Special Alerts

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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Proton Pump Inhibitors (Esomeprazole, Omeprazole): Ongoing Safety Review Regarding Long-Term Use − August 9, 2007

The Food and Drug Administration (FDA) and Health Canada issued public notifications regarding the results from two small, nonblinded, long-term, European clinical trials of patients with GERD. Patients in these trials were randomized to antireflux surgery or omeprazole or esomeprazole treatment. AstraZeneca, the manufacturer of Prilosec® (U.S.)/Losec® (CAN) (omeprazole) and Nexium® (esomeprazole), notified the FDA and Health Canada of concerns regarding an association between long-term use of omeprazole or esomeprazole and cardiovascular side effects in May, 2007. It was observed that patients using either of these proton pump inhibitors may have experienced more heart attacks and cardiac deaths than patients who had surgery.

The FDA and Health Canada have evaluated the two studies, other published trials, and an analysis of postmarketing safety data from the FDA and WHO since that time, and have issued independent statements saying that preliminary reviews do not confirm the existence of a possible cardiovascular risk.

The FDA and Health Canada are continuing to review the data available and will complete their reviews by the end of the year.

For additional information is available at:

http://www.fda.gov/medwatch/safety/2007/safety07.htm#Omeprazole

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

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World Health Organization (WHO) VinCRIStine Preparation Recommendations − August, 2007

The WHO World Alliance for Patient Safety has issued an alert with recommendations to dispense vincristine diluted in a small volume intravenous bag (in a “minibag”) rather than a syringe to prevent inadvertent or accidental intrathecal/spinal administration of vincristine. All labeling of vincristine should include a clear warning label that reads: For intravenous use only. Fatal if given by other routes.

The WHO recommendations follow administration errors that continue to occur worldwide. Vincristine (and other vinca alkaloids) should only be administered intravenously. Intrathecal or spinal administration of vincristine is usually fatal.

Additional information may be found at http://www.who.int/medicines/publications/drugalerts/Alert_115_vincristine.pdf

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Thiazolidinediones: Strengthened Warnings Concerning Heart Failure Risk − August, 2007

The Food and Drug Administration (FDA) is notifying healthcare professionals of a request to manufacturers of thiazolidinedione (TDZ) antidiabetic agents to update their prescribing information. Request includes emphasizing their potential to cause or exacerbate heart failure with a boxed warning and a contraindication against use in patients with NYHA class III or IV heart failure. Additional details concerning close monitoring for signs/symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases, is also recommended. Request was prompted by postmarketing reports of heart failure and signs/symptoms of heart failure occurring with TDZ use. Clinical trials have also revealed an increased risk compared to placebo.

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

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FDA Alert (Progressive Multifocal Leukoencephalopathy) - Updated August, 2007

Hoffman-La Roche Limited, in conjunction with Health Canada, has issued a “Letter to Healthcare Professionals” concerning reports of progressive multifocal leukoencephalopathy (PML) associated with Rituxan® use in systemic lupus erythematosus (SLE) and vasculitis. A similar alert was previously reported by the U.S. Food and Drug Administration (FDA) in December, 2006. Patients have developed fatal PML after being treated with rituximab for non-Hodgkins lymphoma (NHL), and for certain autoimmune diseases including SLE and vasculitis. Rituximab is approved by the FDA and Health Canada to treat NHL and rheumatoid arthritis; rituximab is NOT approved for the treatment of SLE or vasculitis.

PML is a demyelinating disease caused by reactivation of the polyomavirus JC virus (JCV). PML has also been reported in patients with SLE and vasculitis receiving other immunosuppressants who have not received rituximab and has been rarely reported in NHL patients receiving chemotherapy alone (without rituximab).There is no known effective treatment for PML. Patients receiving rituximab with any new neurologic symptoms (eg, major vision changes, unusual eye movements, loss of balance or coordination, confusion, disorientation, difficulty walking) should be evaluated for PML.

Additional information is available at the following websites:

http://www.fda.gov/cder/drug/InfoSheets/HCP/rituximab.pdf

http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/rituxan_4_hpc-cps_e.html

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FDA Issues Letter Concerning Entecavir-Associated HIV Resistance − Updated August, 2007

Bristol-Myers-Squibb, in conjunction with the Food and Drug Administration (FDA), has issued a Dear Healthcare Provider letter concerning the report (previously noted in Canadian alert) of HIV resistance associated with the use of entecavir (Baraclude®). In that patient, testing at the onset of entecavir therapy failed to demonstrate any resistance, but was noted 6 months after entecavir therapy began. Furthermore, entecavir therapy was associated with a decreased HIV viral load. Bristol-Myers-Squibb has revised the labeling reflecting this concern. The labeling has been updated to include a boxed warning advising of the potential for developing resistance to HIV nucleoside reverse transcriptase inhibitors in HIV patients not receiving highly-active antiretroviral therapy (HAART).

Additional information including a copy of the Dear Healthcare Provider is available at http://www.fda.gov/medwatch/safety/2007/safety07.htm#Baraclude

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Codeine and Breast-feeding − August, 2007

The Food and Drug Administration (FDA) has notified healthcare providers of life-threatening adverse events reported in a nursing infant following maternal use of codeine. Codeine and its metabolite (morphine) are found in breast milk and can be detected in the serum of nursing infants. Exposure to the nursing infant is generally considered to be low. However, excessively high serum concentrations of morphine were reported in a breastfed infant following maternal use of acetaminophen with codeine. The mother was later found to be an “ultra-rapid metabolizer” of codeine; symptoms in the infant included feeding difficulty and lethargy, followed by death. The FDA recommends that caution be used when prescribing codeine to nursing women, since most persons are not aware if they have the genotype resulting in “ultra-rapid metabolizer” status. When codeine is prescribed, it is recommended to use the lowest dose for the shortest duration of time and to observe the infant for increased sleepiness, difficulty in feeding or breathing, or limpness.

For additional information, refer to the following FDA website: http://www.fda.gov/cder/drug/advisory/codeine.htm

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Nelfinavir Warning Concerning Process-Related Impurity - Updated November, 2007

Pfizer, Inc, in conjunction with the Food and Drug Administration (FDA) and Health Canada, has issued “Dear Health Care Professional” letters concerning a possible impurity in Viracept® (nelfinavir). Nelfinavir was recently recalled in Europe because of unacceptably high levels of ethyl methanesulfonate (EMS), an impurity created during the manufacturing process. EMS has been shown to be teratogenic, mutagenic, and carcinogenic in animal studies. No human data is available.

Testing has revealed that levels of EMS in Viracept® manufactured by Pfizer in the U.S. and Canada are lower than those in Viracept® manufactured by Roche in Europe. Until all testing is complete, Pfizer is working with both regulatory agencies to refine the manufacturing process in order to ensure that the product meets specifications for the amount of EMS that is acceptable.

Use in Children: Toxicity data concerning EMS in humans is not available. However, it is thought that pediatric patients may have an increase in lifetime cancer risk from this agent. Therefore, until additional information is available, the FDA and Health Canada have both asked that new pediatric patients not be started on regimens containing nelfinavir. The FDA is suggesting that pediatric patients already taking nelfinavir may continue the product, as the benefits of a stable regimen outweigh the potential risks. Health Canada, however, is suggesting that all pediatric patients taking nelfinavir be switched to alternative therapies if this can be done safely. Nelfinavir is approved for use in children ≥2 years of age in the United States and Canada.

Use in Pregnancy: It is not known if EMS crosses the placenta or is found in breast milk. The Perinatal HIV Guidelines Working Group previously recommended nelfinavir as the preferred protease inhibitor in combination regimens during pregnancy. Although the Antiretroviral Pregnancy Registry has not found an increased incidence of birth defects following maternal use of nelfinavir, the FDA, Health Canada, and the Perinatal HIV Guidelines are are recommending that pregnant women not be started on new regimens which contain nelfinavir. The agencies are also recommending that pregnant women currently taking regimens with nelfinavir be switched to alternative antiretroviral therapy unless other treatment options are not available.

Use in all Other Patients: Only the prescribing of nelfinavir to pediatric and pregnant patients is affected by the FDA notice; all other patients may continue to use nelfinavir as currently recommended. However, Health Canada is recommending that all HIV-infected patients be switched from nelfinavir to alternative therapies if this can be done safely. Patients should not discontinue use of nelfinavir without first consulting their healthcare provider as a positive risk ratio may still exist for patients with no other viable treatment options. Health Canada recommends that the pharmacist contact the prescriber when patients present with renewals of their nelfinavir prescriptions.

Steps to reduce the amount of EMS formation in nelfinavir are being taken. By allowing only product meeting interim specifications for the amount of EMS that is acceptable to be marketed, a shortage of nelfinavir is not anticipated, but temporary shortages may occur.

For additional information, refer to the following FDA and Health Canada websites:

http://www.fda.gov/medwatch/safety/2007/safety07.htm#Viracept

http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/viracept_hpc-cps_e.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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Withdrawal of Infant OTC Cough and Cold Medications − October 11, 2007

Several manufacturers have announced that they are removing over-the-counter (OTC) infant cough and cold products from the market in order to help reduce dosing errors and overdoses in children under the age of 2 years. Products labeled for use in children ≥2 years are not affected. This action is voluntary and not mandated by the Food and Drug Administration (FDA). A joint meeting of the FDA Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee will be held October 18-19, 2007, to discuss the safety and efficacy of OTC cough and cold products in children.

In January 2007, the Centers for Disease Control and Prevention (CDC) released a report concerning the use of cough and cold medications in children <2 years of age. Products containing nasal decongestants (eg, pseudoephedrine), antihistamines (eg, carbinoxamine), cough suppressants (eg, dextromethorphan), and expectorants are often used in this age group, however, safety and efficacy data is limited in this population. The CDC notes that during 2004 and 2005, ∼1519 children <2 years of age were seen in emergency departments for adverse effects, including overdose, associated with these medications. The Food and Drug Administration (FDA) notes that there are no approved OTC uses for these products in children <2 years of age. This age group is particularly vulnerable to adverse effects from the medications. Caregivers are reminded that OTC cough and cold products should not be used in children <2 years of age except under specific direction by their healthcare provider.

For additional information, refer to the following websites:

http://www.Otcsafety.org

http://www.fda.gov/OHRMS/DOCKETS/98fr/E7-16169.htm

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.

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Perflutren Lipid Microsphere (Definity®) and Perflutren Protein Type A Microsphere (Optison™): Serious Cardiopulmonary Reactions and Fatalities - Updated, October, 2007

In conjunction with the manufacturers, the Food and Drug Administration (FDA) and Health Canada are informing U.S. and Canadian healthcare professionals respectively, of updated prescribing information particularly for patients with unstable cardiopulmonary status.

The FDA and Health Canada have received reports of deaths and serious cardiopulmonary reactions following the administration of ultrasound micro-bubble contrast agents used in echocardiography. These reports have mostly occurred with Definity®. Optison™ has been off the market since late 2005 due to manufacturing issues, but is expected to be reintroduced. Four of the 11 reported fatalities were caused by cardiac arrest occurring either during infusion or within 30 minutes following the administration of the contrast agent. In addition, both regulatory agencies have received numerous reports of serious nonfatal reactions resembling anaphylactoid reactions (eg, dyspnea, urticaria), cardiac or respiratory arrest, symptomatic arrhythmias, hypotension, respiratory distress, and cardiac ischemia. One hundred ninety serious, nonfatal reactions associated with Definity® use and nine serious, nonfatal reactions associated with Optison™ use have been reported to the FDA.

As a result, the FDA and Health Canada have both requested that a Boxed Warning and other warnings emphasizing the risk of cardiopulmonary reactions be added to the labeling of these products and administration be contraindicated in patients with known cardiac shunts, symptomatic atrial or ventricular arrhythmias, or at high risk for arrhythmias due to QT prolongation. Additional contraindications include patients with pulmonary arterial vascular compromise (eg, severe emphysema, pulmonary embolism) and an unstable cardiopulmonary status (eg, unstable angina, acute MI, respiratory failure, or recent worsening CHF).

Healthcare providers should monitor patients (eg, vital signs, cardiac rhythm, and oxygen saturation) during and for at least 30 minutes following administration of these products. Equipment for resuscitation and trained personnel experienced in handling emergencies should always be immediately available.

In light of these safety concerns, the U.S. indications section of the product labeling for perflutren lipid microsphere (Definity®) now contains the statement: Safety and efficacy of the use of Definity® with exercise or pharmacological stress testing have not been established. Health Canada recommends using caution with the administration of Definity® in exercise or pharmacological stress testing.

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

http://www.fda.gov/cder/drug/InfoSheets/HCP/microbubbleHCP.htm

Canadian healthcare professionals may refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/definity_hpc-cps_e.html

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Exenatide (Byetta™): Postmarketing Reports of Acute Pancreatitis – October, 2007

The Food and Drug Administration (FDA) is informing healthcare professionals of postmarketing reports of acute pancreatitis occurring in patients taking exenatide (Byetta™). The FDA has reviewed 30 reports, to date, of patients treated with exenatide, and an association between exenatide use and pancreatitis is suspected in some of these cases. Twenty-seven of the 30 patients did have at least one other risk factor for acute pancreatitis (eg, gallstones, severe hypertriglyceridemia, alcohol use); however, 22 of the 30 patients reportedly improved following exenatide discontinuation. According to the FDA, 3 reports included information that exenatide rechallenge resulted in a return of symptoms. Amylin Pharmaceuticals has agreed to update the product labeling to include information regarding acute pancreatitis.

Clinicians should instruct patients to report any unexplained severe abdominal pain (with or without vomiting) and if pancreatitis is suspected, exenatide should be discontinued. The FDA is also recommending that if pancreatitis not resulting from any other etiology is confirmed, exenatide should not be resumed.

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

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Phosphodiesterase Type-5 (PDE-5) Inhibitors: Sudden Hearing Loss - October, 2007

The Food and Drug Administration (FDA) is notifying healthcare professionals of changes to the product labeling for sildenafil (Viagra®, Revatio™), tadalafil (Cialis®), and vardenafil (Levitra®) to include the potential for sudden decrease or loss of hearing. Labeling changes were prompted by 29 postmarketing reports of sudden hearing loss (some occurring with tinnitus, vertigo or dizziness) associated with PDE-5 inhibitors. In a majority of the reports, hearing loss was one-sided involving partial or complete loss of usual hearing. In one-third of the cases, the loss was temporary although details in the remainder of the cases concerning a temporary nature of the change are either unavailable or the loss was on-going at the time of reporting. A causal relationship between sudden hearing changes and PDE-5 inhibitors use cannot be determined; however, the FDA believes a strong temporal relationship exists. There is not enough data to determine if a dose-relationship contributes to the potential risk.

Patients experiencing sudden hearing changes and using either sildenafil (Viagra®), tadalafil, or vardenafil for erectile dysfunction should discontinue the medication immediately and contact their healthcare provider. Patients receiving sildenafil (Revatio™) for the treatment of pulmonary arterial hypertension who experience sudden hearing changes should not stop taking the medication, but should contact their healthcare provider immediately.

Additional information can be found at http://www.fda.gov/medwatch/safety/2007/safety07.htm#PDE5.

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Mycophenolate Mofetil (CellCept®) Product Labeling: Pregnancy Category Changed / Pregnancy Warnings Updated - November, 2007

Roche Laboratories Inc, in conjunction with the Food and Drug Administration (FDA), has distributed a "Dear Healthcare Professional" letter notifying healthcare providers of updated product labeling for mycophenolate mofetil (CellCept®). Updates in the form of a boxed warning, warnings, and precautions reflect postmarketing data indicating an increased risk of first trimester pregnancy loss and an increased risk of structural abnormalities in the infants born to mothers receiving mycophenolate during pregnancy. The pregnancy category for CellCept® has been changed from category C to category D.

Women of childbearing potential should have a negative serum or urine pregnancy test within 1 week prior to beginning therapy. In addition, women of childbearing potential must receive contraceptive counseling and use two reliable forms of effective contraception initiated 4 weeks prior to beginning treatment. Contraceptive use should continue during therapy and for 6 weeks after discontinuing CellCept®. Of note, mycophenolate mofetil may reduce serum levels of oral contraceptives, and theoretically may reduce their efficacy.

Additional information, including a copy of the "Dear Healthcare Professional" letter, is available at http://www.fda.gov/medwatch/safety/2007/safety07.htm#CellCept2

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Thiazolidinediones: Strengthened Warnings Concerning Heart Failure Risk - August, 2007; Updated November, 2007

GlaxoSmithKline (GSK), in conjunction with the U.S. Food and Drug Administration (FDA), has updated the product labeling for rosiglitazone (Avandia®) to acknowledge a potential increased risk of myocardial ischemic events. A boxed warning has been added detailing the increased risk of angina or MI, however, noting these data are inconclusive. At the request of the FDA, GSK has further agreed to conduct a new, long-term safety study to better assess these risks. New labeling also emphasizes the potential of rosiglitazone to cause or exacerbate heart failure with a boxed warning and a contraindication against use in patients with NYHA class III or IV heart failure. Additional details concerning close monitoring for signs/symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases, were also recommended. These changes were prompted by postmarketing reports of heart failure and signs/symptoms of heart failure occurring with thiazolidinedione use. Patients with or at an increased risk for heart disease should consult their primary healthcare practitioner concerning the risks associated with therapy.

GlaxoSmithKline Inc., in conjunction with Health Canada, is notifying Canadian healthcare practitioners and consumers of labeling updates for products containing rosiglitazone (Avandia®, Avandamet®, Avandaryl™). Changes to the Canadian labeling include a contraindication for use in any stage of heart failure (eg, NYHA Class I, II, III, or IV), and for use as monotherapy. Rosiglitazone can be used alone or in combination with a sulfonylurea but only when metformin use is contraindicated or not tolerated. In Canada, rosiglitazone is not indicated for use with insulin or in triple therapy (with metformin and sulfonylurea).

Additional information can be found at U.S.: http://www.fda.gov/medwatch/safety/2007/safety07.htm#Avandia2

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/avandia_hpc-cps_5_e.html

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Erythropoiesis-Stimulating Agents (ESAs): Product Labeling Revised - November, 2007

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®]). Labeling changes consist of strengthened boxed warnings, safety information, and revised dosing information. Updates also provide additional details and clarifications to the revisions made in the previous labeling update (March, 2007) and include recommendations from FDA advisory committees on appropriate ESA use in cancer and chronic renal failure patients.

The boxed warning regarding use in cancer patients has been expanded to include the association of decreased overall survival and/or time to tumor progression observed in clinical studies using ESAs in patients with advanced breast, head and neck, lymphoid, and nonsmall cell lung cancer. This risk was noted in studies using ESAs dosed with the intent to achieve and maintain a target hemoglobin level of ≥12 g/dL (not all studies achieved intended hemoglobin target). Based on this risk, as well as the risk of serious cardio- and thrombovascular events, new dosing guidelines in cancer patients recommend not exceeding a hemoglobin of 12 g/dL and using the lowest dose of ESAs to avoid red blood cell transfusions. The risk of increased mortality and tumor progression has not been excluded when ESAs are dosed to achieve hemoglobin levels <12 g/dL based on present data. 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 include 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.

Modifications have also been made to qualify particular parameters (eg, quality of life, fatigue, symptoms of anemia) as either not having been demonstrated or having been demonstrated in controlled clinical trials according to current standards. Medication guides are currently being developed to communicate the risks and benefits of ESAs for patients.

Additional information for healthcare providers, including the revised labeling, may be found at http://www.fda.gov/medwatch/safety/2007/safety07.htm#ESA2.

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Cefepime: Safety Review Prompted By Meta-Analysis - November, 2007

The Food and Drug Administration (FDA) is informing practitioners of a review of new safety data and a request for additional data for cefepime after a recently published meta-analysis (Yahav, 2007) raised concerns of an increased risk of death in patients treated with cefepime. The authors of the meta-analysis reviewed the results from 57 randomized controlled trials comparing cefepime to other beta-lactams in a variety of infections. The studies included in the review allowed for additional non-beta-lactam therapy, but only if both study groups (cefepime group and beta-lactam comparator) used the additional therapy. The primary outcome of the analysis was 30-day all-cause mortality; however, all-cause mortality data was only available in 41 of the trials. In addition, distribution of specific type pathogens to infections in relation to all-cause mortality was not available, including patients with documented gram-negative and Pseudomonas infections. In the cases where the primary outcome data was not available, mortality at end of study follow-up and up to 30 days was used. The authors reported an increase in all-cause mortality in the cefepime group relative to the comparator group (relative risk 1.26 [95% CI 1.08 to 1.40]; p=0.005). Only two subsets showed a significant difference in all cause mortality and include the group comparing cefepime to piperacillin-tazobactam (relative risk 2.14 [95% CI 1.17 to 3.89]; p=0.01) and the subset of patients with febrile neutropenia (relative risk 1.42 [95%CI 1.09 to 1.84]; p=0.009).

The FDA is currently evaluating the data, and in the interim, is reminding practitioners to consider the risks and benefits of cefepime prior to use. The FDA will provide additional communication and any recommendations, if necessary, following the conclusion of the evaluation, which is expected to take approximately 4 months.

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

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Aprotinin (Trasylol®) Marketing Suspended in U.S. and Canada - November, 2007

Bayer Pharmaceuticals Inc is suspending the marketing of aprotinin (Trasylol®) in the U.S. and Canada at the request of both the U.S. Food and Drug Administration (FDA) and Health Canada. Preliminary data from the now suspended, Blood Conservation Using Antifibrinolytics: A Randomized Trial in a Cardiac Surgery Population (BART) study in Canada, suggests an increased risk of death associated with aprotinin use when compared with other antifibrinolytic agents. In the study, hemorrhage-related deaths were observed more often in the aprotinin study population. Both regulatory agencies are in the process of further evaluating the data obtained from the BART study and are working with the manufacturer to ensure the availability of aprotinin through a limited access for patients in whom it is determined the benefits of use outweigh the risks. Until evaluation of the data is complete, healthcare providers comtemplating aprotinin use must be aware of the potential risks and growing evidence suggesting the increased risk of death in association with use.

Further information can be found at the following websites:

U.S.: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01738.html

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2007/2007_157_e.html

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Varenicline: Psychiatric and central nervous system adverse events - November, 2007

The Food and Drug Administration (FDA) has issued preliminary information for healthcare professionals regarding postmarketing reports of suicidal thoughts and erratic/aggressive behavior in patients who have taken varenicline (Chantix™) to aid in smoking cessation. Many cases suggest new-onset depression, suicidal ideation, and emotion/behavioral changes within days to weeks after treatment initiation. Because smoking cessation (with or without treatment) is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness, the role of varenicline in these events is unclear. Some of the cases described above occurred in patients without a history of psychiatric disease and in patients who had not discontinued smoking. The FDA also has reports of excessive drowsiness which may impair the ability to perform tasks requiring mental alertness. The investigation by the FDA is ongoing.

Patients taking varenicline for smoking cessation should be monitored for behavioral changes and psychiatric symptoms. Patients should be informed to report any behavioral and/or mood changes to their healthcare provider and to use caution when performing tasks requiring mental alertness.

Additional information is available at http://www.fda.gov/medwatch/safety/2007/safety07.htm#chantix

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Mycophenolate Mofetil (CellCept®) and Mycophenolic Acid (Myfortic®) Product Labeling: Pregnancy Category Changed / Pregnancy Warnings Updated - November 30, 2007

Roche Laboratories Inc and Novartis Pharmaceuticals, in conjunction with the Food and Drug Administration (FDA), have distributed a "Dear Healthcare Professional" letter notifying healthcare providers of updated product labeling for mycophenolate mofetil (CellCept®) and mycophenolic acid (Myfortic®). Updates in the form of a boxed warning, warnings, and precautions reflect postmarketing data indicating an increased risk of first trimester pregnancy loss and an increased risk of structural abnormalities in the infants born to mothers receiving mycophenolate during pregnancy. The pregnancy category has been changed from category C to category D.

Women of childbearing potential should have a negative serum or urine pregnancy test within 1 week prior to beginning therapy. In addition, women of childbearing potential must receive contraceptive counseling and use two reliable forms of effective contraception initiated 4 weeks prior to beginning treatment. Contraceptive use should continue during therapy and for 6 weeks after discontinuing treatment. Of note, mycophenolate may reduce serum levels of oral contraceptives, and theoretically may reduce their efficacy.

Additional information, including a copy of the "Dear Healthcare Professional" letter, is available at http://www.fda.gov/medwatch/safety/2007/safety07.htm#CellCept2

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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