Special Alerts

Leukotriene Inhibitors: Potential Association with Neuropsychiatric Events - Updated August 2009

The Food and Drug Administration (FDA) is updating healthcare professionals regarding the possible association between leukotriene inhibitor use and neuropsychiatric events including agitation, aggression, anxiousness, dream abnormalities, hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide) and tremor. The FDA has requested that manufacturers of leukotriene inhibitors add a precaution regarding this potential risk to the drug prescribing information. In addition, the FDA recommends that both patients and healthcare providers are aware of the potential neuropsychiatric risks of taking these medications. Patients should be encouraged to report any neuropsychiatric effects to a healthcare provider. Healthcare professionals should consider discontinuing leukotriene inhibitors if a patient exhibits or reports a neuropsychiatric symptom.

In August, the respective manufacturers updated the prescribing information for Singulair® (montelukast), Accolate® (zafirlukast), and Zyflo CR®/Zyflo® (zileuton) to include information about neuropsychiatric events.

Additional information can be found at http://www.fda.gov/Safety/MedWatch/Safety...

Intelence™ (Etravirine): Severe Skin and Hypersensitivity Reactions - August 2009

Tibotec Therapeutics, in conjunction with the U.S. Food and Drug Administration (FDA), has issued a ?Dear Healthcare Professional? letter informing of a labeling update for etravirine (Intelence™) to include warnings of severe skin and hypersensitivity reactions. Cases of skin reactions have included Stevens-Johnson syndrome, toxic epidermal necrolysis (may be fatal), and erythema multiforme. Hypersensitivity reactions, ranging from rash and/or constitutional symptoms to occasional organ dysfunction (including hepatic failure), have been reported. Immediately discontinue etravirine with signs or symptoms of severe skin reaction or hypersensitivity. Monitor hepatic transaminases and clinical status if signs or symptoms of hypersensitivity (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia) are present. Life-threatening reaction may occur due to a delay in stopping therapy after onset of severe rash.

Additional information, including a copy of the ?Dear Healthcare Professional? letter, is available at http://www.fda.gov/Safety/MedWatch/Safety...

Levemir®: MedWatch Alert Concerning Certain Lots of Stolen Product That May Be Dangerous - Updated August 2009

The U.S. Food and Drug Administration (FDA) is concerned that vials of stolen insulin detemir may still be on the market. Efficacy issues due to lack of proper handling and storage are causing patients to experience a lack of glucose control.

For complete information and a list of affected lot numbers, please refer to the MedWatch alert at http://www.fda.gov/Safety/MedWatch/Safety...

Orlistat: Liver-Related Adverse Events and Ongoing Safety Review - August 2009

The U.S. Food and Drug Administration (FDA) is communicating information regarding an ongoing safety review of orlistat prompted by reports of liver-related adverse events. Between 1999 and October 2008, 32 reports of serious liver injury (commonly reported as jaundice, weakness, and abdominal pain), including six cases of liver failure, were submitted to the FDA?s Adverse Event Reporting System. Thirty of the 32 reports occurred outside of the United States. In addition to these reports, the FDA is reviewing other data submitted by the manufacturer regarding suspected cases of hepatic injury.

The FDA analysis is ongoing, and at present time no definite association between liver injury and orlistat has been established. The FDA is not recommending that healthcare professionals change their prescribing practices, and patients currently receiving therapy should continue taking orlistat as directed. However, patients should be encouraged to report any signs/symptoms associated with liver injury (eg, fatigue, fever, jaundice, brown urine, nausea, vomiting, abdominal pain) to a healthcare professional.

For more information, please refer to http://www.fda.gov/Safety/MedWatch/Safety..

Ibuprofen: Unapproved Topical Products - August 2009

The U.S. Food and Drug Administration (FDA) issued information for healthcare providers and consumers regarding unapproved topical combination products containing ibuprofen. Unlike oral ibuprofen products (which are FDA-approved), topical products containing ibuprofen are not FDA-approved. Safety claims for topical products containing ibuprofen have not been reviewed by the FDA.

For information, including a list of the unapproved products, please refer to: http://www.fda.gov/Safety/MedWatch/Safety...

Tumor Necrosis Factor-Alpha Blockers Associated with Malignancies and New-Onset Psoriasis - Updated August 2009

The U.S. Food and Drug Administration (FDA) has completed its previously announced analysis of Tumor Necrosis Factor-Alpha (TNF) blockers, and is alerting healthcare professionals of an increased risk of lymphomas in children and adolescents and leukemia in all patients, including adults. Health Canada has recently issued a similar alert to Canadian practitioners. The FDA analysis is an update to the June 2008 Early Communication About an Ongoing Safety Review regarding a possible association between the use of TNF blockers and the development of lymphoma and other cancers in children and young adults. In addition, as a result of a separate analysis, the FDA is also notifying healthcare professionals of an increased risk of new-onset psoriasis in all patients, including adults.

Pediatric malignancies: Forty-eight cases of malignancy were identified by the FDA in children and adolescents with the use of TNF blockers. Etanercept and infliximab were the only TNF blockers included in the analysis. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin's and non-Hodgkin's lymphoma). Other malignancies such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate); however, the role of TNF blockers in the development of malignancies in children could not be excluded. Further data regarding the incidence of these malignancies is expected from ongoing postmarketing studies and registries conducted by the TNF blocker manufacturers.

Leukemia: The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients using TNF blockers. Average onset time to development of leukemia was within the first 1-2 years of TNF blocker initiation. Although most patients were receiving other immunosuppressive agents, the role of TNF blockers in the development of leukemia could not be excluded. The FDA concluded that there is a possible association with the development of leukemia and the use of TNF blockers.

New-onset psoriasis: In a separate analysis, the FDA reviewed 69 cases of new-onset psoriasis (including pustular, palmoplantar) occurring in patients using TNF blockers for the treatment of conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, 2 were reported in children and 12 required hospitalization, the most severe outcome. Improvement was seen when the TNF blocker was discontinued. The FDA concluded that there is a possible association with new-onset psoriasis and the use of TNF blockers.

The FDA has required the manufacturers of TNF blockers to update the Boxed Warnings and the Warnings in the prescribing information as it relates to malignancies, to update the Adverse Events section to include reported cases of new-onset psoriasis, and to revise the medication guide to reflect this information. Health Canada is also working with their respective manufacturers to update the Canadian labeling with this important safety information. Patients should be monitored closely for signs and symptoms suggestive of malignancy or new-onset psoriasis, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation.

Additional information can be found at:

U.S.: http://www.fda.gov/Safety/MedWatch/Safety...

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_137-eng.php

Clopidogrel (Plavix®) and Proton Pump Inhibitors (PPIs): Health Canada Issues Notice - August 2009

Health Canada, in conjunction with Sanofi-Aventis Canada Inc., and Bristol Myers Squibb Canada Co., has issued a Dear HealthCare Professional letter to Canadian practitioners regarding the potential interaction between clopidogrel (Plavix®) and proton pump inhibitors (PPIs). A similar notice had previously been issued in the U.S. by the Food and Drug Administration (FDA). Certain PPIs may inhibit the cytochrome enzyme (CYP2C19) which metabolizes clopidogrel to its active metabolite, thus potentially resulting in decreased clinical efficacy of clopidogrel.

Health Canada is recommending that healthcare providers continue to prescribe clopidogrel and patients continue taking clopidogrel as directed. Health Canada recommends against the use of drugs (including PPIs) which inhibit CYP2C19 in patients receiving clopidogrel. Prescribers should consider the risk-benefits of combination (PPI-clopidogrel) therapy as well as use of alternative gastroprotective agents. Health Canada is currently working with the manufacturers mentioned to update the Canadian product monograph with this important safety information.

Further information may be found at: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/plavix_hpc-cps-eng.php

Mycophenolate Mofetil: Reports of Pure Red Cell Aplasia (PRCA); Health Canada Issues Warning - August 2009

Hoffman-La Roche Limited (Roche) and Roche Laboratories, Inc., in conjunction with Health Canada and the Federal Drug Administration (FDA), have issued a "Dear Healthcare Professional" letter regarding reports of PRCA in patients receiving mycophenolate mofetil (CellCept®) therapy concomitantly with other immunosuppressive agents (eg, cyclosporine, corticosteroids, tacrolimus). As of February 2008, forty-one cases had been reported. Following a review of the reported data, Health Canada deemed, in a few cases, a causal relationship with mycophenolate therapy could not be ruled out. In some cases, mycophenolate dose reduction or discontinuation resulted in reversal of PRCA.

Although the mechanism is not precisely known, PRCA development may be related to immunosuppression. Symptoms may include fatigue, lethargy, and/or pallor; however, of primary concern is the risk for anemia which can range from subclinical to severe. Symptoms of severe anemia may include weakness, tachycardia, and/or dyspnea. Treatment usually involves discontinuation of the agent inducing PRCA or treatment of the underlying disease state. Prior to discontinuing mycophenolate or other immunosuppressive therapy, clinicians are advised to consider the potential contribution of the drugs to PRCA, as well as the risk for transplant rejection. The Canadian and U.S. labeling has been updated to include this safety information.

Further information may be found at:

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/cellcept_2_hpc-cps-eng.php

U.S.: http://www.fda.gov/Safety/MedWatch/Safety...

Dextroamphetamine and Amphetamine Recall Due to Exceeded Weight Requirement ) - August 2009

Barr Laboratories, Inc. has issued a voluntary recall of dextroamphetamine and amphetamine 20 mg tablets, 100 count bottle, lot number 311756. This lot may contain tablets that exceed weight requirements, potentially resulting in supratherapeutic doses. Possible adverse effects associated with a supratherapeutic dose include cardiovascular, neurologic, psychiatric and gastrointestinal reactions. The affected lot was distributed between 6/11/09 and 6/16/09. Patients are instructed to discontinue use of this lot and return it to their pharmacy. Wholesalers and retailers should cease distribution of all medication from this lot only.

For additional information, please refer to http://www.fda.gov/Safety/MedWatch/Safety...

Omalizumab (Xolair®): Interim Findings From Ongoing Safety Review (EXCELS Study) - August 2009

The U.S. Food and Drug Administration (FDA) and Health Canada have issued independent communication to their respective healthcare professionals regarding interim safety findings from an ongoing observational trial titled Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS) involving ~5000 patients treated with omalizumab and ~2500 patients not receiving omalizumab. Preliminary findings suggest an increased risk of cardiovascular (eg, arrhythmias, cardiomyopathy, ischemic heart disease, heart failure, pulmonary hypertension), cerebrovascular, and thromboembolic adverse events in patients treated with omalizumab compared to those not receiving omalizumab. The primary objective of the trial is to assess long-term safety (5 years) of omalizumab in patients ≥12 years of age with moderate-to-severe persistent asthma and a positive skin/blood test for an aeroallergen.

At this time, the FDA and Health Canada are not recommending patients discontinue omalizumab therapy or recommending any changes to the current prescribing information for Xolair®. Analysis of this preliminary safety data is ongoing and neither regulatory agency has reached any conclusions at this time. The final results from the EXCELS trial are not expected until 2012.

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

U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInfor...

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_129-eng.php

Oral Sodium Phosphate Products: Health Canada Issues Updated Safety Information - August 2009

Health Canada has issued a "Dear Health Care Professional" letter regarding updated safety information associated with the use of oral sodium phosphate bowel cleansing agents. In Canada, over-the-counter (OTC) oral sodium phosphate products are now indicated for laxative use only and are no longer indicated for purgative use. Manufacturers of these products have revised or are working to revise the labeling, which will no longer include instructions for purgative use.

Further information may be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/oral_sodium_phos_hpc-cps-eng.php

Tumor Necrosis Factor-Alpha Blockers Associated with Malignancies and New-Onset Psoriasis - August 2009

The U.S. Food and Drug Administration (FDA) has completed its previously announced analysis of Tumor Necrosis Factor-Alpha (TNF) blockers, and is alerting healthcare professionals of an increased risk of lymphomas in children and adolescents and leukemia in all patients, including adults. This analysis is an update to the June 2008 Early Communication About an Ongoing Safety Review regarding a possible association between the use of TNF blockers and the development of lymphoma and other cancers in children and young adults. In addition, as a result of a separate analysis, the FDA is also notifying healthcare professionals of an increased risk of new-onset psoriasis in all patients, including adults.

Pediatric malignancies: Forty-eight cases of malignancy were identified by the FDA in children and adolescents with the use of TNF blockers. Etanercept and infliximab were the only TNF blockers included in the analysis. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin's and non-Hodgkin's lymphoma). Other malignancies such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate); however, the role of TNF blockers in the development of malignancies in children could not be excluded. Further data regarding the incidence of these malignancies is expected from ongoing postmarketing studies and registries conducted by the TNF blocker manufacturers.

Leukemia: The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients using TNF blockers. Average onset time to development of leukemia was within the first 1-2 years of TNF blocker initiation. Although most patients were receiving other immunosuppressive agents, the role of TNF blockers in the development of leukemia could not be excluded. The FDA concluded that there is a possible association with the development of leukemia and the use of TNF blockers.

New-onset psoriasis: In a separate analysis, the FDA reviewed 69 cases of new-onset psoriasis (including pustular, palmoplantar) occurring in patients using TNF blockers for the treatment of conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, 2 were reported in children and 12 required hospitalization, the most severe outcome. Improvement was seen when the TNF blocker was discontinued. The FDA concluded that there is a possible association with new-onset psoriasis and the use of TNF blockers.

The FDA has required the manufacturers of TNF blockers to update the Boxed Warnings and the Warnings in the prescribing information as it relates to malignancies, to update the Adverse Events section to include reported cases of new-onset psoriasis, and to revise the medication guide to reflect this information. Patients should be monitored closely for signs and symptoms suggestive of malignancy or new-onset psoriasis, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation.

Additional information can be found here.

Botulinum Toxin Types A and B: Name Changes and Revisions to Prescribing Information - August 2009

On July 31, 2009, the U.S. Food and Drug Administration (FDA) approved the following revisions to the prescribing information of licensed botulinum toxin products, including the newest botulinum toxin type A, Dysport™, which was granted FDA approval in April 2009:

• A Boxed Warning regarding the risk of potentially life-threatening spread of toxin effect from the local injection site.
• A Risk Evaluation and Mitigation Strategy (REMS) which includes a medication guide to explain risks to patients and caregivers.
• The established drug names of the botulinum toxin products have been changed to emphasize the potency differences and the lack of interchangeability among the products (see below). Clinical doses expressed in units cannot be compared or converted from one product to the next. Of note, the marketed trade names and the product formulations have not changed for these products.

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

• http://www.fda.gov/Safety/MedWatch/...
• http://www.fda.gov/Drugs/DrugSafety/...

Colchicine: FDA Approved Oral Product (Colcrys™) and Safety Issues Associated With Colchicine Use - July 2009

The Food and Drug Administration (FDA) has approved an oral colchicine product, Colcrys™, for the treatment of familial Mediterranean fever (FMF) and acute gout flares. Prior to the approval of Colcrys™, colchicine had been available as an unapproved medication without FDA-approved prescribing information. In addition, the FDA is also notifying healthcare professionals of two new safety concerns associated with colchicine involving drug interactions and the safety of doses historically used in the treatment of acute gout.

The FDA analyzed safety data from published literature, pharmacokinetic and drug interaction studies, as well as previously reported adverse events, and discovered cases of fatal colchicine toxicity in certain patients. The cases occurred in patients receiving concomitant medications that interact with colchicine, such as clarithromycin (despite receiving standard therapeutic doses of colchicine). These reports suggest a role of concomitant medications which affect the gastrointestinal absorption and/or hepatic metabolism of colchicine in the development of toxicity (particularly in patients with renal or hepatic impairment).

In addition, the FDA analysis of safety and efficacy data of colchicine in acute gout revealed that a substantially lower dose of colchicine (total cumulative dose: 1.8 mg) demonstrated efficacy compared to the higher dose (total cumulative dose: 4.8 mg) traditionally used. There were also fewer adverse events reported with the lower dose.

In light of the safety issues, the FDA is recommending that colchicine not be used concurrently with P-glycoprotein (P-gp) or strong CYP3A4 inhibitors in patients with renal or hepatic impairment, and a dose reduction or interruption of colchicine therapy be considered in those patients without renal or hepatic impairment. A medication guide has also been developed for patient distribution.

For additional information, please refer here.

Mecasermin Rinfabate (Iplex™): Updated Supply Information and Postponement of Phase II Clinical Trial in ALS Patients - July 2009

Insmed, Inc, the manufacturer of mecasermin rinfabate (Iplex™), has announced it will cease supplying Iplex™ to any new patient due to their extremely limited inventory. In addition, Insmed will postpone the initiation of the Phase II clinical trial for amyotrophic lateral sclerosis (ALS) patients previously announced with the U.S. Food and Drug Administration (FDA) in March 2009. Insmed no longer has the capability to manufacture the medication and has determined it must conserve the current inventory to ensure the existing patients (~70 patients worldwide) continue to receive therapy. In the U.S., there are 12 patients with access to Iplex™ through a single-patient IND application approved by the FDA. Insmed believes there is sufficient inventory to supply the existing patients for no more than 24 months.

Insmed intends to analyze data collected from the use of Iplex™ in various indications, including myotonic muscular dystrophy and ALS, to determine the possibility of future clinical trials and explore manufacturing options with third party manufacturers, if feasible.

Iplex™ is a combination of recombinant human insulin-like growth factor 1 (rhIGF-1) and human insulin-like growth factor-binding protein-3 (rhIGFBP-3). Iplex™ was FDA approved in 2005 for the treatment of severe growth failure in children with primary IGF-1 deficiency (primary IGFD), or with growth hormone (GH) deletion who have developed neutralizing antibodies to GH, but has not been currently marketed for that indication due to a court order related to patent infringement.

Additional information can be found at:

http://investor.insmed.com/releasedetail.cfm?ReleaseID=399059

http://www.fda.gov/Drugs/ResourcesForYou/HealthProfessionals/ucm118117.htm

Fosamprenavir: Health Canada Issues Notice Regarding Possible Risk For Myocardial Infarction - July 2009

GlaxoSmithKline Inc, in conjunction with Health Canada, has issued a "Dear HealthCare Professional" letter regarding a possible risk for myocardial infarction (MI) in adult patients with human immunodeficiency virus (HIV) receiving fosamprenavir (Telzir®). Data recently reported from a nested case-control study, linked cumulative fosamprenavir exposure to an increased risk of MI (OR = 1.55 per additional year of exposure [95% CI, 1.20-1.99]). Previously, the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study identified a possible association between MI and the use of protease inhibitors.

Protease inhibitor therapy can increase serum lipids. Therefore, clinicians are reminded to evaluate cholesterol and triglyceride levels prior to initiation and periodically during fosamprenavir therapy. Physical signs of fat distribution (associated with combination antiretroviral therapy), as well as modifiable risk factors for cardiovascular disease (eg, smoking, diabetes, hypertension), should also be evaluated and addressed as appropriate.

Health Canada is working with the manufacturer to incorporate this important safety information within the fosamprenavir Canadian product monograph.

Additional information may be found here.

Omalizumab (Xolair®): Interim Findings From Ongoing Safety Review (EXCELS study) - July 2009

The U.S. Food and Drug Administration (FDA) is communicating information regarding interim safety findings from an ongoing observational trial titled Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS) involving ~5000 patients treated with omalizumab and ~2500 patients not receiving omalizumab. Preliminary findings suggest an increased risk of cardiovascular (eg, arrhythmias, cardiomyopathy, ischemic heart disease, heart failure, pulmonary hypertension), cerebrovascular, and thromboembolic adverse events in patients treated with omalizumab compared to those not receiving omalizumab. The primary objective of the trial is to assess long-term safety (5 years) of omalizumab in patients ≥12 years of age with moderate to severe persistent asthma and a positive skin/blood test for an aeroallergen.

At this time, the FDA is not recommending patients discontinue omalizumab therapy or recommending any changes to the current prescribing information for Xolair®. The FDA's analysis of this preliminary safety data is ongoing and the FDA has not reached any conclusions at present. The final results from the EXCELS trial are not expected until 2012.

For more information, healthcare professionals may refer to the following website http://www.fda.gov/Safety/MedWatch/SafetyInformation/Sa...

Acetaminophen Concentrated Drops (16 ounce) Recall Due to Potential For Overdosing - July 2009

Brookstone Pharmaceuticals, with awareness of the U.S. Food and Drug Administration (FDA), has issued a voluntary recall of all lots of concentrated acetaminophen drops (80 mg/0.8 mL) in 16 ounce bulk containers. The manufacturer states this is a cautionary measure to minimize confusion between this bulk container of the concentrated acetaminophen preparation and the bulk container of the regular strength acetaminophen liquid preparations (160 mg/15 mL), and to limit the risk of potential dosing errors.

For additional information, please refer to http://www.fda.gov/Safety/MedWatch/...

Immunosuppressant Drugs: Risk of Opportunistic Infections - July 2009

The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of updated labeling requirements to emphasize an increased risk for opportunistic infections (eg, activation of latent viral infections, including BK virus-associated nephropathy) in patients treated with certain immunosuppressant agents. The labeling changes will be required for cyclosporine (Neoral®, Sandimmune®), mycophenolate (Cellcept®, Myfortic®), and sirolimus (Rapamune®). This risk has been previously reported and reflected in the prescribing information for tacrolimus (Prograf®). Analyses of the FDA's Adverse Event Reporting System (AERS) has shown an association between BK virus-associated nephropathy and immunosuppressant drug use (primarily in renal transplant patients) which can lead to renal allograft loss. Patients should be monitored for this risk and early intervention is essential. Immunosuppressant therapy adjustments should be considered in patients who develop BK virus-associated nephropathy.

For additional information, refer to the following FDA website: http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety...

Propoxyphene-Containing Products and Fatal Overdose - July 2009

The Food and Drug Administration (FDA) is requiring the manufacturers of propoxyphene to strengthen product labeling, emphasizing the risk of fatal overdose with its use. Manufacturers will be required to update their boxed warnings and also to develop medication guides which would be provided to patients with every new or refilled prescription. This action is being taken in response to concerns that propoxyphene may be more lethal in overdose (accidental or intentional) when compared to other pain medications.

The FDA is also requiring the manufacturers of propoxyphene products to conduct safety studies which will asses the effects of higher than recommended doses of propoxyphene on the heart. Additional safety studies (including a study of propoxyphene in the elderly) are being planned or are under consideration.

Propoxyphene has been available in the United States since 1957 for the treatment of mild-to-moderate pain. Because the FDA considers propoxyphene to be effective at recommended doses, it is not proposing that propoxyphene be removed from the U.S. market at this time. However, additional regulatory action may be taken based on the results of the proposed safety studies.

Healthcare providers should be aware of the risk of fatal overdose when prescribing propoxyphene and carefully review patient histories when considering an appropriate pain medication.

For additional information, refer to the following FDA website: http://www.fda.gov/Safety/MedWatch/...

Smoking Cessation Aids (Bupropion and Varenicline): Boxed Warnings and Medication Guides Highlighting Neuropsychiatric Risks Required by the Food and Drug Administration (FDA) - July 2009

The U.S. Food and Drug Administration (FDA) has announced it will require manufacturers to add a black box warning and provide a medication guide regarding the previously reported association between varenicline or bupropion use and neuropsychiatric adverse effects. Reports of postmarketing events temporally associated with these medications (including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide) continue to be collected and reviewed by the FDA. Events may occur in patients without a history of psychiatric disease and may also be difficult to diagnose due to similarities to typical symptoms of nicotine withdrawal including irritation, depression, insomnia, and anxiety.

Healthcare professionals should instruct patients to stop taking these medications and contact a healthcare provider if neuropsychiatric symptoms occur. Family members or friends who notice any changes in behavior (especially suicidal thoughts or behavior) of patients using these medications should inform the patient, and recommend they discontinue the medication and call a healthcare professional.

For additional information, see http://www.fda.gov/Drugs/DrugSafety/Postmarket...

Piroxicam: Health Canada Issues New Restrictions for Use - June 2009

Health Canada is notifying Canadian healthcare professionals and residents of forthcoming changes to piroxicam labeling regarding restrictions for use. Following a safety review, Health Canada has determined that benefits of piroxicam use in treating acute, short-term pain/inflammation no longer outweigh risks for serious skin and/or gastrointestinal (GI) adverse events associated with its use relative to similar agents.

Healthcare practitioners are now advised to utilize alternative agents (eg, other nonselective NSAIDS) for treatment of acute, short-term pain/inflammation. Residents are advised to consult with their healthcare providers for appropriate alternative treatment. Piroxicam may still be used to treat pain/inflammation associated with chronic arthritic conditions (eg, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis).

Health Canada is currently working with the manufacturers to include this important safety information in the product monograph. Of note, revisions will be made only to the labeling of piroxicam products approved for acute use.

Further information may be obtained at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_102-eng.php

Cefepime: Ongoing Safety Review Update - June 2009

The Food and Drug Administration (FDA) has announced completion of data analysis regarding the possible association between cefepime use and increased mortality. An earlier meta-analysis prompted this review (Yahav, 2007). The FDA analysis included 50 additional trials and found no association between increased mortality and cefepime. The FDA will continue to review the safety profile of cefepime. In addition, the manufacturer and the FDA are both completing independent analyses using hospital use data. The results of these analyses are expected in 2010.

Additional information may be found here.

Stimulant Medications for ADHD: Ongoing Safety Review Assessing the Potential Association With Sudden Death in Children - June 2009

The Food and Drug Administration (FDA) has released a statement concerning the findings of a recent retrospective study on the possible association between stimulant medication use and sudden death in children. In this study, 564 previously healthy children who died suddenly in motor vehicle accidents were compared to a group of 564 previously healthy children who died suddenly. Two of the 564 (0.4%) children in motor vehicle accidents were taking stimulant medications compared to 10 of 564 (1.8%) children who died suddenly. While the authors of this study conclude there may be an association between stimulant use and sudden death in children, there were a number of limitations to the study and the FDA cannot conclude this information impacts the overall risk/benefit profile of these medications.

Parents are instructed not to discontinue a child's stimulant medication based upon this information and should discuss the issue with the prescriber. If a child displays symptoms of cardiovascular disease including chest pain, dyspnea or fainting, parents should seek immediate medical care for the child.

Further assessment of the strength of this potential association is ongoing through research conducted by the FDA and the Agency for Healthcare Research and Quality. Data collection will be completed by the end of 2009.

For additional information, refer here

Levemir®: MedWatch Alert Concerning Certain Lots of Stolen Product That May Be Dangerous - June 2009

For complete information, please refer to the MedWatch alert here

Increased Mortality in Stable Liver Transplant Recipients Converted to Sirolimus (Rapamune®) - June 2009

The Centers for Disease Control and Prevention (CDC) has provided interim guidance on which groups should be vaccinating using the 23-valent pneumococcal polysaccharide vaccine (PPSV23) during the novel influenza A (H1N1) outbreak. Pneumococcal vaccines may be useful in preventing secondary pneumococcal infections during influenza outbreaks. Influenza predisposes patients to bacterial community-acquired pneumonia and was an important factor of illness and death associated with the 20th century influenza pandemic. However, at present, the role of pneumococcal infections among severe cases (ie, requiring hospitalization) of the current H1N1 outbreak is unclear.

The CDC's Advisory Committee on Immunization Practices (ACIP) recommends a single dose of PPSV23 be given to following patient populations due to their increased risk of pneumococcal disease and from suffering complications arising from influenza infection:

1. All patients ≥65 years of age
2. Patients 2-64 years of age with certain high-risk condition(s):
   • Chronic cardiovascular disease (heart failure and cardiomyopathies)
   • Chronic pulmonary disease (including COPD and emphysema)
   • Diabetes mellitus
   • Alcoholism
   • Chronic liver disease (including cirrhosis)
   • Cerebrospinal fluid leaks
   • Functional or anatomic asplenia (including sickle cell disease and splenectomy)
   • Immunocompromising conditions (including HIV infection, leukemia, lymphoma, Hodgkin's disease, multiple myeloma, generalized malignancy, chronic renal failure, nephrotic syndrome; patients receiving immunosuppressive chemotherapy, including corticosteroids; patients who have received an organ or bone marrow transplant).
3. Adults aged 19-64 years of age who smoke cigarettes or have asthma

PPSV23 vaccination, including revaccination, should continue during the present H1N1 outbreak according to current ACIP recommendations for patients with existing indications. At present, the CDC is not recommending vaccination using PPSV23 in patients without existing ACIP recommended indications.

Of note, the 7-valent pneumococcal conjugate vaccine (PCV7) is recommended for use in children <5 years of age; however, expanding the use of PCV7 to patients ≥5 years is not recommended due to the declining circulation of the 7 serotypes included in this vaccine.

Recommendations may change or be revised as more information concerning the clinical impact of the novel influenza A (H1N1) virus becomes available. For the most recent recommendations, please refer to:http://www.cdc.gov/h1n1flu/guidance/ppsv_h1n1.htm

Increased Mortality in Stable Liver Transplant Recipients Converted to Sirolimus (Rapamune®) - June 2009

The Food and Drug Administration (FDA) is alerting healthcare professionals about recent data from a randomized, open-label study in stable liver transplant patients, comparing calcineurin inhibitor (CNI) maintenance therapy with conversion of CNI to sirolimus (Rapamune®). Of the cohort of patients in the sirolimus arm, an increased mortality rate was observed. Additionally, this patient group showed an increased rate of treatment failure (acute rejection), drug discontinuation due to adverse events, as well as increased incidence of mucocutaneous, dermatologic, and/or hyperlipidemic side effects. There are no new changes to the product labeling at this time; however, clinicians are reminded of the existing U.S. boxed warning stating that sirolimus is not recommended for use in de novo liver transplant patients due to increased risk of hepatic artery thrombosis, graft failure, and increased mortality when used in combination with cyclosporine and/or tacrolimus.

Additional information can be found here

Mycophenolate Mofetil: Reports of Pure Red Cell Aplasia (PRCA); Health Canada Issues Warning - June 2009

Hoffman-La Roche Limited (Roche), in conjunction with Health Canada, has issued a "Dear Healthcare Professional" letter to Canadian practitioners regarding reports of PRCA in patients receiving mycophenolate mofetil (CellCept®) therapy concomitantly with other immunosuppressive agents (eg, cyclosporine, corticosteroids, tacrolimus). As of February 2008, forty-one cases had been reported. Following a review of the reported data, Health Canada deemed, in a few cases, a causal relationship with mycophenolate therapy could not be ruled out. In some cases, mycophenolate dose reduction or discontinuation resulted in reversal of PRCA.

Although the mechanism is not precisely known, PRCA development may be related to immunosuppression. Symptoms may include fatigue, lethargy, and/or pallor; however, of primary concern is the risk for anemia which can range from subclinical to severe. Symptoms of severe anemia may include weakness, tachycardia, and/or dyspnea. Treatment usually involves discontinuation of the agent inducing PRCA or treatment of the underlying disease state. Prior to discontinuing mycophenolate or other immunosuppressive therapy, clinicians are advised to consider the potential contribution of the drugs to PRCA, as well as the risk for transplant rejection. The Canadian labeling has been updated to include this safety information.

Further information may be found at:

Canada: click here

Propylthiouracil-Induced Hepatic Failure - June 2009

The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of an increased risk of serious liver injury (including liver failure and death) associated with the use of propylthiouracil. The FDA has received reports of propylthiouracil-related hepatotoxicity in both adults (22 cases) and children (10 cases), including cases of liver transplant (5 in adults; 6 in children) and death (12 in adults; 1 in children). In contrast to propylthiouracil, methimazole-related hepatotoxicity has been reported in 5 cases (adults), including 3 deaths.

In general, propylthiouracil is considered second-line therapy to methimazole, except in cases of allergy or intolerance to methimazole or in patients with Graves' disease in their first trimester of pregnancy. Avoid use of propylthiouracil in pediatric patients unless no other treatment options are available. Counsel patients on possible signs or symptoms of hepatotoxicity (eg, fatigue, loss of appetite, weakness, yellowing of eyes or skin); monitor all patients for a minimum of 6 months after propylthiouracil initiation; and discontinue propylthiouracil if liver injury is suspected.

Additional information can be found here

Tumor Necrosis Factor-Alpha Blockers Associated with Unrecognized Invasive Fungal Infections - May 2009

The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of an increased risk for opportunistic fungal infections in patients treated with antitumor necrosis factor (anti-TNF) agents adalimumab (Humira®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), and infliximab (Remicade®). The FDA has received reports of pulmonary and disseminated cases of histoplasmosis, coccidioidomycosis, blastomycosis, and other fungal infections associated with use of these agents. In some cases, the symptoms of fungal infection (eg, fever, cough, malaise, dyspnea, fatigue) were unrecognized and precluded prompt antifungal treatment, resulting in 12 deaths. In response, the FDA is requiring manufacturers of these agents to strengthen the boxed warning statement in the labeling to further emphasize the risk of invasive fungal infection. Patients should be monitored closely for signs and symptoms suggestive of fungal infection, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation. Symptomatic patients should be questioned about their residence in or travel from areas of endemic mycoses, which should prompt consideration of empiric antifungal therapy.

Additional information can be found at:

http://www.fda.gov/medwatch/safety/2008/safety08.htm#TNF2

http://www.fda.gov/medwatch/safety/2009/safety09.htm#Simponi

FDA Issues Information Concerning Stockpiled Antivirals - May 2009

The U.S. Food and Drug Administration (FDA) is recommending that all companies, U.S. states and localities, and other organizations consider keeping any oseltamivir (Tamiflu®) and zanamivir (Relenza®) that are nearing or are past the labeled expiration dates. These two medications are covered under the Emergency Use Authorization that the FDA has issued for the 2009 influenza (H1N1) outbreak. At present, the U.S. Department of Health and Human Services is evaluating options and may decide to utilize these stockpiled medications, if needed.

Any organization that decides to retain the soon-to-expire or expired zanamivir or oseltamivir should maintain the product(s) under the labeled storage requirements, and should contact the FDA's Emergency Operations Center (301-443-1240) with the amounts of antivirals in their stockpiles. The FDA is not directing this statement to individual patients with either of the antivirals in their home.

For additional information, please refer to the following websites:

http://www.fda.gov/oc/opacom/hottopics/H1N1Flu/stockpile.html

http://www.fda.gov/cder/drug/antivirals/influenza/default.htm

Topical Anesthetic Use for Cosmetic or Medical Procedures: Public Health Advisory - May 2009

Health Canada has issued a "Dear Healthcare Professional" letter and a notice to the Canadian public regarding important safety information associated with the use of topical anesthetic agents. Recently in the U.S., the The Food and Drug Administration (FDA) issued a Public Health Advisory to remind consumers, caregivers, and healthcare professionals of potential life-threatening side effects associated with the use of topical anesthetics available as prescription and over-the-counter (OTC) products for a variety of uses, including numbing skin prior to cosmetic or medical procedures (topical lidocaine has been recently evaluated to relieve mammography discomfort).

Topical application can result in high systemic levels and lead to toxic effects (eg, methemoglobinemia, irregular heart beats, seizures, coma, respiratory depression, death). Children may be at an increased risk for adverse effects, as well as individuals who, without the supervision of trained professionals, apply large amounts of anesthetics (or cover large areas of the skin), leave these products on for long periods of time, or use materials, wraps, or dressings to cover the skin after anesthetic application.

Both the FDA and Health Canada are recommending that when topical anesthetics are needed prior to procedures, consumers ask their healthcare provider for instructions on safe use of these products, use only approved products, and use products with the lowest amount of anesthetic while applying the least amount possible to relieve pain. If a high degree of pain is expected that is not controlled by appropriate amounts of topical anesthetics, consumers should ask their physician for alternative techniques for pain control.

Additional information can be found at:

U.S.: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Anesthetics

Canada: Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/emla_ametop_hpc-cps-eng.php

Erlotinib: Serious Dermatologic, Gastrointestinal, and Ocular Reactions - May 2009

OSI Pharmaceuticals, Inc and Genetech, Inc, in conjunction with the U.S. Food and Drug Administration (FDA), have issued a "Dear Healthcare Professional" letter regarding serious, life-threatening events (gastrointestinal perforation, bullous and exfoliative skin conditions, corneal ulceration/perforation) that occurred during the use of erlotinib (Tarceva®). In Canada, a similar notice has been issued by Hoffman-La Roche Limited, in conjunction with Health Canada. The incidence of gastrointestinal perforation has been reported at a rate of 0.1% to 1%, while both skin and ocular events have been reported in <0.01% of treated patients.

Perforation: Patients with increased risk of GI perforation include those receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, a taxane derivative, or have a prior history of peptic ulcers or diverticular disease. The U.S. prescribing information has been updated to include this important safety information and recommends permanently discontinuing erlotinib if perforation occurs. The Canadian product monograph is under review and will be updated accordingly. At this time, Canadian providers are advised to interrupt or discontinue erlotinib therapy if perforation occurs.

Bullous/exfoliative skin conditions: Cases suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. In the U.S. and Canada, interruption or discontinuation of treatment is recommended with severe bullous, blistering, or exfoliating skin conditions.

Corneal ulceration/perforation: Abnormal eyelash growth, keratoconjunctivitis sicca, or keratitis are known risk factors for corneal ulceration/perforation. In the U.S. and Canada, interruption or discontinuation of therapy is recommended if patient presents with acute or worsening ocular symptoms (eg, eye pain).

Further information may be found at:

U.S.: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Tarceva

Canada:http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/tarceva_2_hpc-cps-eng.php

Digoxin Tablet Recall Due to Potentially Variable Content of Active Ingredient - May 2009

Caraco Pharmaceutical Laboratories, Ltd, with awareness by the U.S. Food and Drug Administration (FDA), has issued a voluntary recall of all unexpired lots of 0.125 mg and 0.25 mg digoxin tablets distributed prior to March 31, 2009, and within expiration of September 2011. The manufacturer states that the tablets may be of differing sizes, thus posing a risk of variable digoxin content.

For additional information, including the product NDC numbers affected, please refer to:

http://www.fda.gov/oc/po/firmrecalls/caraco03_09.html

http://www.fda.gov/medwatch/safety/2009/safety09.htm#Digoxin

Erlotinib: Serious Dermatologic, Gastrointestinal, and Ocular Reactions - May 2009

OSI Pharmaceuticals, Inc and Genetech, Inc, in conjunction with the U.S. Food and Drug Administration (FDA), have issued a "Dear Healthcare Professional" letter regarding serious, life-threatening events (gastrointestinal perforation, bullous and exfoliative skin conditions, corneal ulceration/perforation) that occurred during the use of erlotinib (Tarceva®).

Perforation: Patients with increased risk of GI perforation include those receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, a taxane derivative, or have a prior history of peptic ulcers or diverticular disease. Permanently discontinue erlotinib if perforation occurs.

Bullous/exfoliative skin conditions: Cases suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. Interruption or discontinuation of treatment is recommended with severe bullous, blistering, or exfoliating skin conditions.

Corneal ulceration/perforation: Abnormal eyelash growth, keratoconjunctivitis sicca, or keratitis are known risk factors for corneal ulceration/perforation. Interrupt or discontinue therapy if patient presents with acute or worsening ocular symptoms (eg, eye pain).

Further information may be found at http://www.fda.gov/medwatch/safety/2009/safety09.htm#Tarceva

Testosterone Gel Products: Boxed Warning Concerning Risk of Inadvertent Secondary Testosterone Exposure to Children - May 2009

The Food and Drug Administration (FDA) is requiring the product labeling of topical testosterone gel products (AndroGel® and Testim®) be updated to include a boxed warning regarding the potential risk of inadvertent secondary exposure of testosterone via contact with the treated patient. The addition of a boxed warning was prompted by reports of eight cases of secondary testosterone exposure in children (ages 9 months to 5 years) as of December 2008, despite precautions in the current product labeling. Since December, additional cases have been reported to the FDA. Of the reviewed cases, adverse effects in the children included aggressive behavior, increased libido, genitalia enlargement, advanced bone age, and premature development of pubic hair.

The FDA is reminding practitioners and patients of precautions to minimize secondary exposure by covering the application site with clothing after the gel has dried, washing hands with soap and warm water after each application, washing the application site with soap and warm water prior to any skin-to-skin contact with another person, and for children and women to avoid contact with the application site of men using these products.

Additional information can be found at http://www.fda.gov/medwatch/safety/2009/safety09.htm#testosterone

CDC Antiviral Treatment Recommendations for Novel H1N1 Influenza - May 2009

The Centers for Disease Control (CDC) has revised interim guidance and antiviral therapy recommendations for confirmed, probable, or suspected cases of novel influenza A (H1N1) virus (formerly known as swine-origin influenza A). As soon as possible after the onset of symptoms, any hospitalized person suspected or confirmed to have novel influenza (H1N1) virus infection or any patient at a higher risk for seasonal influenza complications should receive antiviral treatment with 5 days of either zanamivir or oseltamivir. Areas with continued seasonal human influenza activity (particularly with known oseltamivir-resistance to human A [H1N1] viruses) should refer to the CDC website for recommendations. Treatment recommendations for antiviral pre- and postexposure chemoprophylaxis, as well as information for use during pregnancy are also available from the CDC.

Antiviral doses and schedules for treatment or chemoprophylaxis of novel (H1N1) influenza are the same those recommended for seasonal influenza. Additionally, the U.S. Food and Drug Administration (FDA) has issued a temporary Emergency Use Authorization to allow the use of oseltamivir in children <1 year of age. The CDC has issued dosing recommendations for children <1 year of age.

CDC recommendations are changing frequently as more information on antiviral susceptibilities and effectiveness becomes available. For the most recent recommendations and information from the CDC, please refer to http://www.cdc.gov/h1n1flu/recommendations.htm.

Botulinum Toxin Types A and B: Risk of Serious Adverse Events - April 2009

The U.S. Food and Drug Administration (FDA) has issued follow up information on the communication issued in February 2008 for botulinum toxin types A (Botox® and Botox® Cosmetic) and B (Myobloc®). Based on a safety review, the FDA is requiring manufacturers of licensed botulinum toxin products to strengthen the warnings and add a boxed warning regarding the increased risk for adverse events when the toxin spreads beyond the site of local injection. Reports of difficulty breathing and swallowing, aspiration pneumonia, respiratory depression, muscular weakness, facial and eyelid drooping, double vision, speech disorder, and constipation were revealed in the FDA's safety review, including complications requiring hospitalization, mechanical ventilation, and reports of mortality.

To ensure the benefits of botulinum toxin are greater than the risks, a Risk Evaluation and Mitigation Strategy (REMS) must be developed and implemented by the manufacturers. The REMS must include a plan to communicate information regarding complications which may arise with systemic spread of the toxin beyond the local injection site. To assess the signal of serious risk, manufacturers are required to submit safety data to the FDA after a specified number of children and adults with spasticity have received multiple botulinum toxin injections. Additionally, a medication guide will be developed to explain risks to patients and caregivers.

The FDA continues to support the initial safety recommendations for botulinum toxin use:

• Botulinum products are not interchangeable; potency differences may exist between the products.
• Educate and monitor patients for the development of complications, including muscle weakness, voice alteration, speech disorder, bladder control loss, difficulty breathing, difficulty swallowing, and vision problems.
• Adverse events may occur as early as several hours after injection or may be delayed up to several weeks.
• Instruct patients to seek immediate medical attention if symptoms develop.

Additional information may be found: http://www.fda.gov/cder/drug/early_comm/botulinium_toxins200904.htm

CDC Antiviral Treatment Recommendations for Swine Influenza - April 2009

Updated interim guidance from the Centers for Disease Control (CDC) notes that the swine influenza A (H1N1) virus (S-OIV) is resistant to amantadine and rimantadine. With the exception of areas with continued seasonal human influenza activity (particularly with known oseltamivir-resistance to human A [H1N1] viruses), these medications should NOT be used in the treatment of confirmed, probable, or suspected cases of swine influenza, or for chemoprophylaxis of swine influenza.

CDC recommendations are changing frequently as more information on antiviral susceptibilities and effectiveness becomes available. For the most recent recommendations and information from the CDC, please refer to http://www.cdc.gov/swineflu/recommendations.htm.

Trastuzumab: Postmarketing Reports of Oligohydramnios in Pregnant Women; Health Canada Issues Warning - April 2009

Hoffman-La Roche Limited, in conjunction with Health Canada, has issued a Dear Healthcare Professional letter (as well as a notice to the Canadian public) regarding postmarketing reports of oligohydramnios (insufficient amniotic fluid) during the second and third trimesters in pregnant women receiving Herceptin® (trastuzumab) therapy. Similar warnings had previously been added to the U.S. prescribing information as well. Between 2004 and 2008, oligohydramnios has been reported in five pregnant women (one with twins) who were treated with trastuzumab.

During pregnancy, all women with a single fetus had received treatment with at least one other chemotherapeutic agent, and additionally, had received chemotherapy prior to trastuzumab. However, 7 weeks after initiating trastuzumab, decreased levels of amniotic fluid were observed in three cases and a causal relationship could not be ruled out. In all cases, postpartum complications were limited and normal development of these children has been observed up to 5 years following birth. Insufficient data was available to further assess the twin gestation.

With the limited data reported, fetal outcome is expected to be the same as for that of women without trastuzumab exposure. The manufacturer has updated the product monograph to include these case reports and continues to recommend that use of trastuzumab during pregnancy be avoided unless the potential benefit to the mother outweighs potential risks to the fetus. Amniotic fluid should be monitored when therapy is needed during pregnancy.

Further information may be found at the following Health Canada website: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/herceptin_hpc-cps-eng.php

CDC Antiviral Treatment Recommendations for Swine Influenza - April 2009

The Centers for Disease Control (CDC) has issued interim guidance and antiviral therapy recommendations for confirmed or suspected cases of swine influenza A (H1N1) virus. As soon as possible after the onset of symptoms, any person suspected to have swine influenza A (H1N1) virus infection should receive empiric antiviral treatment with 5 days of either zanamivir monotherapy or oseltamivir in combination with either amantadine or rimantadine. Confirmed swine flu cases should receive 5 days of treatment with either oseltamivir or zanamivir.

Pre- and postexposure chemoprophylaxis with oseltamivir or zanamivir for 7 days is recommended for:

• Individuals at high risk for influenza complications with close household contacts of confirmed or suspected cases
• School children at high risk for influenza complications with face-to-face contact with confirmed or suspected cases
• Travelers to Mexico at high risk for influenza complications
• Border workers at high risk for influenza complications
• Healthcare and public health workers who had unprotected close contact with a confirmed swine influenza case

Pre- and postexposure antiviral chemoprophylaxis with oseltamivir or zanamivir may be considered for healthcare and public health workers at high risk for influenza complications working in an area with confirmed cases of swine influenza and caring for patients with acute febrile respiratory illness, and for nonhigh-risk travelers to Mexico, first responders, and border workers who work in areas with confirmed swine flu cases.

Antiviral doses and schedules for treatment or chemoprophylaxis of swine influenza are the same those recommended for seasonal influenza. Additionally, the U.S. Food and Drug Administration (FDA) has issued a temporary Emergency Use Authorization to allow the use of oseltamivir in children <1 year of age.

CDC recommendations may change as more information on antiviral susceptibilities becomes available. For additional information from the CDC, please refer to:

http://www.cdc.gov/swineflu/recommendations.htm

http://www.fda.gov/bbs/topics/NEWS/2009/NEW02002.html

Etanercept: Health Canada Issues Updated Safety Information - April 2009

Amgen Canada Inc, in conjunction with Health Canada, has issued a Dear Healthcare Professional letter (as well as a notice to the Canadian public) regarding updated safety information within the Enbrel® (etanercept) product labeling. The purpose of this update is to draw attention to the need for prompt diagnosis and treatment of opportunistic fungal infections which have been observed in patients treated with antitumor necrosis factor (anti-TNF) agents (including etanercept). A similar update was previously issued by the U.S. Food and Drug Administration (FDA).

Further detail may be found at:

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/enbrel_hpc-cps-eng.php

U.S.: http://www.fda.gov/medwatch/safety/2008/safety08.htm#TNF2

Plan B® Availability - April 2009

In August 2006, the Food and Drug Administration (FDA) approved the marketing of Plan B® (levonorgestrel oral tablets) as an over-the-counter (OTC) product for women ≥18 years of age. It has also been available by prescription for women ≤17 years of age. On April 22, 2009, the FDA announced that Duramed, the manufacturer of Plan B®, would be permitted to expand the OTC use of the product to women ≥17 years of age. Plan B® will become available to this age group once new labeling is submitted and approved. Plan B® is approved for emergency contraception following unprotected intercourse or possible contraceptive failure.

For additional information, refer to the following FDA website: http://www.fda.gov/bbs/topics/NEWS/2009/NEW01999.html

Ceftriaxone: Update on the Warning Concerning Concomitant Use of Calcium-Containing Products - April 2009

The U.S. Food and Drug Administration (FDA) has issued an update to a previous alert regarding an interaction between ceftriaxone and intravenous calcium-containing products. Based on the results of two in vitro studies conducted in both adult and neonatal plasma, the FDA now states that ceftriaxone may be used concomitantly with I.V. calcium-containing products in patients >28 days of age. However, concomitant use of ceftriaxone and I.V. calcium-containing products at any time during the course of therapy is contraindicated in neonates (≤28 days). In patients >28 days of age, the following safety recommendations have also been issued and/or reiterated:

• Ceftriaxone and I.V. calcium-containing products may be given sequentially in patients >28 days of age as long as the infusion lines are thoroughly flushed (with a compatible fluid) between infusions.
• Ceftriaxone should not be administered simultaneously with any calcium-containing solution via Y-site in any patient.
• Do not reconstitute or admix ceftriaxone with calcium-containing solutions (eg, LR, Hartmann's solution, parenteral nutrition).

For more information, U.S. healthcare professionals may refer to the following FDA website: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Ceftriaxone

Efalizumab: Removal From U.S, and Canadian Markets - April 2009

Genentech, Inc and the U.S. Food and Drug Administration (FDA) are informing patients and healthcare professionals about the voluntary withdrawal of efalizumab (Raptiva®) from the United States market. In February 2009, EMD Serono Canada Inc, in conjunction with Health Canada announced that efalizumab would be removed from the Canadian market within a few months. In the United States, Genentech is initiating a voluntary phased withdrawal of the product and it will no longer be available after June 8, 2009.

Efalizumab is being removed from the U.S. and Canadian markets due to the increased risk of progressive multifocal leukoencephalopathy (PML) in association with therapy. Physicians are being asked not to initiate efalizumab therapy in new patients and begin reviewing alternative therapy for any patient(s) currently receiving this medication. Patients currently receiving therapy should contact their healthcare providers about alternative treatments. Abrupt discontinuation without implementing alternative therapy may lead to disease relapse, and should be avoided.

PML is a demyelinating central nervous system disease due to latent JC virus. A total of three confirmed cases and one possible case of PML have been reported in patients using efalizumab for the treatment of moderate-to-severe plaque psoriasis. Of these patients, three have died (two with confirmed and one with possible PML). All three patients were on therapy for >3 years. Additionally, efalizumab therapy has been associated with encephalitis, encephalopathy, meningitis, sepsis, opportunistic infections, and Guillain-Barr? and Miller-Fisher syndromes. There are no effective therapies to treat PML.

Patients should be closely monitored for signs/symptoms of neurologic infection, even upon discontinuation of therapy. The immunosuppressive effects of efalizumab last up to 8-12 weeks. Any serious adverse events should be reported to the manufacturer or the FDA MedWatch reporting system.

Further information concerning efalizumab withdrawal in the U.S. can be found at http://www.fda.gov/medwatch/safety/2009/safety09.htm#Raptiva

Further information concerning efalizumab withdrawal in Canada can be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/raptiva_2_hpc-cps-eng.php

Previous U.S. and Canadian information related to this issue can be found on the following websites:

U.S.:

http://www.fda.gov/cder/drug/advisory/efalizumab.htm

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

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

Canada:

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

Digoxin Tablet Recall Due to Potentially Variable Content of Active Ingredient - April 2009

Caraco Pharmaceutical Laboratories, Ltd, with awareness by the U.S. Food and Drug Administration (FDA), has issued a voluntary recall of all unexpired lots of 0.125 mg and 0.25 mg digoxin tablets distributed prior to March 31, 2009, and within expiration of September 2011. The manufacturer states that the tablets may be of differing sizes, thus posing a risk of variable digoxin content.

For additional information, including the product NDC numbers affected, please refer to http://www.fda.gov/oc/po/firmrecalls/caraco03_09.html

Propafenone Tablets: Voluntary Recall - March 2009

The U.S. Food and Drug Administration (FDA) and Watson Pharmaceuticals announced to healthcare professionals and patients that one lot of propafenone 225 mg tablets has been voluntarily recalled. These tablets may contain an increased amount of the active ingredient and thus result in serious adverse effects. This precautionary measure is to ensure patient safety and decrease risk to patients. The manufacturer does not expect any drug shortages due to this recall.

For information on returning the recalled propafenone product, contact Watson Labs at (888) 352-9616.

For more information, please refer to the FDA MedWatch alert: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Propafenone

Insulin Pens: Sharing Results in Cross-Contamination - March 2009

The U.S. Food and Drug Administration (FDA) has issued a warning to healthcare providers and their patients regarding the sharing of insulin pens and cartridges among patients. This practice may result in transmission of a number of pathogens including hepatitis, HIV, and other blood-borne pathogens and should be abandoned. Insulin pens are FDA-approved for single-patient use only.

For more information, U.S. healthcare professionals may refer to the following FDA website: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Insulin

Mecasermin Rinfabate (Iplex™): Access Allowed Under an Investigational New Drug (IND) Application - March 2009

The U.S. Food and Drug Administration (FDA) and Insmed, the manufacturer of mecasermin rinfabate (Iplex™), have announced the decision to allow patients with amyotrophic lateral sclerosis (ALS) access to Iplex™ under an IND. Currently, Iplex™ is not commercially available in the U.S. and there is a very limited supply of the drug. Under the newly created IND, ALS patients may receive Iplex™ through either a single-patient IND request for compassionate use or through a clinical trial IND. Single-patient IND requests will be granted only for those requests received by the FDA as of March 6, 2009. The remaining supply of Iplex™ will be made available via a lottery system for those patients interested in participating in the clinical trial IND conducted by Insmed. The rationale behind the IND system was based on the need to determine safety and efficacy of the experimental use of mecasermin rinfabate in ALS, as well as consideration for the limited supply of the medication. The FDA has also made documents available to the public of the limited clinical information at present concerning the use of Iplex™ in ALS patients. In addition, clinical information has also been posted regarding the investigational use of recombinant human IGF-1 (proposed trade name Myotrophin) which did not demonstrate a benefit in ALS patients.

Iplex™ is a combination of recombinant human insulin-like growth factor 1 (rhIGF-1) and human insulin-like growth factor-binding protein-3 (rhIGFBP-3). Iplex™ was FDA approved in 2005 for the treatment of severe growth failure in children with primary IGF-1 deficiency (primary IGFD), or with growth hormone (GH) deletion who have developed neutralizing antibodies to GH, but is not currently being marketed due to a court order related to patent infringement.

Additional information can be found at http://www.fda.gov/cder/drug/infopage/mecasermin_rinfabate/default.htm

Acute Phosphate Nephropathy Associated with Prescription and Over-the-Counter [OTC] Oral Sodium Phosphate (OSP) Bowel Cleansing Products - March 2009

Health Canada has issued a notice to Canadian consumers regarding important safety information associated with the use of oral sodium phosphate (OSP) products for bowel cleansing. Recently in the U.S., the Food and Drug Administration (FDA) issued an alert notifying healthcare practitioners and consumers of reports of acute phosphate nephropathy associated with OSP products (eg, over-the-counter products Fleet® Phospho-soda® and prescription products Visicol® and OsmoPrep®) when used as bowel cleansing preparations prior to colonoscopy and other procedures.

Acute phosphate nephropathy is associated with calcium-phosphate crystal deposits in the renal tubules and may result in permanent renal dysfunction. Risk factors for acute phosphate nephropathy include age >55 years, hypovolemia, patients with pre-existing renal impairment, bowel obstruction, or active colitis; and patients taking medications that may affect renal perfusion or function (eg, diuretics, ACE Inhibitors, angiotensin receptor blockers, and possibly NSAIDs). Some cases have been reported in patients without apparent risk factors.

The FDA is requiring the manufacturers of the prescription OSP products, Visicol® and OsmoPrep®, to add boxed warnings regarding acute phosphate nephropathy to the product labeling. Additionally, the FDA is requiring the manufacturers to develop and implement a risk management program which will include a Medication Guide and conducting a postmarketing clinical trial to further evaluate the risk of acute kidney injury with these agents. In Canada, the 3 OSP products approved for use include Phoslax®, Fleet® Phospho-soda® Oral Laxative, and Phosphate Solution (marketed as Option + Phosphates Solution, Pharmasave Phosphates Solution, Reserve Phosphates Solution); however, the manufacturer of Fleet® Phospho-soda® has voluntarily discontinued the sale of this product in Canada.

Both regulatory agencies are recommending that over-the-counter OSP products not be used for bowel cleansing, and consumers should only use OSPs for bowel cleansing when prescribed by a healthcare provider. The FDA will also remove bowel cleansing from the professional labeling for all over-the-counter OSPs. Health Canada also is working with the manufacturers to reduce risks and ensure the safe use of these products.

Additional information can be found at:

U.S.: http://www.fda.gov/medwatch/safety/2008/safety08.htm#OSP

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_37-eng.php

Transdermal Patches: Risk of Burns During MRI - March 2009

The U.S. Food and Drug Administration (FDA) has issued a public health advisory regarding the risk of burns associated with the use of transdermal medication patches containing aluminum or other metals during MRI screening. The package labeling for certain metal-containing patches includes a warning related to the risk of burns if the patches are not removed prior to MRI procedures. However, not all transdermal medication patches with metallic backings have this warning in the labeling. Although metal materials are present in certain patches, it may not be visible. The FDA is currently reviewing the components of all transdermal medication systems to ensure that proper warnings are present in the labeling of those patches that do contain metal materials. In the interim, the FDA recommends that healthcare professionals who refer patients to have an MRI procedure should identify patients who are wearing a transdermal medication patch prior to the scan. Those patients who are wearing a transdermal medication patch should be advised on the proper removal of the patch prior to the procedure as well as reapplication following the scan.

Additional information can be found at http://www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

Topical Anesthetic Use for Cosmetic or Medical Procedures: Public Health Advisory - March 2009

Health Canada has issued a "Dear Healthcare Professional" letter and a notice to the Canadian public regarding important safety information associated with the use of topical anesthetic agents. Recently in the U.S., the The Food and Drug Administration (FDA) issued a Public Health Advisory to remind consumers, caregivers, and healthcare professionals of potential life-threatening side effects associated with the use of topical anesthetics available as prescription and over-the-counter (OTC) products for a variety of uses, including numbing skin prior to cosmetic or medical procedures (topical lidocaine has been recently evaluated to relieve mammography discomfort).

Topical application can result in high systemic levels and lead to toxic effects (eg, methemoglobinemia, irregular heart beats, seizures, coma, respiratory depression, death). Children may be at an increased risk for adverse effects, as well as individuals who, without the supervision of trained professionals, apply large amounts of anesthetics (or cover large areas of the skin), leave these products on for long periods of time, or use materials, wraps, or dressings to cover the skin after anesthetic application.

Both the FDA and Health Canada are recommending that when topical anesthetics are needed prior to procedures, consumers ask their healthcare provider for instructions on safe use of these products, use only approved products, and use products with the lowest amount of anesthetic while applying the least amount possible to relieve pain. If a high degree of pain is expected that is not controlled by appropriate amounts of topical anesthetics, consumers should ask their physician for alternative techniques for pain control.

Additional information can be found at:

U.S.: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Anesthetics

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/emla_ametop_hpc-cps-eng.php

Metoclopramide: Tardive Dyskinesia with Chronic Treatment - February 2009

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of the requirement for manufacturers to add a boxed warning to the metoclopramide prescribing information related to a link between chronic use and the development of tardive dyskinesia (involuntary and repetitive movements of the body). Current labeling warns of the risk, but the warning will now become a boxed warning. This labeling change was prompted by study data analysis and continued spontaneous reports of tardive dyskinesia to the FDA. The majority of reports are associated with higher doses, long-term use (>3 months), and use in the elderly (particularly older women. Metoclopramide-induced tardive dyskinesia symptoms include impaired movement of the fingers, lip smacking, rapid eye movements or blinking, and tongue protrusion. These symptoms are rarely reversible following discontinuation of metoclopramide and treatment is not available at this time. The FDA is also requiring manufacturers to provide a medication guide to patients discussing the risk of tardive dyskinesia.

Additional information can be found at http://www.fda.gov/medwatch/safety/2009/safety09.htm#Metoclopramide

Zonisamide: May Cause Metabolic Acidosis - February 2009

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals that zonisamide use may cause metabolic acidosis in certain patients. Predisposing factors or conditions for the development of zonisamide-induced metabolic acidosis include patients with renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diets, and use of other medications (such as acetazolamide). In addition, pediatric patients may also be at an increased risk for metabolic acidosis with zonisamide use, and the metabolic acidosis may be more severe.

Zonisamide-induced metabolic acidosis may occur anytime during therapy, but generally occurs early in treatment. In addition, the risk of metabolic acidosis appears to be dose-dependent; however, metabolic acidosis has occurred at doses as low as 25 mg/day. The effects on serum bicarbonate are generally mild-moderate (serum bicarbonate decreases of ~2 mEq/L) in adults, but in certain cases, up to a 10 mEq/L decrease in serum bicarbonate was observed. Metabolic acidosis is usually asymptomatic although chronic metabolic acidosis may result in fatigue, hyperventilation, anorexia, and cardiac arrhythmias and stupor in severe cases. If left untreated, chronic metabolic acidosis may result in kidney stones, nephrocalcinosis, and bone abnormalities (which may lead to an increased risk of fractures). Chronic untreated metabolic acidosis due to other causes may result in decreased growth rates in children, and decreased fetal growth and fetal death following exposure during pregnancy. The specific effects of metabolic acidosis caused by zonisamide in children or pregnant and breast-feeding women are not known.

In light of this association, the FDA is now recommending a serum bicarbonate level prior to initiation and periodically during therapy. If metabolic acidosis develops, consider decreasing the dose or discontinuing use with appropriate dose tapering. If therapy is continued despite acidosis, alkali treatment should be considered. The FDA is working with the manufacturers to revise the product labeling concerning these risks.

Additional information may be found at http://www.fda.gov/medwatch/safety/2009/safety09.htm#Zonisamide

Efalizumab: Removal From Canadian Market - February 2009

EMD Serono Canada Inc, in conjunction with Health Canada, has issued a "Dear Healthcare Professional" letter regarding the upcoming removal of efalizumab (Raptiva®) from the Canadian market, due to the potential risk for serious infections including progressive multifocal leukoencephalopathy (PML) in association with efalizumab therapy. In December 2008, Health Canada issued warnings regarding labeling changes to include a boxed warning concerning the risk for these serious adverse events; however, further evaluation has demonstrated an unfavorable risk/benefits for efalizumab use. Efalizumab will be removed from the Canadian market within a few months.

PML is a demyelinating central nervous system disease due to latent JC virus. A total of three confirmed cases and one possible case of PML have been reported in patients using efalizumab for the treatment of moderate-to-severe plaque psoriasis. Of these patients, three have died (two with confirmed and one with possible PML). All three patients were on therapy for >3 years. Additionally, efalizumab therapy has been associated with encephalitis, encephalopathy, meningitis, sepsis, opportunistic infections, and Guillain-Barr? and Miller-Fisher syndromes.

At this time, Canadian healthcare providers should avoid initiating new efalizumab therapy and begin reviewing alternative therapy for any patient(s) currently receiving therapy, avoid abrupt discontinuation of therapy without implementing alternative therapy (may lead to disease relapse), and closely monitor patients for signs/symptoms of neurologic infection following discontinuation of therapy. The immunosuppressive effects of efalizumab last up to 8-12 weeks.

Further information may be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/raptiva_2_hpc-cps-eng.php

Efalizumab and Progressive Multifocal Leukoencephalopathy - February 2009

In October, 2008 the Food and Drug Administration (FDA) informed healthcare professionals of the addition of boxed warnings to the efalizumab prescribing information related to the development of progressive multifocal leukoencephalopathy (PML). This labeling change was prompted by a case of PML reported in a patient who had received efalizumab (for >4 years) for the treatment of plaque psoriasis. In addition, Health Canada also issued a similar warning in December 2008. Since the approval of efalizumab in October 2003, the FDA now has a total of three confirmed cases and one possible case of PML in patients using efalizumab for the treatment of moderate-to-severe plaque psoriasis. Of these patients, three have died (two with confirmed and one with possible PML). None of these patients were taking other immunosuppressant medications.

PML is a demyelinating central nervous system disease due to latent JC virus. Any neurological change in patients receiving efalizumab should be evaluated promptly and efalizumab should be discontinued in patients who develop PML. Prolonged, continuous use of efalizumab may increase the risk of developing PML (all four patients were on therapy for >3 years). Patients should be re-evaluated periodically to evaluate the benefits versus risks of treatment and consideration should be given to other therapies if appropriate. Patients should be informed to contact their healthcare provider in case of unusual weakness, loss of coordination, vision changes, difficulty speaking, or changes in personality.

The FDA is currently evaluating the benefits and risks of efalizumab for the treatment of moderate-to-severe plaque psoriasis. Additional information can be found at:

http://www.fda.gov/cder/drug/advisory/efalizumab.htm

http://www.fda.gov/medwatch/safety/2009/safety09.htm#Raptiva

Myozyme® Shortage - February 2009

Inventory levels of Myozyme® (alglucosidase alfa) are low because of increased global demand. Increased production is planned once regulatory agencies throughout the world approve a larger scale manufacturing process. In the U.S., the Food and Drug Administration (FDA) is expected to respond by the end of February. In the meantime, recommended guidelines have been developed to help with clinical decisions during this temporary period of supply constraint. Pediatric dosing regimens will be maintained. However, to continue providing therapy to adult patients, adult regimens will be adjusted by increasing the dosing interval. Children with newly-diagnosed disease may begin therapy, but no new adults will be enrolled in the Myozyme® Temporary Access Program (MTAP). Any physician who feels their patient is in urgent need of therapy may contact Genzyme Medical Information at (800) 745-4447, option 2.

Additional information may be found at:

http://www.myozyme.com/pdf/MTAP_Supply_Update_January%202009.pdf

http://www.myozyme.com/MTAP/mtap_pt.asp

Acyclovir Injectable: Critical Shortage - February 2009

There is a critical shortage of acyclovir injection in the U.S. due to increased demand and manufacturing changes being made at Bedford Labs. APP Pharmaceuticals (APP), another manufacturer of injectable acyclovir, has issued a Dear Healthcare Professional letter regarding the shortage. APP is working with the U.S. Food and Drug Administration (FDA) to increase the availability of the injectable product by using supplies manufactured for Pharmaceutical Partners of Canada (PPC), an APP affiliate. The only difference between the two products is the external labeling. The Canadian labeling has printing in red, includes instructions in French, and does not include an NDC number.

APP has begun manufacturing additional acyclovir to alleviate the U.S. shortage; resolution expected in March 2009.

Additional information may be found at http://www.fda.gov/cder/drug/shortages/default.htm#Acyclovir

Drotrecogin Alfa (Xigris®) and Bleeding Risk: Ongoing Safety Review - February 2009

The U.S. Food and Drug Administration (FDA) is communicating important information regarding an ongoing safety review of drotrecogin alfa and its use in patients with sepsis and baseline bleeding risk factors.

A recent retrospective study by Gentry, et al compared outcomes in 73 patients with and without baseline bleeding risk factors who received drotrecogin alfa (these same factors are outlined in the Contraindications and Warnings and Precautions in the current prescribing information). Serious bleeding events occurred in 7 of 20 patients (35%) who had baseline bleeding risk factors, as compared to 2 of 53 patients (3.8%) who did not have any baseline bleeding risk factors (p<0.0001). In an accompanying editorial, Sweeney and colleagues suggested that drotrecogin alfa not be administered to patients with sepsis and any baseline bleeding risk factors in an attempt to increase the safety of therapy; thereby changing bleeding risk factors contained within the Warnings and Precautions of the product labeling to additional contraindications.

The FDA has acknowledged the results of the study by Gentry and emphasizes that the results from this study are consistent with the information in the current product labeling. In addition, the FDA is working with the manufacturer of Xigris® to further evaluate the incidence of serious bleeding events and mortality. In the meantime, the FDA urges prescribers to refer to the product labeling for the specific contraindications, warnings, and, precautions and to carefully weigh the increased risk of bleeding against the benefits of drotrecogin alfa.

For more information, healthcare providers may refer the following FDA website: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Xigris

Clopidogrel (Plavix®) and Proton Pump Inhibitors (PPIs): Ongoing Safety Review - January 2009

The U.S. Food and Drug Administration (FDA) is communicating important information regarding an ongoing safety review of clopidogrel and its effectiveness when used with proton pump inhibitors (PPIs).

Clopidogrel is a prodrug requiring hepatic conversion via CYP3A4 and/or CYP2C19 to its active metabolite. Impaired clopidogrel conversion to its active metabolite may be due to either CYP450 polymorphisms or drug-drug interactions resulting in suboptimal antiplatelet activity.

A PPI is often prescribed with the combination of aspirin and clopidogrel to prevent gastrointestinal bleeding. A number of PPIs are available and include esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. Several studies have reported greater clinical event rates (eg, myocardial infarction, death) or greater platelet reactivity associated with concurrent use of clopidogrel and a PPI (Ho, 2008; Pezella, 2008; Gilard, 2006). Similarly, a prospective, randomized, double-blind trial demonstrated a reduction in antiplatelet activity when omeprazole and clopidogrel are used concurrently (Gilard, 2008). Another controlled trial with the PPI lansoprazole also found evidence of a possible interaction resulting in less antiplatelet activity (Small, 2008). This interaction is thought to result from competitive inhibition of the CYP2C19-mediated activation of clopidogrel by omeprazole and other PPIs, which are all metabolized to at least some degree by CYP2C19. In contrast, one study with esomeprazole and pantoprazole did not find evidence of reduced antiplatelet activity when administered with clopidogrel (Siller-Matula, 2009), highlighting the need for additional studies to determine the degree to which individual PPIs may differ in their potential for interacting with clopidogrel.

The manufacturer of Plavix® has agreed to conduct further studies to better understand the effect of other drugs (including PPIs) and genetic factors on the effectiveness of clopidogrel. The FDA is recommending that healthcare providers continue to prescribe clopidogrel while reevaluating the need for prescription or over-the-counter (OTC) PPIs in patients taking clopidogrel. Patients should continue taking clopidogrel as directed. If taking a PPI with clopidogrel, patients should consult with their healthcare provider.

For more information, healthcare professionals may refer to the following FDA website: http://www.fda.gov/cder/drug/early_comm/clopidogrel_bisulfate.htm

Methadone: Recommendations for QTc Interval Screening Before and During Methadone Treatment - January 2009

The Center for Substance Abuse and Treatment (CSAT) of the Substance Abuse and Mental Health Services Administration has developed a consensus guideline statement outlining recommendations regarding ECG monitoring in patients being considered for and being treated with methadone regardless of indication. Of note, these recommendations should not supersede clinical judgment or patient preferences and may not apply to patients with terminal, intractable cancer pain.

Five recommendations have been developed:

Recommendation 1 [Disclosure]: Clinicians should inform patients of arrhythmia risk when methadone is prescribed.

Recommendation 2 [Clinical History]: Clinicians should inquire about any history of structural heart disease, arrhythmia, and syncope.

Recommendation 3 [Screening]: Clinicians should obtain pretreatment ECG for all patients to measure QTc interval, follow up ECG within 30 days, then annually (monitor more frequently if patient receiving >100 mg/day or if unexplained syncope or seizure occurs while on methadone).

Recommendation 4 [Risk Stratification]: If before or at anytime during therapy:

QTc >450-499 msecs: Discuss potential risks and benefits; monitor QTc more frequently

QTc ≥500 msecs: Consider discontinuation or reducing methadone dose or eliminate factors promoting QTc prolongation (eg, potassium-wasting drugs) or use alternative therapy (eg, buprenorphine)

Recommendation 5 [Drug Interactions]: Clinicians should be aware of interactions between methadone and other drugs that either prolong the QT interval or reduce methadone elimination.

The panel also concluded that the arrhythmia risk is directly associated with methadone's ability to block the delayed rectifier potassium channel (Ikr) and prolong repolarization. The guideline further states that the use of the Bazett formula is adequate even though it is likely to overcorrect with high heart rates. The patient should remain supine for at least 5 minutes prior to obtaining ECG. In addition, screening for QTc prolongation using automated readings does not require a specialist (eg, cardiologist) and may be performed in a primary care setting. However, in cases when uncertainty exists about whether or not clinically significant QTc prolongation is present, the ECG should be repeated or interpreted by a cardiologist.

For more information, refer to: Krantz MJ, Martin J, Stimmel B, et al, "QTc Interval Screening in Methadone Treatment," Ann Int Med, 2009, 150(1):1-10 (epub ahead of print).

Topical Anesthetic Use for Cosmetic or Medical Procedures: Public Health Advisory - January 2009

The Food and Drug Administration (FDA) is issuing a Public Health Advisory to remind consumers, caregivers, and healthcare professionals of potential life-threatening side effects associated with the use of topical anesthetics available as prescription and over-the-counter (OTC) products for a variety of uses, including numbing skin prior to cosmetic or medical procedures (topical lidocaine has been recently evaluated to relieve mammography discomfort). Topical application can result in high systemic levels and lead to toxic effects (eg, irregular heart beats, seizures, coma, respiratory depression, death). At risk are consumers, particularly without the supervision of trained professionals, who apply large amounts of anesthetics (or cover large areas of the skin), leave these products on for long periods of time, or use materials, wraps, or dressings to cover the skin after anesthetic application. The FDA is working with healthcare professional organizations and other media to spread the message about the potential hazards and safe use of topical anesthetics. The FDA is recommending that if topical anesthetics are needed prior to procedures, consumers ask their healthcare provider for instructions on safe use of these products, use only FDA-approved products, and use products with the lowest amount of anesthetic while applying the least amount possible to relieve pain. If a high degree of pain is expected that is not controlled by appropriate amounts of topical anesthetics, consumers should ask their physician for alternatives techniques for pain control.

Additional information can be found at http://www.fda.gov/medwatch/safety/2009/safety09.htm#Anesthetics

Ezetimibe (Zetia®), Ezetimibe/Simvastatin (Vytorin®), and Simvastatin (Zocor®): Completed Review of the ENHANCE Trial - January 2009

On January 25, 2008, the U.S. Food and Drug Administration (FDA) communicated that they would be reviewing the data from the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial (Kastelein, 2008).

The FDA has completed its review of the ENHANCE trial which evaluated the effects of simvastatin (Zocor®) and ezetimibe/simvastatin (Vytorin®) on carotid-artery intima-media thickness (CIMT) in patients with familial hypercholesterolemia. CIMT 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). Following two years of treatment, CIMT was increased by 0.011 mm in the ezetimibe and simvastatin combination group and by 0.006 mm in the simvastatin alone group. This difference was not statistically significant even though the combination group demonstrated statistically significant greater reductions in LDL.

Possible explanations for this observation include: 1) Issues with enrolled patient population (eg, prior exposure to lipid-lowering therapy; baseline CIMT), 2) duration of trial, and 3) other unknown properties of ezetimibe that may negate the beneficial effects of statin therapy on LDL reduction.

Based on this information, the FDA has not changed its position that an elevated LDL level is a risk factor for cardiovascular disease and that lowering LDL reduces this risk. Three large clinical outcome trials evaluating the use of ezetimibe/simvastatin will be presented over the next 2-3 years.

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

Efalizumab: Life-Threatening Infections (including Progressive Multifocal Leukoencephalopathy): Health Canada Issues Warning To Healthcare Professionals - December 2008

Health Canada, in conjunction with EMD Serono Canada Inc, has issued a "Dear Healthcare Professional" letter concerning the development of life-threatening infections (including progressive multifocal leukoencephalopathy [PML]) in association with the use of efalizumab (Raptiva®). As a result, the Canadian product labeling will be updated to include this important safety information. Similar warnings have previously been released by the U.S. Food and Drug Administration (FDA). Further detail may be found at:

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

U.S.:

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

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

Health Canada: Labeling Changes for OTC Cough and Cold Preparations - December 2008

Health Canada has issued an advisory to Canadian consumers regarding upcoming labeling changes for the use of over-the-counter (OTC) cough and cold medicines in children. Specific labeling changes as well as other important information may be found at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_184-eng.php.

CDC Interim Recommendations Concerning Use of Antivirals During 2008-09 Influenza Season - December 2008

The Centers for Disease Control (CDC) has issued a Health Advisory with interim recommendations for chemoprophylaxis or influenza treatment with the following antiviral agents: Oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®), amantadine (Symmetrel®).

The recommendations were prompted by preliminary data in a limited number of states indicating a high prevalence of the oseltamivir-resistant influenza A (H1N1) strain. Influenza activity remains low at the present time, but of the 50 H1N1 isolates from 12 states tested between October 1 and December 19, 2008, 49 (98%) were resistant to oseltamivir. The CDC is unable to make any accurate predictions of which influenza virus types (A or B) or subtypes of influenza A (H1N1 or H3N2) will predominate during the 2008-09 season, but based on the current findings, the following recommendations have been made:

Patients testing positive for influenza type B: If treatment is indicated, patients may receive either oseltamivir or zanamivir (no preference).

Patients testing positive for influenza type A (or patients testing negative for influenza, but likelihood of influenza infection is high): If treatment is indicated, patient may receive zanamivir. If zanamivir therapy is inappropriate (eg, patients with chronic respiratory disease, patients <7 years of age) or zanamivir is unavailable, combination treatment with oseltamivir and rimantadine is acceptable (if rimantadine is unavailable, amantadine may be substituted). Oseltamivir monotherapy should only be used if local surveillance indicates that influenza A (H3N2) or influenza type B viruses are likely.

If confirmatory diagnostic testing to distinguish between subtypes of influenza A (H1N1 or H3N2) is available, and treatment is indicated:

Patients testing positive for influenza A (H3N2): Use oseltamivir or zanamivir (no preference)

Patients testing positive for influenza A (H1N1): Use zanamivir (or combination treatment with oseltamivir and rimantadine as an alternative)

Patients requiring chemoprophylaxis due to potential exposure with laboratory-confirmed influenza A (H3N2) or influenza B should receive oseltamivir or zanamivir. Patients requiring chemoprophylaxis due to influenza A (H1N1) virus should receive zanamivir (or rimantadine, if zanamivir use contraindicated).

The CDC is reminding clinicians to continue to vaccinate patients using the influenza vaccine, which is expected to be effective against all circulating influenza vaccines, including the oseltamivir-resistant strain.

For additional information, including the CDC Health Advisory, please refer to http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp?AlertNum=00279

Reports of Toxic Anterior Segment Syndrome (TASS), Endophthalmitis, and Eye Inflammation with Intravitreal Use - December 2008

Hoffman-La Roche Limited (Roche), in conjunction with Health Canada, has issued a "Dear Healthcare Professional" letter concerning intravitreal (off-label) use of bevacizumab (Avastin®) and reports of endophthalmitis, eye inflammation, blurred vision, floaters, and toxic anterior segment syndrome (TASS). TASS, a sterile postoperative inflammatory reaction that leads to intraocular tissue toxicity, is due to the introduction of a noninfectious substance into the anterior segment of the eye.

As of November 2008, all cases reported in Canada (n=25) have been associated with intravitreal use of a specific lot of bevacizumab (B3002B028). In Canada, bevacizumab is approved for intravenous administration in the treatment of metastatic colon or rectal carcinoma and is not authorized for use in the ophthalmology setting.

Further information can be found at:

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/avastin_4_hpc-cps-eng.php

Erlotinib: Health Canada Issues Warning Concerning Hepatoxicity - December 2008

Hoffmann-La Roche Limited, in conjunction with Health Canada, has issued a "Dear Healthcare Professional" letter regarding important safety information concerning erlotinib (Tarceva®) use in patients with hepatic impairment. The warning is similar to that released previously by the U.S. Food and Drug Administration (FDA). Further information may be found at:

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

U.S.: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Tarceva

Antiepileptics: Increased Risk of Suicidal Behavior or Ideation - December 2008

The U.S. Food and Drug Administration (FDA) has issued an update following the completion of its analysis concerning the risk of suicidality (suicidal behavior or ideation) observed during clinical trials of various antiepileptic drugs (compared to placebo) in the treatment of epilepsy, psychiatric disorders, and other conditions. The pooled analysis of 199 clinical trials involving 11 antiepileptic drugs (carbamazepine, divalproex sodium, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zonisamide) as either monotherapy or as adjuvant therapy showed that patients receiving an antiepileptic had a 0.43% risk of suicidal behavior/ideation compared to 0.24% of patients receiving placebo. As a result of the findings, the FDA will require that the product labeling of the entire class of antiepileptics include a warning concerning the risk of suicidality, and a medication guide be developed informing patients of this risk.

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

Sacrosidase (Sucraid®): Manufacturing Change May Lead to an Increase in Papain-Induced Hypersensitivity Reactions - December 2008

To prevent any shortages of sacrosidase (Sucraid®) oral solution, the Food and Drug Administration (FDA) has allowed for a manufacturing change which permits QOL Medical, the sole manufacturer of Sucraid®, to obtain the active ingredient, sacrosidase, from a different manufacturer. However, the newly manufactured product may contain increased levels of papain, which may be introduced during the manufacturing process performed to obtain sacrosidase. Steps are taken to remove any papain contamination, but there is no assurance that papain has been completely eliminated from the final product. Papain exposure has been associated with severe hypersensitivity reactions, including anaphylaxis. Tachycardia and hypotension have also been observed in association with some papain-induced hypersensitivity reactions. In addition, some data also suggest a possible cross-sensitivity may exist between patients with natural rubber latex hypersensitivity and papaya, the source of papain.

For additional information, refer to:

http://www.fda.gov/bbs/topics/NEWS/2008/NEW01915.html

http://www.fda.gov/cder/news/papain/qa.htm

Acute Phosphate Nephropathy Associated with Prescription and Over-the-Counter [OTC] Oral Sodium Phosphate (OSP) Bowel Cleansing Products - December 2008

The U.S. Food and Drug Administration (FDA) has issued an alert notifying healthcare practitioners and consumers of reports of acute phosphate nephropathy associated with OSP products (eg, over-the-counter products Fleet® Phospho-soda® and prescription products Visicol® and OsmoPrep®) when used as bowel cleansing preparations prior to colonoscopy and other procedures. Acute phosphate nephropathy is associated with calcium-phosphate crystal deposits in the renal tubules and may result in permanent renal dysfunction. Risk factors for acute phosphate nephropathy include age >55 years, hypovolemia, patients with pre-existing renal impairment, bowel obstruction, or active colitis; and patients taking medications that may affect renal perfusion or function (eg, diuretics, ACE Inhibitors, angiotensin receptor blockers, and possibly NSAIDs). Some cases have been reported in patients without apparent risk factors.

The FDA is requiring the manufacturers of the prescription OSP products, Visicol® and OsmoPrep®, to add boxed warnings regarding acute phosphate nephropathy to the product labeling. Additionally, the FDA is requiring the manufacturers to develop and implement a risk management program which will include a Medication Guide and conducting a postmarketing clinical trial to further evaluate the risk of acute kidney injury with these agents. Over-the-counter OSP products should not be used for bowel cleansing, and consumers should only use OSPs for bowel cleansing when prescribed by a healthcare provider. The FDA will also remove bowel cleansing from the professional labeling for all over-the-counter OSPs.

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

Tinzaparin (Innohep®): Preliminary Results of Clinical Study Showing an Increase in All-Cause Mortality - December 2008

The Food and Drug Administration (FDA) is communicating information to healthcare professionals regarding the clinical trial Innohep in Renal Insufficiency Study (IRIS). This multicenter European trial was prematurely halted in February 2008 after interim results showed an increase in all-cause mortality in patients receiving tinzaparin compared to patients receiving unfractionated heparin (UFH) in the treatment of deep vein thromboses (DVT) and/or pulmonary embolism (PE). Patients in the study were ≥70 years of age with impaired renal function and had a confirmed diagnosis of DVT and/or PE. Of the 350 patients completing 90 days of follow-up when the study was stopped, 23 of the 176 patients (13%) receiving tinzaparin died, compared to 9 of the 174 patients (5%) treated with UFH. According to the FDA, there is no clear pattern in the cause of death and it does not appear to be dose related (under- or overdosing). In addition, results do not appear to be attributed to a manufacturing issue with either agent.

In light of the IRIS preliminary data, the FDA is advising healthcare professionals to consider the use of alternative agents to tinzaparin in the treatment of DVT and/or PE in elderly patients >70 years of age with renal impairment. Of note, prescribing information for Innohep® was updated in July 2008, restricting its use in patients ≥90 years of age. The FDA is now requesting the manufacturer revise prescribing information to include the IRIS study results which suggest the risk of mortality may not be limited to only patients ≥90 years of age.

The final IRIS study report is expected to be submitted in January 2009, and after the review is complete, the FDA will communicate its conclusions and any further recommendations.

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

Phenytoin and Fosphenytoin: Genetic Susceptibility to Serious Skin Reactions - November 2008

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of preliminary information concerning the potential for serious skin reactions in susceptible patients treated with phenytoin (or fosphenytoin). Data suggests that patients testing positive for the human leukocyte antigen (HLA) allele HLA-B*1502 have an increased risk of developing Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN). The risk appears to be highest in the early months of therapy initiation. The presence of this genetic variant exists in up to 15% of people of Asian descent in China, Thailand, Malaysia, Indonesia, Taiwan, and the Philippines, and may vary from < 1% in Japanese and Koreans, to 2% to 4% of South Asians and Indians. This variant is virtually absent in those of Caucasian, African-American, Hispanic, or European ancestry. Of note, carbamazepine, another antiepileptic with a chemical structure similar to phenytoin, updated its prescribing information (December 2007) to include a warning of an increased risk of SJS and TEN in patients carrying the HLA-B*1502 allele and a recommendation to screen patients of Asian descent for the allele prior to initiating therapy. In contrast to carbamazepine, the FDA is not recommending testing for the presence of HLA-B*1502 prior to initiating phenytoin therapy until more information is available. In the interim, the FDA is advising that prescribers avoid phenytoin or fosphenytoin as alternatives to carbamazepine therapy in patients positive for HLA-B*1502.

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

Alemtuzumab: Reports of Infection-Related Fatalities - November 2008

Bayer HealthCare and Genzyme, in conjunction with Health Canada, have issued notice to Canadian hospitals concerning reports of infection-related fatalities in patients receiving consolidation therapy with MabCampath® (alemtuzumab). Preliminary safety data from the ongoing phase II U.S. clinical trial CALGB10101 has reported fatalities in 6 out of 51 patients with B-cell chronic lymphocytic leukemia (B-CLL) receiving fludarabine and rituximab induction therapy followed by alemtuzumab therapy for remission consolidation.

Fatal infections included viral meningitis, Listeria meningitis, Legionella pneumonia, cytomegalovirus (CMV), Pneumocystis jiroveci pneumonia (PCP), and Epstein-Barr virus (EBV) associated lymphoproliferative disorder.

The potential contributory role of any of the three chemotherapeutic agents is not clear based on available data. The infectious complications may have resulted from prolonged immunosuppression. An additional noninfection-related fatality, thought to be transfusion-associated graft-versus-host disease (TAGVHD), has also been reported.

Use of alemtuzumab as consolidation therapy is presently not approved in Canada. An updated product monograph including this new important safety information is forthcoming. Further information can be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/mabcampath_nth-aah-eng.php

Papain-Containing Topical Products: FDA Enforcement Action - November 2008

In September 2008, the U.S. Food and Drug Administration (FDA) ordered companies to discontinue manufacturing papain-containing topical products by November 24, 2008, and to cease shipping of these products by January 21, 2009. At present, all topical products containing papain (~35 products under various trade names) lack FDA approval. Safety concerns have also been raised from reports of serious hypersensitivity reactions, including anaphylaxis, associated with papain use. Hypotension and tachycardia has also been observed in association with these hypersensitivity reactions. In addition, the medical literature also suggests that patients with latex hypersensitivity may also be allergic to papaya, the source of papain.

Papain-containing topical products manufactured prior to the ordered stop date may still be found on pharmacy shelves for a short period of time. However, healthcare providers are reminded that alternative products with FDA approval for the management of wounds are available.

Additional information may be found at http://www.fda.gov/cder/news/papain/qa.htm

North American Coral Snake Antivenin Expiration Date Extended - November 2008

Wyeth Pharmaceuticals no longer manufactures this antivenin; the last available lot (4030026) expired on October 31, 2008. There is no alternative antidote to treat coral snake envenomations. As a result, the FDA has extended the expiration on this lot until October 31, 2009. Lot 4030026 continues to be available and Wyeth will supply product to their direct customers.

Additional information available at the following FDA website: http://www.fda.gov/cber/safety/wyecor102808.htm

Medication Safety Issue: Change in Concentration/Dosage of Fer-In-Sol® Pediatric Oral Iron Drops - November 2008

Mead Johnson Nutritionals, the maker of Enfamil® oral liquid iron supplement drops Fer-In-Sol®, has recently changed the concentration, and therefore, the dosing of its product. The new labeling indicates that the dose needed to deliver 15 mg of elemental iron has changed from 0.6 mL to 1 mL. Prior to this change, 0.6 mL of Fer-In-Sol® provided 15 mg of elemental iron. The markings on the provided dropper have changed to 0.5 mL and 1 mL instead of 0.3 mL and 0.6 mL to reflect the dosing change. Ferrous sulfate drops made by other manufacturers are still available as the 15 mg/0.6 mL concentration. Due to the concern for potential medication errors, healthcare providers need to be aware of this change and verify the concentration of iron in the actual product being dispensed (generics or unused inventory of Fer-In-Sol® manufactured prior to the change) to ensure the correct volume needed to provide the dose intended. It is recommended that prescribers write prescriptions using dose required, rather than mL needed, and pharmacists should clarify dose if a prescription is written as volume.

Benzoyl Peroxide 10% Acne Products: Recall Prompted by Bacteria Contamination - November 2008

Certain products of benzoyl peroxide have been recalled because samples of the products were found to contain Burkholderia cepacia (formerly known as Pseudomonas cepacia) which may increase the risk of infection in patients with compromised skin conditions or immunosuppressed patients.

For additional information on products affected, please refer to the FDA MedWatch alert: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Benzoyl

Infants' Mylicon® Gas Relief Dye Free Drops: Recall Due to Possible Metal Fragments - November 2008

Johnson & Johnson Merck Consumer Pharmaceuticals Company (JJMCP) is voluntarily recalling Infants' Mylicon® Gas Relief Dye Free Drops distributed after October 5, 2008 due to concern that metal fragments may have been generated during the manufacturing process.

For more information, including lots involved, please refer to the FDA MedWatch alert:
http://www.fda.gov/medwatch/safety/2008/safety08.htm#mylicon

Bisphosphonates: Safety Update Regarding Possible Association With Atrial Fibrillation - November 2008

The Food and Drug Administration (FDA) has been reviewing placebo-controlled trials of the 7 bisphosphonates currently marketed in the US. This review is in response to study results associating an increased incidence of atrial fibrillation (AF) with alendronate or zoledronic acid use in women (65-89 years of age) with osteoporosis.

The FDA reviewed all the submitted data (19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients) from these studies. Overall, the occurrence of AF was rare in each study with an absolute difference in event rates between each of the bisphosphonate and placebo arms of 0-3 per 1000. A zoledronic acid study showed a statistically significant increase in the rate of AF in the active treatment arm. However, no clear association between bisphosphonate use and AF could be established. In this study, AF events were diagnosed more than 30 days after receiving zoledronic acid in 47 of the 50 patients diagnosed with AF. According to the FDA, healthcare providers should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their medication.

The FDA will continue monitoring the safety of bisphosphonates through postmarketing reports and is assessing the need for additional epidemiologic studies.

Further information is available at http://www.fda.gov/cder/drug/early_comm/bisphosphonates_update_200811.htm

Isosorbide Mononitrate, Propafenone, Morphine Sulfate, and Dextroamphetamine: Recall Due to Potential for Oversized Tablets - November 2008

Certain lots of generic isosorbide mononitrate, propafenone, morphine sulfate, and dextroamphetamine tablets have been recalled due to possibility of oversized tablets. Oversized tablets may contain up to twice the amount of the active ingredient which may result in serious or life-threatening effects.

For more information, including lots involved, please refer to the FDA MedWatch alert: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Ethex

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