MedWatch - August 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) -- August 2006

The detailed view includes drug products with safety labeling changes to the BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, or ADVERSE REACTIONS sections. Deletions or editorial revisions made to these sections are not included in this summary. 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
Aptivus (tipranavir) Capsules (click product name to read prescribing information) See MedWatch Safety Alert posted 6/30/2006 for additional information on Aptivus and intracranial hemorrhage.	BOXED WARNING WARNINGS Intracranial Hemorrhage Platelet Aggregation Inhibition Drug Interactions PRECAUTIONS Information for Patients Drug Interactions Table 9: Established and Other Potentially Significant Drug Interactions..... Antidepressants Trazadone Inhaled Nasal Steroids Fluticasone PDE5 Inhibitors ADVERSE REACTIONS Nervous System Disorders Intracranial Hemorrhage PATIENT PACKAGE INSERT	BOXED WARNING Aptivus co-administered with 200 mg Ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage. WARNINGS/Intracranial Hemorrhage Aptivus, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on Aptivus. WARNINGS/Platelet Aggregation Inhibition In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving Aptivus/ritonavir. Aptivus/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents or anticoagulants. WARNINGS/Drug Interactions 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 Aptivus/ritonavir and fluticasone propionate may produce the same effects..... Particular caution should be used when prescribing phosphodiesterase (PDE5) inhibitors for erectile dysfunction (e.g., sildefafil, tadalafil, or vardenafil) in patients receiving protease inhibitors, including Aptivus.....

Dexedrine (dextroamphetamine sulfate) Spansule Sustained-Release Capsules and Tablets (click product name to read prescribing information) See MedWatch Safety Alert posted 8/21/2006 for additional information on Dexedrine and new safety information on cardiac and psychiatric events.	BOXED WARNING WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Hypertension and Other Cardiovascular Conditions Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Psychiatric Adverse Events Pre-Existing Psychosis Bipolar Illness Emergence of New Psychotic or Manic Symptoms Aggression Long-Term Suppression of Growth Seizures Visual Disturbances	BOXED WARNING Misuse of amphetamines may cause sudden death and serious cardiovascular adverse events. 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.

Prevacid NapraPAC (lansoprazole delayed-release capsules and naproxen tablets kit) (click product name to read prescribing information) See MedWatch 6/15/2005 Safety Alert for additional information on COX-2 Selective and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) labeling.	BOXED WARNING (new) Cardiovascular Risk Gastrointestinal Risk CONTRAINDICATIONS WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Hypertension Congestive Heart Failure and Edema Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation Renal Effects Advanced Renal Disease Anaphylactoid Reactions Skin Reactions Pregnancy PRECAUTIONS General Naprosyn Hepatic Effects Hematological Effects Aspirin-Sensitive Asthma Information for Patients Laboratory Tests Naprosyn Drug Interactions Naprosyn ACE-inhibitors Aspirin Diuretics Lithium Methotrexate Warfarin Pregnancy Teratogenic Effects. Pregnancy Category C Naprosyn Nonteratogenic Effects Naprosyn Labor and Delivery Nursing Mothers Naprosyn Pediatric Use Geriatric Use Naprosyn ADVERSE REACTIONS Naprosyn MEDICATION GUIDE	BOXED WARNING/Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. Prevacid NapraPAC is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. BOXED WARNING/Gastrointestinal Risk NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding and perforation of the stomach and intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Patients with a history of gastric and/or duodenal ulcers (especially patients with a history of bleeding or perforation) and geriatric patients are at greater risk for serious gastrointestinal events. CONTRAINDICATIONS Prevacid NapraPAC is contraindicated in patients who have experienced aspirin or NSAID-related asthma, urticaria, or allergic-type reactions. Severe, rarely fatal, anaphylactic reactions to NSAIDs have been reported in such patients. Prevacid NapraPAC is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. WARNINGS See highlighted WARNINGS section for revised labeling.

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Nafcillin Injection, USP for Intravenous Use Only (click product name to read prescribing information)	SYSTEMIC ANTIBACTERIAL DRUG PRODUCTS STATEMENT to reduce the development of drug-resistant bacteria. CONTRAINDICATIONS PRECAUTIONS General Prescribing Nafcillin Injection, USP 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 Nafcillin Injection, USP should only be used to treat bacterial infections.....	CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

Prevpac (lansoprazole 30mg capsules/amoxicillin 500mg capsules/ clarithromycin 500mg tablets, USP) Please contact TAP Pharmaceutical Products, Inc. at 1-800-622-2011 for prescribing information.	CONTRAINDICATIONS WARNINGS Clarithromycin PRECAUTIONS Drug Interactions Clarithromycin CYP3A Drug Interactions Ergotamine/ dihydroergotamine ADVERSE REACTIONS Postmarketing Body as a Whole Anaphylactic/Anaphylactoid Reactions Clarithromycin Post-marketing Experience Interstitial Nephritis There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients. MEDICATION GUIDE	CONTRAINDICATIONS Concomitant administration of Prevpac with cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine is contraindicated. WARNINGS/Clarithromycin There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients. PRECAUTIONS/Drug Interactions Clarithromycin Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity. CYP3A Drug Interactions: Ergotamine/dihydroergotamine Post-marketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin with ergotamine or dihydroergotamine is contraindicated.

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Cordarone (amiodarone hydrochloride) Intravenous (click product name to read prescribing information)	WARNINGS Thyrotoxicosis PRECAUTIONS Thyroid Abnormalities	Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. If any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered.

Cordarone (amiodarone hydrochloride) Tablets (click product name to read prescribing information)	WARNINGS Thyrotoxicosis PRECAUTIONS Thyroid Abnormalities MEDICATION GUIDE	Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. If any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered.

Coreg (carvedilol) Tablets (click product name to read prescribing information)	WARNINGS Diabetes and Hypoglycemia PRECAUTIONS Effects on Glycemic Control in Type 2 Diabetic Patients .....In a study designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements.	In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. In congestive heart failure patients, there is a risk of worsening hyperglycemia.

Epzicom (abacavir sulfate and lamivudine) Tablets (click product name to read prescribing information)	WARNINGS Use With Interferon- and Ribavirin-Based Regimens PRECAUTIONS Immune Reconstitution Syndrome MEDICATION GUIDE	In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine, a component of Epzicom. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and Epzicom should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of Epzicom should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6).....

Focalin (dexmethylphenidate hydrochloride tablets) (click product name to read prescribing information)	WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Hypertension and Other Cardiovascular Conditions Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Psychiatric Adverse Events Pre-Existing Psychosis Bipolar Illness Emergence of New Psychotic or Manic Symptoms Aggression Long-Term Suppression of Growth Seizures Visual Disturbances PATIENT PACKAGE INSERT	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.

Focalin XR (dexmethylphenidate hydrochloride) Extended-Release Capsules (click product name to read prescribing information)	WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Hypertension and Other Cardiovascular Conditions Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Psychiatric Adverse Events Pre-Existing Psychosis Bipolar Illness Emergence of New Psychotic or Manic Symptoms Aggression Long-Term Suppression of Growth Seizures Visual Disturbances PATIENT PACKAGE INSERT	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.

Forane (isoflurane, USP) Liquid for Inhalation (click product name to read prescribing information)	WARNINGS Perioperative Hyperkalemia Malignant Hyperthermia PRECAUTIONS General As with other halogenated anesthetic agents, Forane (isoflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics. ADVERSE REACTIONS There have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anesthetic agents, including Forane (isoflurane, USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of Forane (isoflurane, USP) to these events cannot be established with certainty.	WARNINGS/Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. WARNINGS/Malignant Hyperthermia In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc.) Treatment includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management). Renal failure may appear later, and urine flow should be sustained if possible.

Keppra (levetiracetam) Tablets and Oral Solution (click product name to read prescribing information)	WARNINGS Neuropsychiatric Adverse Events Pediatric Patients Myoclonic Seizures PRECAUTIONS Hematologic Abnormalities Juvenile Myoclonic Epilepsy ADVERSE REACTIONS Myoclonic Seizures Table 10: Incidence (%) Of Treatment-Emergent Adverse Events in a Placebo-Controlled, Add-On Study In Patients 12 Years Of Age And Older With Myoclonic Seizures Discontinuation or Dose Reduction in Well-Controlled Clinical Studies Myoclonic Seizures Table 13: Adverse Events that Resulted in Discontinuation or Dose Reduction..... Post-marketing Experience Abnormal Liver Function Test Hepatitis Weight Loss PATIENT PACKAGE INSERT	During clinical development, the number of patients with myoclonic seizures exposed to Keppra was considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse events was more likely to occur in the myoclonic seizure population. In adult and adolescent patients experiencing myoclonic seizures, Keppra is associated with somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME.....

Metadate CD (methylphenidate hydrochloride, USP) Extended-Release Capsules (click product name to read prescribing information)	WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Hypertension and Other Cardiovascular Conditions Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Psychiatric Adverse Events Pre-Existing Psychosis Bipolar Illness Emergence of New Psychotic or Manic Symptoms Aggression Long-Term Suppression of Growth Seizures Visual Disturbances PATIENT PACKAGE INSERT	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.

Methylin (methylphenidate hydrochloride chewable tablets) (click product name to read prescribing information)	WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Hypertension and Other Cardiovascular Conditions Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Psychiatric Adverse Events Pre-Existing Psychosis Bipolar Illness Emergence of New Psychotic or Manic Symptoms Aggression Long-Term Suppression of Growth Seizures Visual Disturbances	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.

Methylin (methylphenidate hydrochloride oral solution) (click product name to read prescribing information)	WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Hypertension and Other Cardiovascular Conditions Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Psychiatric Adverse Events Pre-Existing Psychosis Bipolar Illness Emergence of New Psychotic or Manic Symptoms Aggression Long-Term Suppression of Growth Seizures Visual Disturbances	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.

Naropin (ropivacaine HCl) Injection (click product name to read prescribing information)	WARNINGS MANAGEMENT OF LOCAL ANESTHETIC EMERGENCIES Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome.	.....There have been rare reports of cardiac arrest during the use of Naropin for epidural anesthesia or peripheral nerve blockade, the majority of which occurred after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome.

Paxil (paroxetine hydrochloride) Tablets and Oral Suspension (click product name to read prescribing information) See MedWatch Safety Alert posted on 5/12/2006 for additional details on WARNINGS and Clinical Worsening and Suicide Risk. See MedWatch Safety Alert posted on 7/19/2006 for additional details on Triptans, Selective Serotonin Reuptake Inhibitors (SSRIs), Selective Serotonin/ Norepinephrine Reuptake Inhibitors (SNRIs), and Serotonin Syndrome. See MedWatch Safety Alert posted on 7/19/2006 for additional details on SSRIs and Treatment Challenges of Depression in Pregnancy.	WARNINGS Clinical Worsening and Suicide Risk Serotonin Syndrome Usage in Pregnancy Nonteratogenic Effects PRECAUTIONS Discontinuation of Treatment with Paxil Tinnitus Information for Patients Drug Interactions Serotonergic Drugs Triptans Fosamprenavir/Ritonavir Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy). ADVERSE REACTIONS Hallucinations In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 receiving drug and 4 of 3,187 patients receiving placebo.	WARNINGS/Clinical Worsening and Suicide Risk .....In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. WARNINGS/Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur with use of Paxil, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs)..... WARNINGS/Usage in Pregnancy: Nonteratogenic Effects Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality..... .....Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Paxil CR (paroxetine hydrochloride) Controlled-Release Tablets (click product name to read prescribing information) See MedWatch Safety Alert posted on 5/12/2006 for additional details on WARNINGS and Clinical Worsening and Suicide Risk. See MedWatch Safety Alert posted on 7/19/2006 for additional details on Triptans, Selective Serotonin Reuptake Inhibitors (SSRIs), Selective Serotonin/ Norepinephrine Reuptake Inhibitors (SNRIs), and Serotonin Syndrome. See MedWatch Safety Alert posted on 7/19/2006 for additional details on SSRIs and Treatment Challenges of Depression in Pregnancy.	WARNINGS Clinical Worsening and Suicide Risk Serotonin Syndrome Usage in Pregnancy Nonteratogenic Effects PRECAUTIONS Discontinuation of Treatment with Paxil CR Tinnitus Information for Patients Drug Interactions Serotonergic Drugs Triptans Fosamprenavir/Ritonavir Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy). ADVERSE REACTIONS Hallucinations In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 receiving drug and 4 of 3,187 patients receiving placebo.	WARNINGS/Clinical Worsening and Suicide Risk .....In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. WARNINGS/Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur with use of Paxil CR, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs)..... WARNINGS/Usage in Pregnancy: Nonteratogenic Effects Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality..... .....Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Plavix (clopidogrel bisulfate tablets) (click product name to read prescribing information) This supplemental new drug application provides for revisions to the WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the package insert.	WARNINGS Thrombotic thrombocytopenic purpura (TTP) PRECAUTIONS Information for Patients ADVERSE REACTIONS Post-marketing Experience	TTP has been reported rarely following use of Plavix, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

Rebetol (ribavirin, USP) Capsules and Oral Solution (click product name to read prescribing information)	WARNINGS Dental and Periodontal Disorders	Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of Rebetol and interferon alfa-2b or pegylated interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition, some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Ritalin LA (methylphenidate hydrochloride) Extended-Release Capsules (click product name to read prescribing information)	WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Hypertension and Other Cardiovascular Conditions Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Psychiatric Adverse Events Pre-Existing Psychosis Bipolar Illness Emergence of New Psychotic or Manic Symptoms Aggression Long-Term Suppression of Growth Seizures Visual Disturbances PATIENT PACKAGE INSERT	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.

Ritalin (methylphenidate hydrochloride tablets, USP) Ritalin SR (methylphenidate hydrochloride, USP) Sustained-Release Tablets (click product name to read prescribing information)	WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Adults Hypertension and Other Cardiovascular Conditions Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Psychiatric Adverse Events Pre-Existing Psychosis Bipolar Illness Emergence of New Psychotic or Manic Symptoms Aggression Long-Term Suppression of Growth Seizures Visual Disturbances	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.

Roferon-A (interferon alfa-2a, recombinant) Please contact Hoffman- LaRoche, Inc. at 1-973-235-5000 for prescribing information.	WARNINGS Infections Pancreatitis ADVERSE REACTIONS Post-marketing Metabolic and Nutritional Hypertriglyceridemia/ Hyperlipidemia	Infections While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with neutropenia. Serious and severe infections (bacterial, viral, fungal), some fatal, have been reported during treatment with alpha interferons including Roferon-A. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered. Pancreatitis Pancreatitis has been observed in patients receiving alpha interferon treatment, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to Roferon has not been established, marked triglyceride elevation is a risk factor for development of pancreatitis. Roferon should be suspended if symptoms or signs suggestive of pancreatitis are observed. In patients diagnosed with pancreatitis, discontinuation of therapy with Roferon should be considered.

Suprane (desflurane, USP) Liquid for Inhalation (click product name to read prescribing information)	WARNINGS Perioperative Hyperkalemia Malignant Hyperthermia PRECAUTIONS Initial Section As with other halogenated anesthetic agents, Suprane (desflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics. ADVERSE REACTIONS Adverse reactions reported only from post-marketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized. There have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anesthetic agents, including Suprane (desflurane, USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of Suprane (desflurane, USP) to these events cannot be established with certainty.	WARNINGS/Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. WARNINGS/Malignant Hyperthermia In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, desflurane induced malignant hyperthermia. The clinical syndrome is signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia.....

Trizivir (abacavir sulfate/ lamivudine/zidovudine) Tablets (click product name to read prescribing information)	WARNINGS Use with Interferon- and Ribavirin-Based Regimens Other MEDICATION GUIDE	WARNINGS/Use with Interferon- and Ribavirin-Based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine and zidovudine, components of Trizivir. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and Trizivir should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of Trizivir should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6)..... WARNINGS/Other Trizivir contains fixed doses of 3 nucleoside analogues.....

Videx (didanosine) Chewable/Dispersible Buffered Tablets Videx (didanosine) Pediatric Powder for Oral Solution (click product name to read prescribing information)	WARNINGS Hepatic Impairment and Toxicity PRECAUTIONS Peripheral Neuropathy .....Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Immune Reconstitution Syndrome Drug Interactions Table 7: Established Drug Interactions with Videx Tenofovir Disoproxil Fumarate Nucleoside/nucleotide Analogues ADVERSE REACTIONS Initial Section Hepatotoxicity and Severe Peripheral Neuropathy	It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. The safety and efficacy of Videx have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Hepatotoxicity and hepatic failure resulting in death were reported during post-marketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.

Videx EC (didanosine) Delayed-Release Capsules [Enteric-Coated Beadlets] (click product name to read prescribing information)	WARNINGS Hepatic Impairment and Toxicity PRECAUTIONS Peripheral Neuropathy .....Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Immune Reconstitution Syndrome Drug Interactions Table 8: Established Drug Interactions with Videx EC..... Tenofovir Disoproxil Fumarate Nucleoside/nucleotide Analogues ADVERSE REACTIONS Initial Section Hepatotoxicity and Severe Peripheral Neuropathy	It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. The safety and efficacy of Videx EC have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Hepatotoxicity and hepatic failure resulting in death were reported during post-marketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.

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Brand (Generic) Name	Sections Modified
Actonel (risedronate sodium tablets) (click product name to read prescribing information)	PRECAUTIONS Geriatric Use ADVERSE REACTIONS Table 6: Adverse Events Occurring in ≥ 2% of Patients of Either Treatment Group..... Osteoporosis Prevention Men with Osteoporosis PATIENT PACKAGE INSERT

Actoplus Met (pioglitazone hydrochloride and metformin hydrochloride tablets) (click product name to read prescribing information)	PRECAUTIONS General Pioglitazone Hydrochloride Macular Edema ADVERSE REACTIONS Post-marketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received.

Actos (pioglitazone hydrochloride) Tablets (click product name to read prescribing information)	PRECAUTIONS General Macular Edema ADVERSE REACTIONS Post-marketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received.

Atacand (candesartan cilexetil) Tablets (click product name to read prescribing information)	PRECAUTIONS General Major Surgery/Anesthesia

Atacand HCT (candesartan cilexetil and hydrochlorothiazide) Tablets (click product name to read prescribing information)	PRECAUTIONS General Candesartan Major Surgery/Anesthesia

Boniva (ibandronate sodium) Injection (click product name to read prescribing information)	PRECAUTIONS Musculoskeletal Pain PATIENT PACKAGE INSERT

Cozaar (losartan potassium tablets) (click product name to read prescribing information)	PRECAUTIONS Drug Interactions Lithium ADVERSE REACTIONS Post-marketing Experience Nervous System Disorders Dysgeusia Skin Erythroderma

Diprolene (augmented betamethasone dipropionate) AF Cream, 0.05% (click product name to read prescribing information)	PRECAUTIONS Geriatric Use

Diprolene (augmented betamethasone dipropionate) Lotion, 0.05% (click product name to read prescribing information)	PRECAUTIONS Geriatric Use
Diprolene (augmented betamethasone dipropionate) Ointment, 0.05% (click product name to read prescribing information)	PRECAUTIONS Geriatric Use

E.E.S. (erythromycin ethylsuccinate) (click product name to read prescribing information)	PRECAUTIONS Geriatric Use

Hyzaar (losartan potassium/hydrochlorothiazide tablets) (click product name to read prescribing information	PRECAUTIONS Drug Interactions Losartan Potassium Lithium ADVERSE REACTIONS Post-marketing Experience Skin Erythroderma

Lexiva (fosamprenavir calcium) Tablets (click product name to read prescribing information	PRECAUTIONS Drug Interactions Table 13: Established and Other Potentially Significant Drug Interactions..... Antifungals Ketoconazole

OptiMARK (gadoversetamide injection) for Intravenous Injection Only (click product name to read prescribing information)	PRECAUTIONS Laboratory Test Interactions Interference by OptiMARK Injection in the measurement of serum iron, copper and zinc has been observed. OptiMARK Injection causes interference in the measurement of serum calcium using the ortho-cresophthalin complexone (OCP) colorimetric method.....

PCE Dispertab Tablets (erythromycin particles in tablets) (click product name to read prescribing information)	PRECAUTIONS Geriatric Use

Plavix (clopidogrel bisulfate tablets) (click product name to read prescribing information) This supplemental new drug application provides for the following new use of Plavix (clopidogrel bisulfate) 75 mg tablets: For patients with ST-segment elevation acute myocardial infarction, Plavix has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.	PRECAUTIONS Drug Interactions Thrombolytics Oral Anticoagulants Geriatric Use ADVERSE REACTIONS Initial Paragraph In CLARITY, the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in hemoglobin > 5 g/dL) was similar between groups (1.3% versus 1.1% in the Plavix + aspirin..... The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low..... Table 6: Number (%) of Patients with Bleeding Events in COMMIT Table 7: Adverse Events Occurring in ≥2.5% of Plavix Patients in CAPRIE Gastrointestinal System Disorders Any Event No additional clinically relevant events to those observed in CAPRIE with a frequency ≥ 2.5%, have been reported during the CURE and CLARITY controlled studies. COMMIT collected only limited safety data. Gastrointestinal System Disorders Peptic, gastric or duodenal ulcer Gastritis White Cell and Reticuloendothelial System Disorders Neutropenia

Remicade (infliximab) for IV Injection (click product name to read prescribing information)	PRECAUTIONS Nursing Mothers .....Women should not breast-feed their infants while taking Remicade..... ADVERSE REACTIONS Initial Section Immunogenicity Other Adverse Reactions

Ultram ER (tramadol hydrochloride) Extended-Release Tablets (click product name to read prescribing information)	PRECAUTIONS Information for Patients Patients should be informed that Ultram ER is for oral use only and should be swallowed whole. The tablets should not be chewed, crushed, or split.

Ziagen (abacavir sulfate) Tablets and Oral Solution (click product name to read prescribing information)	PRECAUTIONS Immune Reconstitution Syndrome Information for Patients Ziagen should not be coadministered with Epzicom or Trizivir ADVERSE REACTIONS Table 6: Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity..... Hypersensitivity Reaction Table 9: Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in Study CNA3005 MEDICATION GUIDE

Zofran (ondansetron hydrochloride) Injection Zofran (ondansetron hydrochloride) Injection Premixed (click product name to read prescribing information)	PRECAUTIONS General .....Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. ADVERSE REACTIONS Observed During Clinical Practice Cardiovascular QT Prolongation Eye Disorders .....These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.

Zofran (ondansetron hydrochloride) Tablets and Oral Solution Zofran ODT (ondansetron hydrochloride) Orally Disintegrating Tablets (click product name to read prescribing information)	PRECAUTIONS General .....Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. ADVERSE REACTIONS Observed During Clinical Practice Cardiovascular Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. Special Senses Eye Disorders .....These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.

Zyprexa (olanzapine tablets) Zyprexa Zydis (olanzapine orally disintegrating tablets) Zyprexa IntraMuscular (olanzapine for injection) (click product name to read prescribing information)	PRECAUTIONS General Hemodynamic Effects Hypoventilation Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression.....

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Brand (Generic) Name	Sections Modified
Actonel with Calcium (risedronate sodium tablets with calcium carbonate tablets, USP) (click product name to read prescribing information)	ADVERSE REACTIONS Post-marketing Experience Eye Inflammation Osteonecrosis of the Jaw PATIENT PACKAGE INSERT

Aloxi (palonosetron HCl injection) (click product name to read prescribing information)	ADVERSE REACTIONS Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from post-marketing experience.

Crixivan (indinavir sulfate) Capsules (click product name to read prescribing information)	ADVERSE REACTIONS Post-marketing Experience Urogenital System Renal insufficiency PATIENT PACKAGE INSERT

Humira (adalimumab) (click product name to read prescribing information)	ADVERSE REACTIONS Ankylosing Spondylitis Clinical Trials

Invanz (ertapenem for injection) (click product name to read prescribing information)	ADVERSE REACTIONS Adults In a clinical study in adults for the prophylaxis of surgical site infection following elective colorectal surgery in which 476 patients received..... Table 7: Incidence (%) of Adverse Experiences Reported..... Adverse Laboratory Changes Adults In a clinical study in adults for the prophylaxis of surgical site infection following elective colorectal surgery in which 476 patients received.....

Primaxin I.M. (imipenem and cilastatin for injectable suspension) (click product name to read prescribing information)	ADVERSE REACTIONS Systemic Adverse Reactions Gastrointestinal Hepatitis (including Fulminant Hepatitis) Hepatic Failure

Primaxin I.V. (imipenem and cilastatin for Injection) (click product name to read prescribing information)	ADVERSE REACTIONS Systemic Adverse Reactions Gastrointestinal Hepatitis (including Fulminant Hepatitis) Hepatic Failure

Reyataz (atazanavir) Capsules (click product name to read prescribing information)	ADVERSE REACTIONS Post-marketing Experience

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