Special Alerts

Efalizumab: New Boxed Warnings (Associated With Life-threatening Infections, Including Progressive Multifocal Leukoencephalopathy) - October 2008

The Food and Drug Administration (FDA) has informed health care professionals regarding the addition of black boxed warnings to the efalizumab prescribing information related to the development of progressive multifocal leukoencephalopathy (PML) and other life-threatening infections (bacterial, viral, fungal and other opportunistic infections).

Prior to this labeling change, Genentech, Inc issued a "Dear Healthcare Professional" letter informing of a case of PML, reported in a patient who had received efalizumab (for >4 years) for the treatment of plaque psoriasis. This patient was not receiving other immunosuppressants. PML is a demyelinating central nervous system disease due to latent JC virus. Any neurological change in patients receiving efalizumab should be evaluated promptly; if clinically indicated, consider neurology consultation, brain MRI and lumbar puncture for suspected PML. Discontinue efalizumab in patients who develop PML.

Labeling changes also include addition of data from juvenile murine studies, which suggests a risk for permanent immunosuppression in association with repeat efalizumab administration in children. Efalizumab is not approved for use in patients under the age of 18 years.

A medication guide regarding these safety concerns will be available in the near future.

For more information, see:

http://www.fda.gov/medwatch/safety/2008/safety08.htm#Raptiva

http://www.gene.com/gene/products/information/pdf/raptiva_dhcp.pdf

Tylenol® With Codeine: Health Canada Issues Warning Concerning Potentially Increased Morphine Levels In Milk of Nursing Mothers - October 2008

Janssen-Ortho Inc, in conjunction with Health Canada, has issued a "Dear Healthcare Professional" letter concerning use of Tylenol® with Codeine (acetaminophen with codeine) products and the risk of elevated morphine levels in the serum and breast milk of nursing women who are ultra-rapid metabolizers of codeine. Consequently, infants of nursing mothers with a certain CYP2D6 (converts codeine to morphine) genotype, may be exposed to potentially dangerous serum levels of morphine as well.

Available data indicates the incidence of this CYP2D6 genotype in the general population varies and is estimated to occur in the following populations as follows: North African, Ethiopian, and Arab (16% to 28%); Chinese, Japanese, and Hispanic (0.5% to 1%); Caucasian (1% to 10%); African American (3%).

When using codeine in nursing women, healthcare providers are urged to prescribe and administer the lowest possible dose for the shortest time necessary to achieve adequate clinical effect. Nursing women should be advised of signs/symptoms of morphine toxicity for themselves (extreme sedation, confusion, shallow breathing) and for their infants (sedation, dyspnea, decreased tone, difficult breastfeeding). The manufacturer will be updating the product labeling to include these new warnings and precautions. A similar warning had previously been released in the U.S. in August 2007.

Additional information can be found at the following websites:

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/tylenol_codeine_hpc-cps-eng.php

U.S.: http://www.fda.gov/cder/drug/InfoSheets/HCP/codeineHCP.htm

Manufacturers Voluntarily Change Pediatric OTC Product Labeling - October 2008

Leading manufacturers of over-the-counter (OTC) pediatric cough and cold products, in consultation with the Food and Drug Administration (FDA), have announced that they are voluntarily transitioning product labeling as it relates to children <4 years of age. The decision to change the labeling followed a meeting on October 2, 2008, conducted by the FDA to gather additional information related to the use of these products in children. The safety of the ingredients in these products was not in question. It was found that dosing errors and accidental ingestions were the leading cause of rare adverse events in children. The new product labeling will state "Do not use in children under four years of age." In addition, products with certain antihistamines will warn parents not to use these products to sedate or make a child sleepy. Labeling of adult products will not change. New product labels will be introduced during the 2008-2009 cough and cold season and some products will have the updated labeling by mid-October. Products with the old labeling will not be removed from the market. Prescription products are not affected.

It is important to note that these medications have not been shown to be unsafe when used correctly. Pharmacists may continue to see health care practitioners recommending these agents for use in pediatric patients, and should help to ensure that they are being used safely and at appropriate dosages. Parents should be advised that OTC cough and cold products are safe and effective when used as directed, but that they should not be used in children <4 years of age unless instructed to do so by their healthcare provider. Counseling tips from the Consumer Healthcare Products Association (CHPA) also include:

• Always follow dosing instructions exactly and use measuring devices provided with the medicine.
• Never give 2 medicines at the same time that contain the same active ingredient.
• Do not give a medicine intended for use in adults to a child.

Additional tips and information related to the labeling changes can be found on the following educational website of the CHPA: http://www.otcsafety.org.

The FDA had previously issued a Public Health Advisory reminding patients and caregivers that OTC cough and cold medications should not be used to treat infants and children <2 years of age. This is in response to the Centers for Disease Control and Prevention (CDC) report which noted that during 2004 and 2005, ~1519 children <2 years of age were seen in emergency departments for adverse effects, including overdose, associated with products containing nasal decongestants (eg, pseudoephedrine), antihistamines (eg, carbinoxamine), and cough suppressants (eg, dextromethorphan). In October of 2007, several manufacturers voluntarily removed these products in order to help reduce dosing errors and overdose in this age group.

Additional information available at the following FDA website: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01899.html

For additional information on the advisory posted in January 2008, refer to the following websites:

http://www.fda.gov/medwatch/safety/2008/safety08.htm#cough

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5601a1.htm, Centers for Disease Control, "Infant Deaths Associated with Cough and Cold Medications - Two States, 2005," MMWR Morb Mortal Wkly Rep, 2007, 56(01):1-4.

Tiotropium (Spiriva®): Ongoing Safety Evaluation of Stroke Risk - October 2008

The U.S. Food and Drug Administration (FDA) has received preliminary data from the UPLIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium) trial. The UPLIFT trial is an international trial randomizing ~6,000 COPD patients to 4 years of tiotropium or placebo. The primary endpoint determines if tiotropium reduces the rate of decline in lung function over time (Tashkin, 2008). A secondary endpoint evaluates tiotropium's safety profile, with attention on the risk of stroke (mortality caused by stroke and adverse events reported as stroke).

Two recent analyses (Lee, 2008; Singh, 2008) showed an association with inhaled anticholinergics and an increase risk of cardiovascular events in COPD patients. Preliminary evaluation of the UPLIFT trial data did not support an association between the use of tiotropium and an increased risk of stroke.

Based upon these results, the FDA is going to independently examine the data from the UPLIFT trial. The FDA expects to receive the complete report for UPLIFT in November 2008 and review the final results.

Additional information may be found at http://www.fda.gov/cder/drug/early_comm/tiotropium.htm

HMG-CoA Reductase Inhibitors: Evidence Does Not Suggest Increased Incidence of Amyotrophic Lateral Sclerosis (ALS) - Results of FDA Analysis - September 2008

The U.S. Food and Drug Administration's (FDA) review of 41 long-term controlled clinical trials of HMG-CoA reductase inhibitors finds no evidence of an increased incidence of ALS (also known as Lou Gehrig's disease) related to these medications. This analysis occurred after the FDA had received notice of numerous adverse events of which 109 of these reports mentioned ALS, Lou Gehrig's disease, or motor neurone disease. The clinical trials included in the analysis had a median duration of treatment of 3.3 years (range of duration: 6 months to 5 years) and involved 120,964 patients. The analysis identified a total of 19 cases of ALS - 9 cases per 64,602 patients (0.014%) with statin therapy and 10 cases per 56,362 patients (0.017%) with placebo. The incidence rates, based on approximately 400,000 person-years, were 4.2 per 100,000 person-years in the statin-treated group and 5 per 100,000 person-years in the placebo-treated group.

The FDA recommends that health care providers continue to prescribe, and patients continue to use these products as described within their labeling.

For more information, healthcare professionals may refer to the following:

Colman E, Szarfman A, Wyeth J, et al, "An Evaluation of a Data Mining Signal for Amyotrophic Lateral Sclerosis and Statins Detected in FDA's Spontaneous Adverse Event Reporting System," Pharmacoepidemiol Drug Saf, 2008 (epub ahead of print)

Epoetin: Ongoing Safety Review - September 2008

The U.S. Food and Drug Administration (FDA), Amgen Inc, and Ortho Biotech have issued a "Dear Health Care Professional" letter alerting practitioners of revised labeling for erythropoiesis-stimulating agents (ESAs) (epoetin alfa [Epogen®, Procrit®] and darbepoetin alfa [Aranesp®]). The labeling for these products has been updated, including changes to the indications, boxed warnings, and dosing reflecting that ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is curative and ESA therapy should not be initiated if the hemoglobin level is >10 g/dL. Medication guides have been developed to communicate the risks and benefits of ESAs for patients.

Prompted by information from studies on ESA use, over the last year there have been alerts, new labeling and/or "Dear Health Care Professional" letters issued regarding ESA use in both patients with cancer and patients with chronic renal failure. The studies in patients with cancer provided evidence of shortened time to tumor progression and increased mortality (decreased overall survival) in cancer patients (breast, cervical, head and neck, lymphoid, and nonsmall cell lung cancer) who received ESAs; however, in some studies, the ESA doses were targeted to maintain hemoglobin levels >12 g/dL. Based on this risk, as well as the risk of serious cardio- and thrombovascular events, labeling revisions have included recommendations from FDA advisory committees on appropriate ESA use in cancer and chronic renal failure patients and have consisted of expanded and/or strengthened boxed warnings, safety information, and revised dosing information. Practitioners are reminded that ESA use is only appropriate in the treatment of anemia in cancer patients due to concomitant chemotherapy, and therapy should be discontinued following completion of chemotherapy.

Boxed warning changes concerning use in chronic renal failure patients have included data from two studies showing an increased risk of death and serious cardiovascular events when ESAs were administered to achieve higher target hemoglobin compared with lower hemoglobin levels (13.5 vs 11.3 g/dL and 14 vs 10 g/dL). Dosing recommendations for chronic renal failure now specify a target hemoglobin range of 10-12 g/dL to achieve and maintain, including guidelines for increasing doses in patients not achieving recommended target hemoglobin range. Additional recommendations have been created for those patients unable to achieve the target hemoglobin range (despite appropriate titrations) with precautions against continuing to increase the dose and a consideration of ESA discontinuation.

The FDA is also aware of preliminary findings from a German trial of epoetin (at doses higher than recommended for anemia) to treat acute ischemic stroke. Although analysis is ongoing, preliminary findings show increased mortality in the epoetin group, when compared to the placebo group.

The FDA Medwatch alerts and a link to the most recent "Dear Healthcare Professional" letter can be found at

http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA2

http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA3

http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA

Sodium Phenylacetate and Sodium Benzoate: FDA Issues Alert on Particulate Matter Found in Admixture - September 2008

The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of possible particulate matter detected by Ucyclyd Pharma in their Ammonul® injection. The company is advising, to ensure patient safety, that a Millex® Durapore GV 33 mm Sterile Syringe Filter (0.22 micron) be used when injecting Ammonul® into the D10W bag during admixture. This filter should be used regardless of visible particulate matter in the vial. Testing of the filter has confirmed that the filter will remove the particulate matter. Ucyclyd Pharma will be packaging filters with all shipments until further notice. Healthcare providers may contact Ucyclyd Pharma at 1-888-829-2593 or 1-800-900-6389 24 hours/day, 7 days/week with questions or concerns.

Further information may be obtained at http://www.fda.gov/medwatch/safety/2008/safety08.htm#Ammonul

Trivaris™ Injectable Suspension: Product Availability - September 2008

This product was approved by the Food & Drug Administration (FDA) in June, 2008. Product launch is expected to be in the Fall of 2008.

ReFacto®: Product Availability - September 2008

ReFacto® will no longer be available after May 31, 2009. Wyeth has replaced it with Xyntha™ which is available as of September 2008.

Rituximab: Additional Report of Progressive Multifocal Leukoencephalopathy (PML) - September 2008

In conjunction with the U.S. Food and Drug Administration (FDA), Genentech, Inc has issued a "Dear Healthcare Professional" letter informing of an additional case of fatal PML, reported in a patient who had received rituximab for the treatment of rheumatoid arthritis (RA). In this case, PML was diagnosed 18 months after the last rituximab dose; confounding factors include a long history of immunosuppressant therapy and treatment with a tumor necrosis factor (TNF) antagonist for RA, plus development of oropharyngeal cancer (subsequently treated with chemotherapy and radiation therapy [after rituximab therapy, but 9 months prior to the diagnosis of PML]).

PML has previously been associated with rituximab use, although previous reports were confined to patients treated for hematologic malignancies and an unapproved use, systemic lupus erythematosus (SLE). The product labeling, which previously contained warnings regarding PML, has been updated to reflect this new report. Any new-onset neurological changes should be evaluated promptly; consider neurology consultation, brain MRI, and lumbar puncture for suspected PML. Discontinue rituximab in patients who develop PML; consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.

Additional information may be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#Rituxan

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Ezetimibe (Zetia®), Simvastatin (Zocor®), and Ezetimibe/Simvastatin (Vytorin®): Preliminary Results From the SEAS Trial - September 2008

The U.S. Food and Drug Administration (FDA) has communicated important information regarding an ongoing safety review of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. The SEAS trial (Rossebo, 2008), recently available online, evaluated the effects of the combination ezetimibe/simvastatin (Vytorin®) on clinical outcomes in patients with mild-to-moderate asymptomatic aortic stenosis. The 5-year trial demonstrated that ezetimibe/simvastatin was no better than placebo in reducing the primary composite outcomes ? major cardiovascular events (eg, death from cardiovascular causes, aortic-valve replacement, heart failure) or the composite outcome of aortic-valve-related clinical events and ischemia. Additionally, a higher incidence of newly diagnosed cancer of any type (105 patients taking ezetimibe/simvastatin vs 70 patients taking placebo, p=0.01) and cancer-related death (39 patients taking ezetimibe/simvastatin vs 23 patients taking placebo, p=0.05) was observed in the patients receiving ezetimibe/simvastatin compared to those receiving placebo. Of note, 8 patients diagnosed with cancer prior to randomization experienced recurrence (3 in the ezetimibe/simvastatin group vs 5 in the placebo group).

Subsequently, an interim analysis of the ongoing Study of Heart and Renal Protection (SHARP) trial and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) with a total of 20,617 randomized patients demonstrated no overall excess of cancer (313 active-treatment vs 326 control, p=0.61) (Peto, 2008). The SHARP trial randomized patients with chronic kidney disease to either ezetimibe/simvastatin or placebo. The IMPROVE-IT trial randomized patients with acute coronary syndrome to either ezetimibe/simvastatin or simvastatin alone. When the SEAS trial data is included in this analysis, there still is no significant excess of cancer (414 active-treatment vs 391 control, p=0.46). However, cancer-associated deaths were significantly higher when compared to controls (134 vs 92, respectively; p=0.007). Previous trials and meta-analyses involving the use of ezetimibe, simvastatin, or ezetimibe/simvastatin also have not shown an increased risk of cancer.

The FDA estimates that it will take approximately 6 months to fully evaluate the clinical trial data after receipt of the final SEAS trial report. At this time, the FDA recommends that patients continue taking their cholesterol-lowering medications.

For more information, U.S. healthcare professionals may refer to the following:

FDA: http://www.fda.gov/medwatch/safety/2008/safety08.htm#ezetimibe2

Peto R, Emberson J, Landray M, et al, "Analysis of Cancer Data From Three Ezetimibe Trials," N Engl J Med, 2008, http://content.nejm.org/cgi/content/full/NEJMsa0806603

Rossebo AB, Pederson TR, Boman K, et al, "Intensive Lipid Lowering With Simvastatin and Ezetimibe in Aortic Stenosis," N Engl J Med, 2008, http://content.nejm.org/cgi/content/full/NEJMoa0804602

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Natalizumab: Additional Reports of Progressive Multifocal Leukoencephalopathy - August 2008

Two new cases of progressive multifocal leukoencephalopathy (PML) have been reported to the Food and Drug Administration (FDA) by Biogen Idec and Elan, the manufacturer and distributor of natalizumab (Tysabri®). Both cases were noted in European patients and are the first cases reported since the reintroduction of natalizumab since June 2006. PML has been previously reported following the use of natalizumab and its use is contraindicated in patients with a history of PML. As opposed to the previous cases of PML which were associated with natalizumab in conjunction with a beta-interferon, the two new cases were reported in patients on monotherapy for multiple sclerosis. One patient, however, had a history of beta-interferon use.

In the United States, all patients must be enrolled in the Tysabri® Outreach Unified Commitment to Health (TOUCH™) Prescribing Program in order to receive natalizumab. As part of the TOUCH program, patients are monitored closely for the development of opportunistic infections, including PML. Based on the available data, the FDA still believes that the risk of PML is lower with natalizumab monotherapy. Natalizumab should be discontinued in patients where PML is suspected.

Refer to the following FDA website for additional information:http://www.fda.gov/medwatch/safety/2008/safety08.htm#Tysabri2

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Nelfinavir: Health Canada Issues Update on Impurity Warning - August 2008

Health Canada has notified Canadian healthcare professionals that they have reached agreement with Pfizer Canada, on acceptable limits of the impurity, ethyl methanesulfonate (EMS), created during the manufacturing process of nelfinavir (Viracept®). A similar agreement previously was reached between Pfizer and the U.S. Food and Drug Administration (FDA). Health Canada is reassuring Canadians that the nelfinavir product presently on the Canadian market contains acceptable levels of EMS and that warnings against its use in HIV-infected nonpregnant adults and children no longer apply. In contrast to the U.S. FDA recommendations, Health Canada does not recommend the use of nelfinavir during pregnancy due to concerns related to EMS exposure.

Further information may be obtained at: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_144-eng.php

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Ezetimibe (Zetia®), Simvastatin (Zocor®), and Ezetimibe/Simvastatin (Vytorin®): Preliminary Results From the SEAS Trial - August 2008

The U.S. Food and Drug Administration (FDA) is communicating important information regarding an ongoing safety review of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. The unpublished SEAS trial evaluated the effects of the combination ezetimibe/simvastatin (Vytorin®) on clinical outcomes in patients with aortic stenosis. The 5-year trial demonstrated that ezetimibe/simvastatin was no better than placebo in reducing the primary endpoint ? a composite of aortic valve replacement and cardiovascular events. Additionally, a higher incidence of newly diagnosed cancer of all types (102 patients taking ezetimibe/simvastatin vs. 67 patients taking placebo) and cancer-related death was observed in the patients receiving ezetimibe/simvastatin compared to those receiving placebo. Previous trials and meta-analyses involving the use of ezetimibe, simvastatin, or ezetimibe/simvastatin have not shown an increased risk of cancer.

The FDA estimates that it will take about 6 months to fully evaluate the clinical trial data after receipt of the final SEAS trial report which is expected in about 3 months. At this point in time, the FDA has recommended that patients continue taking their cholesterol lowering medications.

For more information, U.S. healthcare professionals may refer to the following: http://www.fda.gov/medwatch/safety/2008/safety08.htm#ezetimibe2

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Exenatide (Byetta®): Hemorrhagic or Necrotizing Pancreatitis - August 2008

The Food and Drug Administration (FDA) has issued an update regarding the incidence of pancreatitis associated with the use of exenatide (Byetta®). In addition to previously reported postmarketing cases of acute pancreatitis, the FDA has received six case reports (including two fatalities) of hemorrhagic or necrotizing pancreatitis in patients receiving exenatide therapy. As a result, the FDA is working with the manufacturer of exenatide, Amylin Pharmaceuticals, to update the prescribing information to strengthen warnings concerning the risk for acute hemorrhagic or necrotizing pancreatitis.

In addition, the FDA is reminding healthcare professionals that exenatide therapy should be promptly discontinued in patients in whom pancreatitis is suspected. If pancreatitis is confirmed, administer appropriate treatment as indicated and do not restart exenatide therapy. Alternative antidiabetic therapy should be considered in patients with a prior history of pancreatitis.

Additional information can be found at http://www.fda.gov/cder/drug/InfoSheets/HCP/exenatide2008HCP.htm

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LEVOleucovorin Availability - August 2008

Levoleucovorin (Fusilev™) for intravenous injection was approved by the U.S. Food and Drug Administration (FDA) as a rescue agent after high-dose methotrexate therapy in osteosarcoma and as an antidote for impaired methotrexate elimination and for inadvertent overdosage of folic acid antagonists. The product is expected to be available in August 2008.

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Fentanyl Transdermal System Patches: Leakage of Active Gel

Various manufacturers of fentanyl transdermal system patches have instituted recalls of fentanyl transdermal patch products due to manufacturing defects resulting in fentanyl gel leakage from the patch. Leakage of active drug out of the patch renders the transdermal system less effective and could potentially expose patients, caregivers, and/or healthcare practitioners handling the products to fentanyl gel. Patients and healthcare professionals should check the drug packaging for affected lots and are advised against directly handling any defective patches. Recommended guidance for product returns and/or disposal should be followed. Anyone exposed to the gel should immediately rinse exposed skin with large amounts of water without using soap or detergents.

For further information regarding specific strengths and lot numbers affected it the U.S. recalls, refer to the following FDA websites:

http://www.fda.gov/medwatch/safety/2008/safety08.htm#Fentanyl

http://www.fda.gov/medwatch/safety/2008/safety08.htm#Duragesic

For information regarding defective patches sold in Canada by Janssen-Ortho, Inc or Ranbaxy see: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_29_e.html

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Rimantadine and Amantadine ACIP 2008-2009 Influenza Guidelines

The Advisory Committee on Immunization Practices (ACIP), as part of their recommendations for the Prevention and Control of Influenza, do not recommend the use of amantadine or rimantadine for the treatment or chemoprophylaxis of influenza A infection. This recommendation is for the 2008-2009 season for residents of the United States and is based on current patterns of resistance to these medications. Oseltamivir or zanamivir are the recommended antiviral agents. In some areas, resistance is developing against oseltamivir. If resistance is suspected, amantadine or rimantadine may be used in combination with oseltamivir for the treatment or prophylaxis of influenza A infection when zanamivir therapy is not indicated (such as in children of certain ages).

For additional information, refer to the ACIP guidelines on the following CDC website: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr57e717a1.htm

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Naltrexone (Vivitrol™): Injection Site Reactions - August 2008

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of reports of serious injection site reactions associated with naltrexone injectable suspension (Vivitrol™). The FDA has received 196 reports of reactions (including cellulitis, induration, hematoma, abscess, and necrosis) following administration. Surgical intervention was required for management of some of the reactions. Instruct patients to report injection site pain, swelling, bruising, pruritus, or redness at the injection site that does not improve (or worsens) within 2 weeks; consider surgical consult for worsening reactions. Naltrexone injectable suspension is for I.M. gluteal administration only, using the provided 1.5 inch 20-gauge administration needle. Alternate treatment should be considered in patients not able to receive an I.M. gluteal injection with the provided needle. Do not administer I.V., SubQ, or into fatty tissue (the risk of serious injection site reaction is increased if given SubQ or into fatty tissue). Patients with higher gluteal fat thickness may be at increased risk for injection site reactions.

Additional information may be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#naltrexone

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Temsirolimus: Health Canada Issues Warning Concerning Hypersensitivity and Infusion Reactions - August 2008

Wyeth Canada, in conjunction with Health Canada, has issued a Dear Healthcare Professional letter concerning hypersensitivity and infusion related reactions associated with temsirolimus (Torisel™). To date there have been no serious postmarketing reports of this type in Canada, however, worldwide there have been 46 case reports including one fatality and six life-threatening reactions. Reported adverse events include loss of consciousness, hypotension, chest pain, dyspnea, apnea, and flushing. Although most reactions have occurred with initial dosing and frequently within minutes of starting the infusion, hypersensitivity reactions have also been reported with subsequent infusions.

Prior to temsirolimus infusion, it is recommended that patients be premedicated with a selective H1-blocker (eg, diphenhydramine) and appropriate supportive care be readily available. Infusions should be interrupted immediately in any patient experiencing hypersensitivity or infusion related reactions and appropriate treatment administered accordingly. Patients in whom reinitiating therapy is considered beneficial, administration of an I.V. H1-blocker and/or I.V. H2-blocker (eg, famotidine) is recommended as well as reducing the infusion rate. Subsequent use of temsirolimus is contraindicated in any patient who has a history of or experiences an anaphylactic reaction associated with temsirolimus therapy, sirolimus therapy, or any component of the formulation.

Further information may be found at
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/torisel_hpc-cps-eng.p

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Darbepoetin (Aranesp®) and Erythropoietin (Epogen®/Procrit®): Labeling Updates, Including Changes to Boxed Warning Regarding Use in Patients With Cancer - August 2008

The U.S. Food and Drug Administration (FDA), Amgen Inc, and Ortho Biotech have issued a "Dear Health Care Professional" letter alerting practitioners of revised labeling for erythropoiesis-stimulating agents (ESAs) (epoetin alfa [Epogen®, Procrit®] and darbepoetin alfa [Aranesp®]). The labeling for these products has been updated, including changes to the indications and boxed warnings, reflecting that ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is curative.

The FDA MedWatch alert can be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA2.

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Tumor Necrosis Factor (TNF) Blockers and Malignancy Risk - June 2008

The U.S. Food and Drug Administration (FDA) issued an Early Communication to healthcare professionals regarding a possible association between TNF blocker (adalimumab, certolizumb pegol, etanercept, and infliximab) use and the development of malignancies in children and young adults. Over the last 10 years, the FDA has received ~30 reports of cancer in children or young adults who had been treated with TNF blockers prior to the age of 18 years. TNF blockers were given for the treatment of Juvenile Idiopathic Arthritis (JIA [formerly termed Juvenile Rheumatoid Arthritis]), Crohn's disease, or other indications in combination with other immunosuppressive medications (eg, azathioprine, 6-mercaptopurine or methotrexate). Approximately half of the reported cancers were lymphomas (Hodgkin 's and non-Hodgkin's), which are cancers involving the cells of the immune system.

TNF blockers work by suppressing the immune system. The prescribing information for each TNF blocker contains warnings regarding the possible association of malignancy development with use. Malignancies may not be detected in short-term studies; long-term studies are necessary to identify the impact of TNF blocker therapy on malignancy development. The manufacturers of the four TNF blockers available in the U.S. are being asked by the FDA to provide information regarding all cases of cancer reported in children taking TNF blockers. The FDA is expected to report its findings in approximately 6 months, after completing a safety review and evaluation.

Additional information is available at http://www.fda.gov/medwatch/safety/2008/safety08.htm#TNF

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Antiepileptics: Increased Risk of Suicidal Behavior or Ideation - February, 2008

The U.S. Food and Drug Administration (FDA) is informing healthcare professionals of an increased risk of suicidality (suicidal behavior or ideation) observed from analysis of clinical studies using various antiepileptic medications compared to placebo. The analysis was performed on 199 placebo-controlled studies involving 43,892 patients (27,863 treated patients versus 16,029 placebo patients) aged =5 years receiving one of the following 11 drugs: carbamazepine (Carbatrol®, Equetro™, Tegretol®, Tegretol® XR), felbamate (Felbatol®), gabapentin (Neurontin®), lamotrigine (Lamictal®), levetiracetam (Keppra®), oxcarbazepine (Trileptal®), pregabalin (Lyrica®), tiagabine (Gabitril®), topiramate (Topamax®), valproate (Depakote®, Depakote® ER, Depakene®, Depacon®), and zonisamide (Zonegran®). Studies examined medication efficacy in a variety of disorders, including epilepsy, psychiatric disorders (eg, depression, bipolar disorder), and other conditions (eg, migraine, neuropathic pain). According to the FDA, the results revealed a statistically significant increased risk of suicidality in 0.43% treated patients compared to 0.22% placebo patients, or an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the treated groups relative to placebo. This increased risk was reported anywhere from 1 week of therapy through 24 weeks. However, most trials were =24 weeks duration and the risk of suicide extending beyond 24 weeks is currently unknown. The relative risk of suicidal behavior or ideation in the treated patients was higher for patients with epilepsy (RR=3.6) compared to patients treated for psychiatric (RR=1.6) or other conditions (RR=2.3). Overall, the incidence of suicidal behavior or ideation occurred consistently across all demographic subgroups and with each of the drugs studied. Of note, four patients receiving an antiepileptic committed suicide relative to none in the placebo groups.

Forthcoming product labeling changes are likely to extend to all antiepileptic drugs and not limited to the drugs used in the studies, pending discussions scheduled for the upcoming advisory committee meeting. Healthcare professionals and family members/caregivers are encouraged to monitor patients receiving any antiepileptic medication for signs/symptoms of suicidality (eg, anxiety, depression, behavior changes). Patients should not stop taking their antiepileptic therapy unless advised by a healthcare professional.

Additional information can be found at: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Antiepileptic.

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Varenicline: Psychiatric and central nervous system adverse events - Updated February 1, 2008 - February, 2008

The Food and Drug Administration (FDA) has issued an update to the November, 2007 alert regarding postmarketing events reported with varenicline (Chantix™). After further review, the FDA feels that there is likely an association between varenicline and the neuropsychiatric events. The product labeling has been revised to include a warning concerning the neuropsychiatric symptoms, which usually occur during treatment, but have also occurred after varenicline treatment has been discontinued. Healthcare providers should monitor all patients taking varenicline for symptoms of serious neuropsychiatric events, including agitation, depression, suicidal behavior, and suicidal ideation. Inform patients to report any behavioral and/or mood changes to their healthcare provider. An FDA-approved patient medication guide is forthcoming.

Additional information is available at: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Varenicline.

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Ezetimibe/Simvastatin (Vytorin®), Ezetimibe (Zetia™), and Simvastatin (Zocor®): ENHANCE Results - January, 2008

The U.S. Food and Drug Administration (FDA) is communicating important information regarding the preliminary results of the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial, originally released on January 14, 2008, by Merck/Schering Plough. This multinational, randomized, double-blind trial was conducted in 720 patients with heterozygous familial hypercholesterolemia (HeFH) over a two-year period. Patients were randomized to either ezetimibe 10 mg/simvastatin 80 mg (Vytorin®) or simvastatin 80 mg alone (Zocor®). The primary endpoint of the trial was mean change in carotid intima-media thickness (CIMT) which is a surrogate endpoint believed to translate in a reduction of future cardiovascular events. It is important to note that this was an imaging trial and was not powered for clinical outcomes (eg, MI, stroke). Although ezetimibe/simvastatin lowered LDL cholesterol more effectively as compared to simvastatin alone, there was no difference seen in mean change in CIMT. Adverse events were similar between both groups.

Upon completion of full data analysis, the manufacturer will submit a final report to the FDA. Once the report is received, the FDA estimates it will take about 6 months to fully evaluate the data and decide whether or not further regulatory action is necessary. Three large clinical outcome trials evaluating the use of ezetimibe/simvastatin will be presented over the next 2-3 years

At this point in time, patients should not stop taking their ezetimibe/simvastatin (Vytorin®), ezetimibe (Zetia™), or simvastatin (Zocor®). Instead patients should talk with their healthcare provider if they have questions about the ENHANCE trial.

For more information, U.S. healthcare professionals may refer to the following:

FDA: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Ezetimibe.

American College of Cardiology (ACC) Statement on ENHANCE Trial: http://www.acc.org/enhance.htm.

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Natalizumab for the Treatment of Crohn’s Disease - January, 2008

Natalizumab (Tysabri®) was approved by the Food and Drug Administration (FDA) for the treatment of moderately- to severely-active Crohn’s disease. Natalizumab is expected to be available for patients with Crohn’s disease through the TOUCH™ Prescribing Program by the end of February, 2008.

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Bisphosphonates: Possible Association with Severe Musculoskeletal Pain - January, 2008

The Food and Drug Administration (FDA) is informing healthcare practitioners of the possible association between bisphosphonate use and the development of severe (possibly incapacitating) bone, muscle, and/or joint pain. The severe musculoskeletal pain may develop days, months, or years after initiating a bisphosphonate. This is a distinct event from the acute phase response (eg, fever, chills, bone pain, myalgia, arthralgia) that may occur following initial bisphosphonate administration which generally resolves within several days of continued use.

Frequency of and contributing risk factors between severe musculoskeletal pain and bisphosphonate use are currently unknown.

Further information is available at http://www.fda.gov/medwatch/safety/2008/safety08.htm#Bisphosphonates

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Erythropoiesis-Stimulating Agents (ESAs): Additional Information on Shortened Time to Tumor Progression and Increase in Mortality - January, 2008

The U.S. Food and Drug Administration (FDA) has issued an update to the November, 2007 alert on ESAs. This update includes information from two additional ESA studies in patients with chemotherapy-associated anemia. The studies provide further evidence of shortened time to tumor progression and increased mortality in patients who received ESAs; however, in the studies, the ESA doses were targeted to maintain hemoglobin levels ≥12 g/dL. The FDA is planning a public advisory committee meeting to further discuss this new information as well as previous alert information.

Additional information may be found at http://www.fda.gov/bbs/topics/NEWS/2008/NEW01769.html

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Product Safety and Fentora™ (Transmucosal Buccal Tablet) − September, 2007

Cephalon, Inc, in conjunction with the Food and Drug Administration (FDA), has notified healthcare providers of fatal adverse events that have occurred in patients treated with Fentora™, a transmucosal buccal tablet formulation of fentanyl. The fatalities have been attributed to several factors, including improper patient selection, improper dosing, and/or improper product substitution. The FDA emphasized that Fentora™ only be used for labeled indications and only in patients who are opioid-tolerant. When using Fentora™ for breakthrough pain (BTP), it is recommended that patients not exceed 2 tablets per BTP episode and that patients allow ≥4 hours to elapse between doses. Additionally, Fentora™ should not be used in patients with acute pain, postoperative pain, headache/migraine, or sports injuries. The FDA also stressed that Fentora™ and Actiq® (transmucosal lozenge) are not equivalent and that these products should not be used interchangeably on a mcg-per-mcg basis.

For more information, refer to the following FDA website: http://www.fda.gov/medwatch/safety/2007/safety07.htm#Fentora

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Haloperidol: Risk of QT Prolongation and Torsade de Pointes − September, 2007

The Food and Drug Administration (FDA), in conjunction with Johnson and Johnson, is informing healthcare professionals of updated prescribing information for haloperidol (Haldol®). The labeling updates note an increased risk of QT prolongation, torsade de pointes (TdP), and sudden death associated with haloperidol use. Incidence appears greater with intravenous administration and with doses higher than recommended. Haloperidol injection is approved for intramuscular use only; however, the FDA is aware of the relatively common off-label clinical practice of intravenous administration using haloperidol lactate injection (haloperidol decanoate should never be administered intravenously). The FDA cites at least 28 case reports of QT prolongation and TdP, including fatalities, occurring with intravenous haloperidol. Case-control studies indicate a dose-response between intravenous haloperidol and TdP.

In light of the potential for adverse cardiac conduction effects, caution or avoidance of haloperidol is advised in patients with predisposing risk factors including electrolyte abnormalities (eg, hypokalemia, hypomagnesemia), hypothyroidism, familial long QT syndrome, concomitant medications which may augment QT prolongation, or any underlying cardiac abnormality which may also potentiate risk. In addition, ECG monitoring is recommended with off-label intravenous use of haloperidol.

For more information, refer to the following FDA website http://www.fda.gov/medwatch/safety/2007/safety07.htm#Haloperidol

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Desmopressin Acetate (DDAVP® Injection, DDAVP® Nasal Spray, DDAVP® Rhinal Tube, DDAVP® Tablets, DDVP®, Minirin™, and Stimate® Nasal Spray) - December, 2007

In conjunction with the manufacturers of several desmopressin acetate products, the U.S. Food and Drug Administration (FDA) is informing U.S. healthcare professionals of updated prescribing information including information regarding severe hyponatremia and seizures.

Desmopressin in combination with excessive fluid consumption can result in hyponatremia, an imbalance between intracellular and extracellular sodium. This imbalance can lead to seizures, brain swelling, coma, and death. The FDA has reviewed 61 postmarketing cases of hyponatremia-related seizures associated with the use of desmopressin acetate. Fifty-five of these cases reported serum sodium levels in the range of 104-130 mEq/L at the time of the seizure; two cases were fatal. Intranasal desmopressin was used in 36 of the 61 cases. Many of the patients were children being treated for primary nocturnal enuresis (PNE). Thirty-nine of the 61 cases were associated with at least one concomitant drug or disease that is also associated with hyponatremia and/or seizures.

As a result, intranasal desmopressin is no longer indicated for the treatment of PNE. In addition, intranasal desmopressin should not be used in patients with hyponatremia or a history of hyponatremia. Desmopressin acetate tablets may be used for the treatment of PNE; however, treatment should be interrupted if the patient experiences an acute illness (eg, fever, recurrent vomiting, diarrhea), vigorous exercise, or any condition associated with an increase in water consumption. Patients and caregivers should also be instructed to restrict fluid intake 1 hour prior to dose until the next morning, or for at least 8 hours after administration.

Caution should be employed when using any desmopressin formulation in patients with habitual or psychogenic polydipsia or using medications known to either increase thirst or cause syndrome of inappropriate antidiuretic hormone secretion (SIADH) (eg, carbamazepine, SSRIs).

For more information, U.S. healthcare professionals may refer to the following FDA website: http://www.fda.gov/cder/drug/InfoSheets/HCP/desmopressinHCP.htm

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Proton Pump Inhibitors (Esomeprazole, Omeprazole): Evidence Does Not Suggest Increased Rates of Cardiac Events - Results of FDA Analysis - December 10, 2007

The U.S. Food and Drug Administration (FDA) review of esomeprazole (Nexium®) and omeprazole (Prilosec®) finds no evidence of increased risk of cardiac events related to these medications. In May 2007, AstraZeneca, the manufacturer of Nexium® (esomeprazole) and Prilosec® (U.S.)/Losec® (CAN) (omeprazole), notified the FDA and Health Canada of concerns regarding a possible association between long-term use of esomeprazole or omeprazole and cardiovascular side effects based on the results of two small, nonblinded, long-term, European clinical trials of patients with GERD. Patients in these trials were randomized to antireflux surgery (fundoplication) or esomeprazole or omeprazole treatment. In these trials, initial data suggested that patients using either of these proton pump inhibitors experienced more heart attacks, heart failure, and cardiac deaths than patients who had surgery. As a result, the FDA and Health Canada issued public notifications regarding these results in August 2007.

The FDA and Health Canada evaluated the two studies, other published trials, and an analysis of postmarketing safety data from the FDA and WHO since that time, and issued independent statements saying that preliminary reviews do not confirm the existence of cardiovascular risk. Upon further analysis of additional information submitted to the FDA by AstraZeneca, the FDA confirmed its preliminary review of the evidence. The FDA recommends that health care providers continue to prescribe (and patients continue to use) these products as described within their labeling. Health Canada has yet to release a statement.

For more information, healthcare professionals may refer to the following FDA and Health Canada websites: http://www.fda.gov/cder/drug/early_comm/omeprazole_esomepazole_update.htm

http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2007/2007_95_e.html

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Carbamazepine Genetic Testing for Susceptibility to Serious Skin Reactions - December, 2007

The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of changes to the prescribing information, including a new boxed warning, for carbamazepine products (Tegretol®, Carbatrol®, Equetro™) regarding the potential for serious, and potentially fatal, skin reactions in susceptible patients. Individuals who possess a genetic susceptibility marker known as the HLA-B*1502 allele have an increased risk of developing Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN) (usually manifests within first few months of treatment) compared to persons without this genotype. The presence of this genetic variant exists in up to 15% of people of Asian descent, varying from <1% in Japanese and Koreans, to 2% to 4% of South Asians and Indians, to 10% to 15% of populations from China, Taiwan, Malaysia, and the Philippines. This variant is virtually absent in those of Caucasian, African-American, Hispanic, or European ancestry. Risk assessments have suggested that incidence of SJS/TEN in Asians could be ~60 cases/10,000 new users depending on the country of origin (a nearly 10-fold higher incidence than in predominantly Caucasian populations). Presence of the HLA-B*1502 allele may signify greater risk of developing SJS/TEN with other antiepileptic agents for which this degree of dermatologic reactions has been documented.

The manufacturers of these products now recommend genetic testing prior to initiation of therapy in most patients of Asian ancestry for the presence of this genetic marker. A positive result should preclude use of carbamazepine, unless the benefit exceeds risk. Patients with negative results are much less likely to develop a serious skin reaction, though careful monitoring is prudent. Patients (including those previously determined to harbor the HLA-B*1502 allele) currently tolerating carbamazepine for several months are likely at a very low risk of developing these reactions.

Additional information, including a copy of the revised prescribing information can be found at: http://www.fda.gov/cder/drug/infopage/carbamazepine/default.htm.

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Deferasirox: Postmarketing Reports of Hepatic Failure - December, 2007

Novartis, in conjunction with the U.S. Food and Drug Administration (FDA) has issued a “Dear Healthcare Professional” letter regarding updates to the warnings, adverse reactions, and dosage and administration sections in the labeling of deferasirox (Exjade®). Labeling changes include clarification and more detailed information concerning serious hepatic reactions (dysfunction/failure) and a recommendation to withhold therapy for severe or persistent hepatic function test abnormalities. The updates were prompted by postmarketing reports of hepatic failure (including fatalities) in association with deferasirox therapy. Most of the reported events occurred in patients > 55 years of age with underlying comorbidities, including hepatic cirrhosis and multi-organ failure. The decision to initiate deferasirox therapy to reduce iron overload should be individualized based on the expected benefits/risks of therapy.

Additional information may be found at: http://www.fda.gov/medwatch/safety/2007/safety07.htm#Exjade

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Nonoxynol 9 Contraceptive Warning - December 19, 2007

The Food and Drug Administration (FDA) has issued a final ruling concerning the warnings associated with over-the-counter (OTC) nonoxynol 9 contraceptives. In January 2003, proposed warning statements were issued noting that nonoxynol 9 does not protect against HIV infection or other sexually-transmitted diseases; that frequent use of products containing nonoxynol 9 have been associated with vaginal irritation which may increase the incidence of STD transmission, including HIV; and that patients should consult with their healthcare provider concerning the best form of birth control if they need to use these products frequently.

The final rule updates and expands these warning statements, including a recommendation that persons with HIV or those who have a sexual partner with HIV should not use any products containing nonoxynol 9. New warnings should also note that rectal irritation associated with the use of these products may also increase the incidence of STD transmission, including HIV. The warnings will apply to OTC products containing only nonoxynol 9. The final rule is effective as of June 19, 2008.

For additional information, refer to the following FDA website: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01758.html

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Haemophilus influenzae Type b (Hib)- Interim Recommendations Related To Recall - December, 2007

Merck and Co. has initiated a voluntary recall in the U.S. for certain lots of two Haemophilus influenzae type b (Hib) conjugate vaccines (PedvaxHIB® and Comvax®) as a precautionary measure because they cannot ensure sterility of the equipment used to produce the lots that have been recalled. The potency of recalled lots was not affected and no contamination of the vaccine has been detected. Children who received vaccine from recalled lots do not need revaccination or any special follow up. Providers should return unused vaccine from these recalled lots according to standard procedure. Merck does not expect normal distribution to resume until late 2008. This will likely lead to short-term shortage of Hib supply in the US. Sanofi Pasteur currently manufactures two other Hib conjugate vaccines (ActHIB® and TriHIBit®) which are unaffected by the recall. However, it is unlikely that Sanofi Pasteur will be able to provide adequate Hib vaccine to keep up with the current CDC recommendations.

The recommended immunization schedule in the U.S. for 2007 consists of a 2 dose primary series given at 2 months and 4 months if PedvaxHIB® or COMVAX® are used, followed by a booster dose at 12-15 months. ActHIB® is recommended as a 3 dose primary series given at 2 months, 4 months, and 6 months, followed by a booster dose at 12-15 months. TriHIBit® is only recommended as a booster dose to be given at 12-15 months. Due to the projected shortage of available Hib doses, the CDC, in conjunction with ACIP, AAFP, and AAP, have recommended to temporarily defer administering the routine booster dose of Hib vaccine administered at age 12-15 months, except for children in high-risk groups. Children who are behind schedule should complete the primary series according to age-appropriate recommendations. The children who are at highest risk for Hib disease should continue to complete the entire series, including the booster dose. Children who are at highest risk include children with asplenia, sickle-cell disease, HIV infection, other immunodeficiency syndromes, malignant neoplasms, American Indian children, and Alaskan Native children. The CDC is encouraging providers who predominantly serve the American Indian/Alaskan Native population to stock and use the PedvaxHIB® and Comvax®, due to the improved response to these agents in this population. The CDC will prioritize distribution of the CDC stockpile to these areas.

For information on specific lots recalled: http://www.cdc.gov/vaccines/recs/recalls/hib-recall-faqs-12-12-07.htm

http://www.merckvaccines.com/PCHRecall.pdf

CDC recommended childhood schedule: http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm

For more information on Hib disease and vaccination: http://www.cdc.gov/vaccines/vpd-vac/hib/default.htm

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FDA Advisory on the Appropriate and Safe Use of Transdermal Fentanyl Systems - December, 2007

The U.S. Food and Drug Administration (FDA) has issued a public health advisory alerting healthcare professionals, patients, and caregivers about the appropriate and safe use of transdermal fentanyl systems (patches). Fatalities and life-threatening adverse events resulting from dangerously high serum levels of fentanyl continue to be reported to the FDA, despite previous advisories concerning the safe use of transdermal fentanyl. Reports include inappropriate prescribing by clinicians (eg, for acute or mild pain, including headaches) and inappropriate use by patients (eg, excessive replacement frequency or applying heat source to patches). Transdermal fentanyl systems are indicated for use only by opioid-tolerant patients (individuals taking routine, around-the-clock narcotic pain medication) with persistent, moderate-to-severe pain. In nonopioid-tolerant patients, use of even low-dose transdermal fentanyl may result in respiratory depression and death.

Practitioners are reminded to only use transdermal patches in opioid-tolerant patients with chronic pain uncontrolled with other agents, to monitor for signs/symptoms of fentanyl overdose, and to follow prescribing information for dosing and contraindications. Patients should be instructed on the appropriate use and removal of patches, and to avoid heat sources (eg, heating pads, electric blankets, saunas) while wearing patches as heat may increase the absorption of fentanyl leading to dangerously elevated serum concentrations. Additionally, patients should report any fever >102°F while patch is being worn to their healthcare provider. In addition to the highlighted safety information, the FDA is requesting all manufacturers to develop medication guides for patients.

For further information, refer to the following FDA website: http://www.fda.gov/cder/drug/InfoSheets/HCP/fentanyl_2007HCP.htm

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Modafinil: Updated Warnings to Labeling - December, 2007

Shire Canada Inc, in conjunction with Health Canada has issued a “Dear Healthcare Professional” letter regarding updates to the warnings section of the Canadian labeling for modafinil (Alertec®). Similar updates to the U.S. labeling were prompted by a MedWatch alert from the U.S. Food and Drug Administration (FDA) in October, 2007. Updates include warnings regarding the association of modafinil use and life-threatening skin reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) in adult and pediatric patients. In addition, hypersensitivity reactions including anaphylaxis, angioedema, and multiorgan hypersensitivity (including at least one fatality) have been reported. Patients should be advised to promptly discontinue modafinil use and seek medical treatment with the onset of rash or any signs or symptoms suggesting angioedema or anaphylaxis.

Psychiatric symptoms, including new onset symptoms (eg, anxiety, mania, hallucinations) have also been reported in adult and pediatric patients. Patients with a history of psychosis, depression, or mania should use modafinil cautiously. Discontinuation of therapy should be considered with the onset of psychiatric symptoms.

Modafinil is not approved for use in pediatric patients <16 years of age (U.S. labeling) or <18 years of age (Canadian labeling).

For further information, refer to the following websites:

U.S.: http://www.fda.gov/medwatch/safety/2007/safety07.htm#provigil

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/alertec_hpc-cps_e.html