contraindicated...

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Aczone (dapsone) Gel, 5% Prescribing Information (in new labeling format) Patient Package Insert	WARNINGS AND PRECAUTIONS Hematological Effects Peripheral Neuropathy DRUG INTERACTIONS Topical Benzoyl Peroxide USE IN SPECIFIC POPULATIONS G6PD Deficiency PATIENT PACKAGE INSERT What should I tell my doctor before using Aczone Gel? ...You and your doctor will need to decide if Aczone is right for you. What are the possible side effects of Aczone Gel? ...When the active ingredients of Aczone Gel (called dapsone) is taken orally as a pill...	WARNINGS AND PRECAUTIONS Hematological Effects Oral dapsone treatment has produced dose-related hemolysis and hemolytic anemia... Peripheral Neuropathy Peripheral neuropathy (motor loss and muscle weakness) has been reported with oral dapsone treatment. No events of peripheral neuropathy were observed in clinical trials with topical Aczone Gel, 5% treatment.

Advair HFA 45/21 (fluticasone propionate 45 mcg and salmeterol 21 mcg) Inhalation Aerosol Advair HFA 115/21 (fluticasone propionate 115 mcg and salmeterol 21 mcg) Inhalation Aerosol Advair HFA 230/21 (fluticasone propionate 230 mcg and salmeterol 21 mcg) Inhalation Aerosol As salmeterol xinafoate salt 30.45 mcg, equivalent to salmeterol base 21 mcg Prescribing Information Medication Guide	WARNINGS Potential drug interaction with CYP 3A4 inhibitors PRECAUTIONS Drug Interactions Inhibitors of Cytochrome P450 Salmeterol and Ketoconazole MEDICATION GUIDE How do I use Advair HFA? While you are using Advair HFA twice a day, do not use other medicines that contain a long-acting beta2-agonist or LABA for any reason...	WARNINGS Potential drug interaction with CYP 3A4 inhibitors Both fluticasone propionate and salmeterol are substrates of CYP 3A4.

Amoxil (amoxicillin capsules, tablets, chewable tablets, and powder for oral suspension) 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....	WARNINGS Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Amoxil, 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 diarrhea 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. 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.

Augmentin (amoxicillin/clavulanate potassium) Powder for Oral Suspension and Chewable Tablets 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...	WARNINGS Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Augmentin, 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 diarrhea 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. 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.

Augmentin (amoxicillin/clavulanate potassium) Tablets 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...	WARNINGS Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Augmentin, 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 diarrhea 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. 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.

Depakote ER (divalproex sodium) Extended Release Tablets Prescribing Information (in new labeling format)	WARNINGS AND PRECAUTIONS Hypothermia Interaction with Carbapenem Antibiotics Suicidal Ideation Monitoring: Drug Plasma Concentration Effect on Ketone and Thyroid Function Tests Effect on HIV and CMV Viruses Replication USE IN SPECIFIC POPULATIONS Pediatric Use Initial Paragraph Mania Migraine Prophylaxis Epilepsy Pediatric Safety Safety Studies - Mania Safety Study-Controlled Mania Trial Table 7 Safety Study - Open Label Mania Safety Data Safety Study - Epilepsy (open label) Safety Studies - Migraine (controlled and open label) Prior Safety Experience Nonclinical Development Toxicology	WARNINGS & PRECAUTIONS Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to < 35° C (95° F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate... Interaction with Carbapenem Antibiotics Carbapenem antibiotics (ertapenem, imipenem, meropenem) may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates... Suicidal Ideation Suicidal ideation may be a manifestation of certain psychiatric disorders, and may persist until significant remission of symptoms occurs. Close supervision of high risk patients should accompany initial drug therapy. Monitoring: Drug Plasma Concentration Since Depakote ER may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy... Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown... Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

Depakote (divalproex sodium) Sprinkle Capsules Prescribing Information (in new labeling format)	WARNINGS AND PRECAUTIONS Hypothermia Interaction with Carbapenem Antibiotics Monitoring: Drug Plasma Concentration Effect on Ketone and Thyroid Function Tests Effect on HIV and CMV Viruses Replication USE IN SPECIFIC POPULATIONS Pediatric Use Initial Section Pediatric Clinical Trials Nonclinical Developmental Toxicology	WARNINGS AND PRECAUTIONS Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate... Interaction with Carbapenem Antibiotics Carbapenem antibiotics (ertapenem, imipenem, meropenem) may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates... Monitoring: Drug Plasma Concentration Since Depakote may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy... Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown... Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

Invanz (ertapenem for injection) Prescribing Information	WARNINGS Seizure Potential PRECAUTIONS Drug Interactions A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics and may result in loss of seizure control...	WARNINGS: Seizure Potential Seizures and other CNS adverse experiences have been reported during treatment with Invanz... Carbapenems, including ertapenem, may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop below the therapeutic range or a seizure occurs...

Merrem I.V. (meropenem for injection) for Intravenous Use Only Prescribing Information	WARNINGS Seizure Potential Clostridium difficile associated diarrhea (CDAD) PRECAUTIONS Drug Interactions A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics and may result in loss of seizure control... Information for Patients Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued... ADVERSE REACTIONS Postmarketing Experience Hematologic A positive direct or indirect Coombs test Hemolytic Anemia	WARNINGS: Seizure Potential Seizures and other CNS adverse experiences have been reported during treatment with Merrem I.V.... Carbapenems, including meropenem, may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop below the therapeutic range or a seizure occurs... WARNINGS: Clostridium difficile Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Merrem I.V., 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 diarrhea 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. 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.

Monurol (fosfomycin tromethamine) Sachet 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...	WARNINGS Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Monurol, 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 diarrhea 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. 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.

NovoLog (insulin aspart [rDNA origin] injection) Solution for Subcutaneous Use Prescribing Information (in new labeling format) Patient Package Insert	WARNINGS AND PRECAUTIONS Hypersensitivity and Allergic Reactions Systemic Reactions ADVERSE REACTIONS Clinical Trial Experience Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus PATIENT PACKAGE INSERT How should I take NovoLog? Read the instructions for use that come with your NovoLog product... If you take too much NovoLog... If you forget to take your dose of NovoLog... What are the possible side effects of NovoLog? Serious allergic reaction (whole body reaction)... Call your doctor for medical advice about side effects... PATIENT INSTRUCTIONS FOR USE: NovoLog FlexPen Prefilled Syringe NovoLog 3 mL PenFill Cartridge	WARNINGS AND PRECAUTIONS Hypersensitivity and Allergic Reactions Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog have been reported post-approval. Generalized allergy to insulin may also cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis...

Penicillin G Potassium Injection, USP For Intravenous Use Only - GALAXY Container (PL 2040 Plastic) 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...	WARNINGS Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Penicillin G Potassium Injection, USP, 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 diarrhea 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. 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.

Premarin Intravenous (conjugated estrogens, USP) for Injection Prescribing Information Patient Package Insert	WARNINGS Malignant Neoplasms Breast Cancer PRECAUTIONS Ovarian Cancer ADVERSE REACTIONS Gastrointestinal Ischemic Colitis Central Nervous System Possible growth potentiation of benign meningioma PATIENT PACKAGE INSERT What can I do to lower my chances of getting a serious side effect with Premarin Intravenous?	WARNINGS Malignant Neoplasms: Breast Cancer The most important randomized clinical trial providing information about this issue in estrogen alone users is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg). In the estrogen alone substudy of WHI, after an average of 7.1 years of followup, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80, 95 percent nominal confidence interval [nCI] 0.62-1.04)...

Premarin (conjugated estrogens tablets, USP) Prescribing Information Patient Package Insert	WARNINGS Malignant Neoplasms Breast Cancer PRECAUTIONS Ovarian Cancer ADVERSE REACTIONS Gastrointestinal Ischemic Colitis Central Nervous System Possible growth potentiation of benign meningioma PATIENT PACKAGE INSERT What can I do to lower my chances of getting a serious side effect with Premarin? If you have a uterus, talk with your healthcare provider...	WARNINGS Malignant Neoplasms: Breast Cancer The most important randomized clinical trial providing information about this issue in estrogen alone users is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg). In the estrogen alone substudy of WHI, after an average of 7.1 years of follow-up, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer ( relative risk [RR] 0.80, 95 percent nominal confidence interval [nCI] 0.62-1.04)...

Premarin (conjugated estrogens) Vaginal Cream in a nonliquefying base Prescribing Information Patient Package Insert	WARNINGS Malignant Neoplasms Breast Cancer PRECAUTIONS Ovarian Cancer ADVERSE REACTIONS Gastrointestinal Ischemic Colitis Central Nervous System Possible growth potentiation of benign meningioma PATIENT PACKAGE INSERT What can I do to lower my chances of getting a serious side effect from Premarin Vaginal Cream? If you have a uterus, talk with your healthcare provider...	WARNINGS Malignant Neoplasms: Breast Cancer The most important randomized clinical trial providing information about this issue in estrogen alone users is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg). In the estrogen alone substudy of WHI, after an average of 7.1 years of followup, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80, 95 percent nominal confidence interval [nCI] 0.62-1.04)...

Prempro (conjugated estrogens/medroxyprogesterone acetate tablets) Premphase (conjugated estrogens/medroxyprogesterone acetate tablets) Prescribing Information Patient Package Insert	WARNINGS Malignant Neoplasms Breast Cancer PRECAUTIONS General Ovarian Cancer Nursing Mothers ...Prempro and Premphase should not be used during lactation. Pediatric Use ...no clinicial data have been collected in children. Geriatric Use ADVERSE REACTIONS Genitourinary System Dysmenorrhea/Pelvic Pain Central Nervous System (CNS) Exacerbation of Chorea	WARNINGS Malignant Neoplasms: Breast Cancer The most important randomized clinical trial providing information about this issue in estrogen plus progestin users is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg). In the estrogen plus progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA...

Prezista (darunavir) Tablets Prescribing Information Patient Package Insert See MedWatch Safety Alert posted 03/12/2008 for additional information on Prezista.	WARNINGS Hepatotoxicity PRECAUTIONS Patients with co-existing conditions Hepatic Impairment Table 11 HMG-CoA Reductase Inhibitors Rosuvastatin ADVERSE REACTIONS Patients co-infected with hepatitis B and/or hepatitis C virus PATIENT PACKAGE INSERT What should I tell my doctor before I take Prezista? have liver problems, including hepatitis B or C Can Prezista be taken with other medications? Digoxin (Lanoxin) What are the possible side effects of Prezista? Your healthcare professional should do blood tests prior to initiating combination treatment including Prezista...	WARNINGS: Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with Prezista/rtv. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with Prezista/rtv. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events. Postmarketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with Prezista/rtv therapy has not been established... Appropriate laboratory testing should be conducted prior to initiating therapy with Prezista/rtv and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Prezista/rtv treatment...

Primaxin I.M. (imipenem and cilastatin for injectable suspension) For Intramuscular Injection Only 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...	WARNINGS Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Primaxin I.M., 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 diarrhea 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. 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.

Primaxin I.V. (imipenem and cilastatin for injection) For Intravenous Injection Only 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...	WARNINGS Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Primaxin I.V., 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 diarrhea 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. 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.

Sandostatin LAR Depot (octreotide acetate for injectable suspension) Prescribing Information (in new labeling format)	WARNINGS AND PRECAUTIONS Cholelithiasis and Gallbladder Sludge Hyperglycemia and Hypoglycemia Thyroid Function Abnormalities ADVERSE REACTIONS Clinical Studies Experience Acromegaly Carcinoid and VIPomas Postmarketing Experience	WARNINGS AND PRECAUTIONS Cholelithiasis and Gallbladder Sludge Sandostatin may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Patients should be monitored periodically... Hyperglycemia and Hypoglycemia Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Sandostatin LAR treatment is initiated, or when the dose is altered. Antidiabetic treatment should be adjusted accordingly... Thyroid Function Abnormalities Octreotide suppresses the secretion of thyroid stimulating hormone, which may result in hypothyroidism...

Serevent Diskus (salmeterol xinafoate inhalation powder) Prescribing Information Medication Guide	WARNINGS Potential Drug Interactions PRECAUTIONS Drug Interactions Inhibitors of Cytochrome P450 3A4 MEDICATION GUIDE How do I use Serevent Diskus? While you are using Serevent Diskus twice a day, do not use other medicines that contain a long-acting beta2-agonist or LABA for any reason...	WARNINGS Potential Drug Interactions Because of the potential for drug interactions and the potential for increased risk of cardiovascular adverse events, the concomitant use of Servent Diskus with strong CYP 3A4 inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Drug Interactions).

Zevalin (ibritumomab tiuxetan) Injection for Intravenous Use Prescribing Information (in new labeling format)	WARNINGS AND PRECAUTIONS Serious Infusion Reactions ADVERSE REACTIONS Severe or life-threatening adverse reactions occuring... Infusion Reaction (1%)... Immunogenicity USE IN SPECIFIC POPULATIONS Pregnancy PATIENT COUNSELING INFORMATION	WARNINGS AND PRECAUTIONS Serious Infusion Reactions Rituximab, alone or as a component of the Zevalin therapeutic regimen, can cause severe including fatal infusiön reactions... ...Temporarily slow or interrupt the rituximab infusion for less severe infusion reactions. Immediately stop rituximab, In-111 Zevalin, or Y-90 Zevalin administration for severe infusion reactions...

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Brand (Generic) Name	Sections Modified
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate (butalbital, acetaminophen, caffeine, and codeine Phosphate) Capsules Prescribing Information	PRECAUTIONS Ultra-rapid Metabolizers of Codeine

Fioricet with Codeine (butalbital, acetaminophen, caffeine, and codeine phosphate) Capsules Prescribing Information	PRECAUTIONS Ultra-rapid Metabolizers of Codeine

Flolan (epoprostenol sodium) for Injection Prescribing Information	PRECAUTIONS General Flolan is a potent inhibitor of platelet aggregation. Therefore, an increased risk for hemorrhagic complications should be considered, particularly for patients with other risk factors for bleeding...

Pexeva (paroxetine mesylate) Tablets Prescribing Information	PRECAUTIONS General Abnormal Bleeding Information for Patients Abnormal Bleeding Drug Interactions Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, Warfarin)

Ponstel (mefenamic acid capsules, USP) Contact Sciele Pharma, Inc. at 1-800-461-3696 for current prescribing information. Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)	PRECAUTIONS Information for Patients In late pregnancy, as with other NSAIDs, Ponstel should be avoided because it may cause premature closure of the ductus arteriosus. MEDICATION GUIDE Table: NSAID that need a prescription - The following footnote was added after the table: *Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.

Prozac (fluoxetine capsules, USP) (fluoxetine oral solution, USP) (fluoxetine delayed-release capsules, USP) Prescribing Information	PRECAUTIONS General Abnormal Bleeding Hyponatremia Information for Patients Abnormal Bleeding Drug Interactions Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin, Warfarin) Geriatric Use

Septra I.V. Infusion (trimethoprim and sulfamethoxazole) Contact King Pharmaceuticals, Inc. at 1-800-776-3637 for current prescribing information.	PRECAUTIONS General Prescribing Septra in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria. Information for Patients Patients should be counseled that antibacterial drugs, including Septra should only be used to treat bacterial infections...

Septra Tablets (trimethoprim and sulfamethoxazole tablets) Septra DS Tablets (trimethoprim and sulfamethoxazole double-strength tablets) Septra Suspension (trimethoprim and sulfamethoxazole suspension) Septra Grape Suspension (trimethoprim and sulfamethoxazole grape suspension) Prescribing Information	PRECAUTIONS General Prescribing Septra in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria. Information for Patients Patients should be counseled that antibacterial drugs, including Septra should only be used to treat bacterial infections...

Symbyax (olanzapine and fluoxetine HCl capsules) Prescribing Information	PRECAUTIONS General Abnormal Bleeding Hyponatremia Information for Patients Abnormal Bleeding Drug Interactions Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin, Warfarin) Geriatric Use

Tigan (trimethobenzamide hydrochloride) Capsules Prescribing Information	PRECAUTIONS General Adjustment of Dose in Renal Failure Geriatric Use

Urex (methenamine hippurate) Tablets Prescribing Information	PRECAUTIONS General Prescribing Urex in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be counseled that antibacterial drugs including Urex should only be used to treat bacterial infections... Carcinogenesis, Mutagenesis, and Impairment of Fertility Methenamine

Ventolin HFA (albuterol sulfate) Inhalation Aerosol Prescribing Information (in new labeling format)	USE IN SPECIFIC POPULATIONS Pediatric Use Table 2

Zoloft (sertraline hydrochloride) Tablets and Oral Concentrate Prescribing Information	PRECAUTIONS Abnormal Bleeding Information for Patients Drug Interactions Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)

Zometa (zoledronic acid) Injection Concentrate for Intravenous Infusion Prescribing Information (in new labeling format)	USE IN SPECIFIC POPULATIONS Pediatric Use Zometa is not indicated for use in children...

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Brand (Generic) Name	Sections Modified
Abilify (aripiprazole) Tablets and Oral Solution Abilify Discmelt (aripiprazole) Orally Disintegrating Tablets Abilify (aripiprazole) Injection for Intramuscular Use Only Prescribing Information (in new labeling format)	ADVERSE REACTIONS Clinical Studies Experience Dose-Related Adverse Reactions Extrapyramidal Symptoms Dystonia - Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.......

Avastin (bevacizumab) for Intravenous Use Prescribing Information	ADVERSE REACTIONS Other Serious Adverse Events Cardiovascular Pulmonary Hypertension

Azmacort (triamcinolone acetonide) Inhalation Aerosol Prescribing Information	ADVERSE REACTIONS Postmarketing ...very rare reports of bone mineral density loss and osteoporosis, especially with prolonged use, which may lead to an increased risk of fractures.

Levitra (vardenafil HCl) Tablets Prescribing Information	ADVERSE REACTIONS Postmarketing Experience Neurologic Seizure and seizure recurrence have been reported postmarketing in temporal association with Levitra.

PegIntron and Rebetol (peginterferon alfa-2b and ribavirin) Prescribing Information Medication Guide	ADVERSE REACTIONS The adverse event profile in Study 3... MEDICATION GUIDE The most serious possible side effects of Peglntron and PegIntron/Rebetol therapy include: Body Organ Problems Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Moban (molindone hydrochloride tablets, USP) Prescribing Information	ADVERSE REACTIONS Neurological Extrapyramidal Symptoms Dystonia

Singulair (montelukast sodium) Tablets, Chewable Tablets, and Oral Granules Prescribing Information See MedWatch Safety Alert posted 03/27/2008 for additional information on Singulair	ADVERSE REACTIONS Postmarketing Experience Erythema Nodosum Suicidal Thinking and Behavior (Suicidality)

Ventavis (iloprost) Inhalation Solution Prescribing Information Patient Package Insert	ADVERSE REACTIONS Pre-marketing Experiences Postmarketing Experience (new subsection) PATIENT PACKAGE INSERT What are the side effects with Ventavis? Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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