Special Alerts

Health Canada Issues Warning for Azithromycin Heart Risks

Pfizer Canada Inc., in collaboration with Health Canada, has informed healthcare professionals of revisions to the Zithromax® and Zmax SR™ (azithromycin) Canadian product monographs regarding the risk of potentially fatal cardiac arrhythmias. Patients with a higher baseline risk for cardiovascular events (eg, elderly, QT prolongation, electrolyte disturbances) appear to be mainly at risk. Adverse events have been reported with therapeutic doses.

For additional information, please refer to:

Canada: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/29199a-eng.php

Zolpidem Label Changes

The U.S. Food and Drug Administration (FDA) has approved label changes specifying new dosing recommendations for zolpidem tartrate products (Ambien®, Ambien CR®, and Edluar™), the widely prescribed sleep medications, because of the known risk of next-morning impairment with these drugs. Ambien® and Edluar™ are indicated for the short-term treatment of insomnia characterized by difficulties in sleep initiation. Ambien CR® is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).

The FDA also warns that patients who take extended-release zolpidem (Ambien CR®), 6.25 or 12.5 mg, should not drive or engage in other activities that require complete mental alertness the day after taking the drug because zolpidem levels can remain high enough the next day to impair these activities. This new recommendation has been added to the Warnings and Precautions section of the package insert and to the patient Medication Guide for zolpidem extended release.

Additional information can be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm334738.htm .

Safety Communication for Valproic Acid and Derivatives

The U.S. Food and Drug Administration (FDA) is advising healthcare providers that valproic acid and derivatives, valproate sodium and divalproex sodium, are contraindicated in pregnant women for the prevention of migraine headaches. Based on final results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, there is evidence that these medications can cause decreased IQ scores in children whose mothers took them while pregnant. Stronger warnings about use during pregnancy will be added to the drug labels, and they will be changed from Category D (the potential benefit of the drug in pregnant women may be acceptable despite its potential risks) to Category X (the risk of use in pregnant women clearly outweighs any possible benefit of the drug) for the indication of prevention of migraine headaches. Valproic acid and derivatives will remain in Pregnancy Category D for treating epilepsy and manic episodes associated with bipolar disorder. However, use is not recommended in women of childbearing potential for any condition unless alternative therapies are not appropriate. Effective contraception should be used during treatment. Pregnant women who may currently be taking one of these products should not stop their medication abruptly, but should contact their healthcare provider.

For additional information, refer to the following FDA website: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350868.htm

Kadcyla™ Safety Alert

The Food and Drug Administration (FDA) has notified healthcare providers that the use of the incorrect generic name for Genentech's Kadcyla™ (ado-trastuzumab emtansine) in some medication-related electronic systems may result in potential medication errors. Using a truncated name (omitting "ado" and the hyphen) may cause confusion with Genentech's Herceptin® (conventional trastuzumab). Kadcyla™ is an antibody drug conjugate which is indicated as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)?positive, metastatic breast cancer who previously received Herceptin® and a taxane either separately or in combination. Dosing and treatment schedules between ado-trastuzumab emtansine (Kadcyla™) and conventional trastuzumab (Herceptin®) are different; confusion between the products may potentially cause harm to the patient.

Ado-trastuzumab emtansine contains a boxed warning regarding this issue: [U.S. Boxed Warning]: Ado-trastuzumab emtansine and conventional trastuzumab are NOT interchangeable. Verify product label prior to reconstitution and administration to prevent medication errors.

The FDA recommends use of both the proprietary name (Kadcyla™) and the nonproprietary name (ado-trastuzumab emtansine) in communications such as medication orders, preprinted order sets, computerized order entry systems, and other publications to help reduce the potential for errors.

For additional information, refer to the following FDA website: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350817.htm

FDA Approves Plan B® One Step Without a Prescription for Women 15 Years and Older

The FDA has approved Teva?s Plan B? One Step (levonorgestrel) for use without a prescription by women 15 years and older. The product will now be labeled ?not for sale to those under 15 years of age *proof of age required* not for sale where age cannot be verified.? Packaging will include a product code prompting the cashier to request and verify the customer?s age, as well as a security tag to prevent theft.

For additional information, please refer to http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm350230.htm?source=govdelivery

FDA Limits Duration and Usage of Tolvaptan

The U.S. Food and Drug Administration (FDA) has determined that tolvaptan should not be used for longer than 30 days and should not be used in patients with underlying liver disease (including cirrhosis) because it can cause liver injury, potentially leading to liver transplant or death. Tolvaptan should be discontinued in patients who develop signs of liver disease. The FDA has worked with the manufacturer to revise the tolvaptan prescribing information to include these new limitations.

Patients should be advised that tolvaptan may cause liver problems, including life-threatening liver failure, and that they should contact their healthcare provider to discuss any questions or concerns.

For more information, refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm

Ezogabine Linked to Retinal Abnormalities and Skin Discoloration

The Food and Drug Administration (FDA) is warning that ezogabine can cause eye abnormalities characterized by pigment changes in the retina, including scleral and conjunctival discoloration on the whites of the eyes and inside of eyelids, and can also cause blue skin discoloration, predominantly on or around the lips or in the nail beds of fingers or toes, although more widespread involvement of the face and legs has also been reported. The skin discoloration generally occurred after 4 years of treatment, but appeared sooner in some patients. In some cases, retinal abnormalities were observed in the absence of skin discoloration. The FDA does not currently know if these changes are reversible.

The FDA recommends that all patients taking ezogabine undergo a baseline eye exam and periodic eye exams that include visual acuity testing and dilated fundus photography. Fluorescein angiograms, ocular coherence tomography, perimetry, and electroretinograms may also be considered.

Patients who develop changes in vision or skin discoloration should contact their healthcare provider immediately.

For more information, refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm349847.htm

Health Canada Issues Notice Regarding Possible Risk of Developing or Worsening Atherosclerosis-Related Disease With the Use of Nilotinib

In collaboration with Health Canada, Novartis Pharmaceuticals Canada Inc. has issued a Dear Healthcare Provider letter acknowledging reports of atherosclerosis-related diseases in patients treated with nilotinib (Tasigna®) for newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML). Events such as peripheral arterial occlusive disease, femoral artery stenosis, coronary artery stenosis, carotid artery stenosis, and cerebrovascular accident were observed in approximately 5% to 6% of patients receiving normal clinical doses in a phase III trial, although many patients had pre-existing cardiovascular disease or risk factors for atherosclerotic disease. Patients should be monitored for signs of new onset or worsening atherosclerosis-related disease, as well as lipid and glucose profiles prior to and during treatment with nilotinib and as clinically indicated. The Canadian product labeling has been updated to reflect these warnings and precautions.

Further information can be found at http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/26651a-eng.php

Extension of Expiration Dating: Update

Wyeth Pharmaceuticals (a subsidiary of Pfizer, Inc) has announced that the expiration date of one lot of antivenin, Lot Number 4030024, has been extended through April 30, 2014. In October 2012, Wyeth announced the expiration date of another lot of antivenin, Lot Number 4030026, has been extended to October 31, 2013. Institutions should retain any remaining inventory of either Lot No. 4030024 or 4030026 until the aforementioned expiration dates. Clinicians should note that due to supply concerns, Pfizer, Inc supplies product only to direct customers on a replacement or emergency basis. To obtain antivenin, Pfizer, Inc may be reached at 800-666-7248; alternatively, clinicians may contact their local Poison Control Center at 800-222-1222 for assistance in locating antivenin. In the event licensed antivenin cannot be secured, an investigational imported antivenin may be available under an Investigational New Drug (IND) protocol with informed consent; for more information contact a local Poison Control Center at 800-222-1222 or the U.S. Food and Drug Administration (FDA) at 800-835-4709 (business hours) or 301-796-8240 (nonbusiness hours).

Bone Fracture Risk with Proton Pump Inhibitors: Health Canada Issues Alert

Health Canada has informed healthcare professionals that proton pump inhibitors (PPIs) may increase the risk of bone fractures. The risk of fracture was observed to be higher in patients receiving multiple daily doses for =1 year; age, gender, and concomitant health conditions may also be a factor. Patients with risk factors for osteoporosis should be closely monitored and should receive a PPI at the lowest effective dose and for the shortest duration of therapy appropriate for the condition.

For more information, refer to http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/26523a-eng.php.

Lapatinib-Based Regimens Less Effective Than Trastuzumab-Based Regimens in Certain Settings

Health Canada, in conjunction with GlaxoSmithKline, Inc, has informed clinicians of an update to the product monograph for lapatinib (Tykerb®) regarding its comparative efficacy versus trastuzumab (Herceptin®) in combination with chemotherapy in HER2+ metastatic breast cancer patients; the update is based on the preplanned interim analysis of two recent trials (CEREBEL and COMPLETE).

The COMPLETE trial (Gelmon, 2012) compared lapatinib versus trastuzumab when combined with taxane-based chemotherapy (eg, paclitaxel or docetaxel) as first-line therapy in patients with HER2+ metastatic breast cancer (n=636). At interim analysis, progression-free survival (PFS) was found to be inferior for the lapatinib-based regimens (PFS 8.8 months; 95% CI 8.3-10.6) as compared to the trastuzumab-based regimens (PFS 11.4 months; 95% CI 10.8-13.7); with a hazard ratio of 1.48 (95%CI 1.15-1.92; p=0.003). No difference in overall survival was detected.

The CEREBEL trial (Pivot, 2012) compared the impact of lapatinib plus capecitabine and trastuzumab plus capecitabine on central nervous system metastases in patients with HER2+ metastatic breast cancer (n=475); prior therapy must have included anthracyclines or taxanes in the neoadjuvant, adjuvant, or metastatic setting. At interim analysis, progression-free survival (PFS) was found to be inferior for the lapatinib-based regimen (PFS 6.6 months) as compared to the trastuzumab-based regimen (PFS 8 months) (HR: 1.3; 95% CI: 1-1.7). Median overall survival was also inferior in the lapatinib arm (22.4 months) versus the trastuzumab arm (27.3 months) (HR: 1.58; 95% CI: 1.07-2.32).

Based on the above interim analyses, lapatinib-based regimens are inferior to trastuzumab-based regimens in patients with HER2+ metastatic breast cancer who have not received prior trastuzumab. Lapatinib should not be used in combination with capecitabine unless patients have progressed on prior trastuzumab therapy in the metastatic setting.

For more information, refer to http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/26285a-eng.php

Gelmon KA, Boyle F, Kaufman B, et al, "Open-label Phase III Randomized Controlled Trial Comparing Taxane-Based Chemotherapy (Tax) With Lapatinib (L) or Trastuzumab (T) as First-Line Therapy for Women With HER2+ Metastatic
   Breast Cancer: Interim Analysis (IA) of NCIC CTG MA.31/GSK EGF 108919," J Clin Oncol, 2012 30(18 Suppl): LBA671 [abstract LBA671 from 2012 ASCO Annual Meeting].

Pivot X, Semiglazov V, Zurawsky B, et al, "CEREBEL (EGF111438): An Open Label Randomized Phase III Study Comparing the Incidence of CNS Metastases in Patients(Pts) With
   HER2+ Metastatic Breast Cancer (MBC), Treated With Lapatinib Plus Capecitabine (LC) versus Trastuzumab Plus Capecitabine (TC)," Ann Oncol, 2012, 23(9 Suppl): LBA11 [abstract LBA11 from 2012 ESMO meeting].

Air/Gas Embolus Associated With Fibrin Sealant Spray - Canadian Product Labeling Updated

Health Canada has announced that manufacturers of fibrin sealant sprays will strengthen the product labeling to to ensure proper use of the devices. The announcement follows reports occurring outside of Canada of air/gas embolus (including 3 fatalities) with spray application of fibrin sealants. Risk of an air air/gas embolism increases when these products are sprayed too close to tissue or if the maximum recommended pressure is exceeded.

Further information may be found at the following website: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/26173a-eng.php

FDA Investigating Unpublished Reports of Pancreatic Toxicity With Incretin Mimetic Drugs

The Food and Drug Administration (FDA) is evaluating unpublished new findings that suggest an increased risk of pancreatitis and pancreatic duct metaplasia in patients with type 2 diabetes treated with incretin mimetics. These findings are based on pancreatic tissue samples taken from patients who died from unspecified causes. The FDA has requested these samples, as well as information on the methodology used to collect them, and will communicate its final conclusions and recommendations. Healthcare providers should continue to prescribe incretin mimetics according to the drug label recommendations and patients receiving incretin mimetics are advised to continue therapy as directed and to discuss any concerns with their healthcare provider.

Further information may be found at the following website: http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm

FDA Issues Warning for Azithromycin Heart Risks

The Food and Drug Administration (FDA) has issued a safety warning that azithromycin (Zithromax? or Zmax?) may cause prolonged cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmia and torsade de pointes. Patients at particular risk include those with known risk factors such as existing QT-interval prolongation, a history of torsade de pointes, congenital long QT syndrome, uncompensated heart failure, use of drugs known to prolong the QT interval, uncorrected hypokalemia or hypomagnesemia, or clinically significant bradycardia.

The warning results from FDA review of a research study and a subsequent study conducted by a manufacturer, both assessing the potential for azithromycin to cause abnormal cardiac activity.

Healthcare providers should be aware of the potential for QT-interval prolongation and heart arrhythmias when prescribing or administering azithromycin for patients who are already at risk for cardiovascular events.

Further information may be found at the following websites:

http://www.fda.gov/Drugs/DrugSafety/ucm341822.htm

http://www.fda.gov/Drugs/DrugSafety/ucm304372.htm

FDA Stops Pediatric Trials

The FDA has stopped all pediatric clinical trials of Sensipar® (cinacalcet hydrochloride) after a recent death of a 14-year old patient in a trial. The FDA is currently evaluating the association of the patient's death and the use of cinacalcet. Cinacalcet is not currently approved for use in patients less than 18 years of age.

The FDA reminds healthcare professionals that patients receiving cinacalcet should be monitored for low serum calcium levels. Serum calcium levels should be monitored 1 week after initiation and after dosage adjustments and monthly thereafter.

Further information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm341255.htm.

Peginesatide (Omontys®) Injection - Product Recall

Affymax and Takeda Pharmaceuticals are voluntarily recalling all lots of Omontys® (peginesatide) injection as a result of postmarketing reports regarding serious hypersensitivity reactions, including anaphylaxis, which can be life-threatening or fatal. The overall rate of hypersensitivity reactions reported is approximately 0.2% (approximately one-third of these reactions reported as serious, including fatalities, and occurred within 30 minutes following administration).

Dialysis organizations should discontinue use of peginesatide. Customers will be provided with instructions on how to return the product to the manufacturer for a refund. For questions, call 1-855-466-6689, 9 AM to 5 PM EST, Monday through Friday. Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of this product to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.

Further information may be found at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm340895.htm.

FDA Warns of Codeine Use in Children After Tonsillectomy and/or Adenoidectomy

The FDA has issued a Drug Safety Communication after reviewing reports of children who developed serious adverse effects, including death, after receiving codeine in the usual dosage range for pain relief following tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. Three deaths occurred in children that had evidence of a genetic variation ("ultrarapid metabolizers") which results in faster and more complete conversion of codeine to morphine, possibly leading to overdose or death. The estimated incidence of this genetic variation is ~1-7 per 100 people, but may be higher in some ethnic groups.

The product labeling for codeine is being updated with a contraindication and boxed warning regarding its use as an analgesic in children undergoing tonsillectomy and/or adenoidectomy. Healthcare professionals should not prescribe codeine to children for pain after these procedures. Alternative analgesics should be used in this setting. For management of other types of pain in children, codeine should only be used if the benefits are anticipated to outweigh the risks. Parents and caregivers who observe signs of overdose in a child (eg, unusual sleepiness, confusion, or difficult or noisy breathing) should stop codeine administration and seek medical attention immediately.

Further information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm.

HMG-CoA Reductase Inhibitors and Risk of Increased Blood Glucose Concentrations and Diabetes

The U.S. Food and Drug Administration (FDA) and Otsuka Pharmaceuticals have notified healthcare providers that findings of a double-blind, placebo controlled trial (n=1445) and its open-label extension trial indicate that treatment with tolvaptan may have resulted in a significant increase in serum alanine aminotransferase (ALT) and serum total bilirubin in three patients with autosomal dominant polycystic kidney disease (ADPKD). Hepatic effects were noted during the first 18 months of therapy and resolved upon discontinuation of tolvaptan therapy; doses used in the trial (120 mg/day) were higher than the maximum daily dose (60 mg/day) currently recommended for its FDA-approved use of hyponatremia. As a result, the FDA, in conjunction with Otsuka Pharmaceuticals, is warning healthcare providers that tolvaptan therapy has the potential to cause irreversible and potentially fatal liver injury.

Clinicians are advised to perform hepatic function tests in patients who develop symptoms consistent with liver injury (eg, fatigue, anorexia, right upper quadrant pain, dark urine, jaundice). If hepatic injury is suspected, discontinue tolvaptan, treat as clinically indicated, and determine the probable cause. Tolvaptan treatment should not be resumed unless the cause for the liver injury is definitively established to be unrelated to tolvaptan.

For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm336669.htm.

HMG-CoA Reductase Inhibitors and Risk of Increased Blood Glucose Concentrations and Diabetes

Health Canada has notified healthcare professionals of updates to the product monographs of HMG-CoA reductase inhibitors (aka, ?statins?) marketed in Canada regarding the risk of increased blood glucose concentrations and a small increased risk of diabetes mellitus following administration of these agents. The risk appears to be greatest in patients already at risk for diabetes (eg, patients with increased blood glucose concentration, hypertriglyceridemia, obesity, hypertension). However, Health Canada continues to acknowledge that the benefits of statin therapy far outweigh the risk of dysglycemia. It is recommended that clinicians carefully monitor the use of statins in patients at high risk of developing diabetes mellitus.

For additional information, please refer to http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/16949a-eng.php.

FDA Recommending Lower Initial Zolpidem Doses to Reduce Risk of Morning Somnolence

The U.S. Food and Drug Administration (FDA) is requiring manufacturers of zolpidem products (Ambien®, Ambien CR®, Edluar™, and Zolpimist®) to change labeling to recommend lower starting doses of zolpidem in women. Blood levels in women may remain high enough the morning after use to impair activities that require alertness, including driving. Women appear to be more sensitive to this effect because they eliminate zolpidem more slowly than men, although the FDA is also recommending that the lower doses be considered for men. The recommendation is focused on zolpidem products approved for use immediately before bedtime. The FDA is recommending that the doses for immediate-release products be lowered from 10 mg to 5 mg and from 12.5 mg to 6.25 mg for extended-release products in women.

Patients already prescribed zolpidem should contact their healthcare provider prior to adjusting their dose.

Additional information can be found at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm334798.htm.

New Black Box Warning for Telaprevir (Incivek™) Concerning Serious Skin Reactions with Combination Treatment

The U.S. Food and Drug Administration (FDA) is adding a boxed warning for Incivek™ (telaprevir) concerning fatal and nonfatal serious skin reactions, including Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), in patients taking telaprevir in combination with peginterferon alfa and ribavirin (Incivek™ combination treatment). Combination treatment is indicated for the treatment of genotype 1 chronic hepatitis C. The boxed warning states that telaprevir, peginterferon alfa, and ribavirin must be discontinued immediately in patients experiencing SJS, DRESS, or TEN, and that consideration should also be given to discontinuing any other medications that may be associated with serious skin reactions. Patients with serious skin reactions should also receive urgent medical care.

For more information, see http://www.fda.gov/Drugs/DrugSafety/ucm332731.htm.

FDA Adds New Contraindication to Xyrem® (Sodium Oxybate)

The U.S. Food and Drug Administration (FDA) added a new contraindication against the concomitant use of alcohol with sodium oxybate (Xyrem®). The use of sodium oxybate is already contraindicated with insomnia agents, and its use with other CNS depressant drugs (eg, such as opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, general anesthetics, muscle relaxants), should generally be avoided. Concomitant use of sodium oxybate with alcohol or CNS depressant drugs may impair consciousness and lead to respiratory depression. After evaluating reports of death in patients taking sodium oxybate with alcohol or other CNS depressants, the FDA suggested that the recommendations in the sodium oxybate drug label be strengthened to remind patients and healthcare providers of the risks associated with concomitant use.

Further information and label revisions can be found at http://www.fda.gov/Drugs/DrugSafety/ucm332029.htm.

Premixed Ondansetron 32 mg I.V. Products to be Removed From Market

The Food and Drug Administration (FDA) is notifying healthcare providers that ondansetron hydrochloride (Zofran®) 32 mg single premixed intravenous doses in a sodium chloride or dextrose solution will no longer be marketed because of the potential for QT prolongation, which can lead to torsade de pointes, a potentially fatal abnormal heart rhythm. The I.V. 32 mg dose has been removed from GlaxoSmithKline's ondansetron (Zofran®) labeling. The FDA is working with the manufacturers of all ondansetron 32 mg, premixed single-dose injectable products to voluntarily recall them from the market. The FDA anticipates these products will be removed from the market through early 2013 and does not expect this recall to contribute to a drug shortage.

The approved labeling continues to recommend I.V. ondansetron for the prevention of chemotherapy induced nausea and vomiting at 0.15 mg/kg every 4 hours for 3 doses. No single I.V. dose should exceed 16 mg. Oral dosing labeling for ondansetron is unchanged.

Further information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm330772.htm.

Cell Culture-Derived Seasonal Influenza Vaccine (Flucelvax®)

Flucelvax® (trivalent influenza virus vaccine) has been approved by the Food and Drug Administration (FDA) to provide active immunity to influenza virus. Flucelvax® is the only inactivated influenza vaccine manufactured using cell culture technology and provides an alternative to influenza vaccines cultured with chicken egg protein. Availability is currently limited, but full distribution is expected during the 2012-2013 influenza season.

For additional information, refer to http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm328982.htm.

Health Canada Issues Update Regarding Atypical Femur Fractures

Amgen Canada, Inc, in consultation with Health Canada, has issued an update for Canadian healthcare professionals in regards to the risk of atypical femur fractures associated with denosumab treatment. Rare cases of atypical femoral fracture have occurred in an ongoing, open label extension study called Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM). These fractures are subtrochanteric or proximal diaphyseal fractures that may occur in both legs without any significant trauma being reported.

There are no confirmed cases in Canada to date; however, Canadian healthcare professionals are being reminded to be aware of this possible risk for fracture and to evaluate and rule out femur fracture in patients reporting new or unusual hip, thigh, or groin pain. Patients should not discontinue denosumab therapy without consulting a healthcare professional and should be encouraged to report dull, unusual aching pain in the hip, thigh, or groin.

Further information may be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/index-eng.php.

FDA Updates Immune Globulin Product Safety Information

The Food and Drug Administration (FDA) has issued an updated Safety Communication regarding thrombotic events and hemolysis potentially associated with the administration of human immune globulin. Because thrombosis has previously been identified as a potential risk following human immune globulin administration, the agency continues to investigate whether specific characteristics of these products account for an increased risk. FDA scientists and product manufacturers have examined different lots of immune globulin products and found elevated levels of the activated clotting factor XIa in certain lots produced by different manufacturers. Higher levels of factor XIa were associated with a greater incidence of arterial and venous clot formation in patients receiving these products.

Acute intravascular hemolysis or delayed hemolytic anemia can also occur after immune globulin therapy. In some cases, this happens because immune globulins contain blood group antibodies that can act as hemolysins by coating red blood cells, causing a positive direct antibody (Coombs) test result and hemolysis. Isolated cases of hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have also been reported following treatment with immune globulins.

Further information may be found at http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm327934.htm?source=govdelivery.

Simvastatin and Dose-Related Myopathy: Health Canada Issues Notice

Health Canada, in conjunction with Merck Canada Inc, has issued notice to Canadian healthcare professionals regarding increased risks of myopathy associated with high-dose (80 mg/day) simvastatin (Zocor®). The simvastatin Canadian product monograph recommends limiting the dose to &243;40 mg/day; an alternative treatment should be used for patients unable to reach their LDL-C goal with this dosage recommendation. Higher doses (80 mg/day) of simvastatin are restricted to patients requiring chronic use and without evidence of myopathy or who are at high risk of cardiovascular complications and unable to tolerate other statins. Specific recommendations regarding simvastatin use and dosage with concomitant medications (eg, verapamil, amiodarone, amlodipine, fusidic acid) and grapefruit juice are also included in the product labeling.

Further information may be found at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/zocor_hpc-cps-eng.php.

Influenza Virus Vaccine 2012-2013

The 2012-2013 influenza virus vaccine contains the same H1N1 virus as in the 2011-2012 vaccine, but different H3N2 and B viruses. The vaccine strains approved for this season in the United States are as follows: A/California/7/2009 (H1N1)-like virus, A/Victoria/361/2011 (H3N2)-like virus, and B/Wisconsin/1/2010-like virus. Because immunity to influenza virus declines over time, and because two of the three strains of the virus are different this year than last, persons should be vaccinated every year even if vaccinated during the previous season.

In addition, a variant influenza A virus (H3N2v) is currently circulating in pigs and infecting humans. Immunization with the 2012-2013 seasonal influenza vaccine is not expected to provide protection against this virus. Symptoms of H3N2v are generally similar to those of seasonal influenza infections. Unfortunately, standard tests used to detect influenza virus cannot differentiate between H3N2v virus from seasonal influenza A (H3N2) virus and there is a potential for false negatives with antigen detection tests. Clinicians who suspect probable H3N2v virus should contact their local or state health department for additional testing for H3N2v at a state public health laboratory. A link to recent swine exposure (within 1 week) of symptom onset should be considered a probable H3N2v case. Antiviral treatment of H3N2v influenza is the same as seasonal influenza.

For additional information refer to the following websites:

FDA approves vaccines for the 2012-2013 influenza season: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315365.htm

CDC, Interim Information about Human Infections with H3N2v Virus: http://www.cdc.gov/flu/swineflu/h3n2v-clinician.htm

Extension of Expiration Dating

Wyeth Pharmaceuticals (a subsidiary of Pfizer, Inc) has announced that the expiration date of one lot of antivenin, Lot Number 4030026, has been extended to October 31, 2013; institutions should retain any remaining inventory of Lot No. 4030026. Clinicians should note that due to supply concerns, Pfizer, Inc supplies product only to direct customers on a replacement or emergency basis. To obtain antivenin, Pfizer, Inc may be reached at 800-666-7248; alternatively, clinicians may contact their local Poison Control Center at 800-222-1222 for assistance in locating antivenin. In the event licensed antivenin cannot be secured, an investigational imported antivenin may be available under an Investigational New Drug (IND) protocol with informed consent; for more information contact a local Poison Control Center at 800-222-1222 or the U.S. Food and Drug Administration (FDA) at 800-835-4709 (business hours) or 301-796-8240 (nonbusiness hours).

Influenza Virus Vaccine 2012-2013

The 2012-2013 influenza virus vaccine contains the same H1N1 virus as in the 2011-2012 vaccine, but different H3N2 and B viruses. The vaccine strains approved for this season in the United States are as follows: A/California/7/2009 (H1N1)-like virus, A/Victoria/361/2011 (H3N2)-like virus, and B/Wisconsin/1/2010-like virus. Because immunity to influenza virus declines over time, and because two of the three strains of the virus are different this year than last, persons should be vaccinated every year even if vaccinated during the previous season.

In addition, a variant influenza A virus (H3N2v) is currently circulating in pigs and infecting humans. Immunization with the 2012-2013 seasonal influenza vaccine is not expected to provide protection against this virus. Symptoms of H3N2v are generally similar to those of seasonal influenza infections. Unfortunately, standard tests used to detect influenza virus cannot differentiate between H3N2v virus from seasonal influenza A (H3N2) virus and there is a potential for false negatives with antigen detection tests. Clinicians who suspect probable H3N2v virus should contact their local or state health department for additional testing for H3N2v at a state public health laboratory. A link to recent swine exposure (within 1 week) of symptom onset should be considered a probable H3N2v case. Antiviral treatment of H3N2v influenza is the same as seasonal influenza.

For additional information refer to the following websites:

FDA approves vaccines for the 2012-2013 influenza season: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315365.htm

CDC, Interim Information about Human Infections with H3N2v Virus: http://www.cdc.gov/flu/swineflu/h3n2v-clinician.htm

Fungal Meningitis Outbreak Associated with Contaminated Injectables

For information regarding the recent meningitis outbreak from products compounded by the New England Compounding Center (NECC), including treatment recommendations, please refer to the following websites:

http://www.cdc.gov/hai/outbreaks/meningitis.html

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm285497.htm

http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm323947.htm?source=govdelivery

Pentacel® Shortage Dosing Guidelines; Updated

The Center for Disease Control and Prevention (CDC) has issued guidelines for vaccinating children during the Pentacel? and Daptacel® shortage. Sanofi Pasteur expects a shortage of these vaccines to continue through March 2013.

Guidelines may be found on the following CDC website: http://www.cdc.gov/vaccines/vac-gen/shortages/downloads/pentacel-guidance.pdf

Ongoing Safety Review Regarding Potential Risk of Heart Failure

The U.S. Food and Drug Administration (FDA) is informing healthcare practitioners of an ongoing safety review of pramipexole. The safety review was prompted by the results of various studies suggesting a potential risk of heart failure (HF) associated with use.

The agency evaluated pooled analysis of randomized, placebo-controlled phase 2 and 3 clinical trials which showed an increased incidence of newly diagnosed HF in patients receiving pramipexole (n=12 /4157; 0.28%) compared to patients receiving placebo (n=4/2820; 0.14%); this difference in incidence is not statistically significant. The FDA also reviewed results of two epidemiologic studies which suggested an increased incidence in HF. The first epidemiologic study, a case-control study in a United Kingdom cohort of patients receiving anti-Parkinson agents (eg, dopamine agonists), revealed a statistically-significant increased risk for HF in patients exposed to any dopamine agonist compared to no exposure (RR: 1.58; 95% CI: 1.26-1.96). Of the dopamine agonist agents, pramipexole use was associated with a statistically-significant risk of HF in patients exposed to pramipexole versus no exposure (RR: 1.86; 95% CI: 1.21-2.85). In the second epidemiologic study, a case-control study in a cohort of Parkinson?s disease patients newly initiated on a dopamine agonist or levodopa, found that among the individual non-ergot dopamine agonists studied, only current use of pramipexole was associated with an increased risk of HF compared to levodopa use (OR: 1.61; 95% CI: 1.09-2.38). This increased risk occurred in the first 3 months of treatment (OR: 3.06; 95% CI: 1.74-5.39) and in patients ≥80 years (OR: 3.30; 95% CI: 1.62-7.13). Of note, the increased risk was not significant with pramipexole use >3 months.

The FDA has not concluded that pramipexole increases the risk of HF. Due to study limitations and the potential for confounders, the FDA is continuing its review. The FDA is reminding patients they should not discontinue pramipexole without consulting a healthcare professional. Practitioners should continue to follow recommendations in the pramipexole prescribing information and counsel patients to seek medical attention if any signs/symptoms of HF occur during use.

Additional information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm320054.htm?source=govdelivery

Reports of Serious Burns Due to Topical Pain Relievers, FDA Issues Warning

The U.S. Food and Drug Administration (FDA) is alerting the public that certain over-the-counter (OTC) topical pain relievers have been associated with rare cases of serious skin injuries (eg, first- to third-degree chemical burns) at the application site. In some cases, hospitalization has been required.

OTC topical pain relievers are available as single- or combination-ingredient products that contain menthol, methyl salicylate, or capsaicin, and are marketed under brand names such as BenGay®, Capzasin®, Icy Hot®, and Mentholatum®. The formulations include creams, lotions, ointments, and patches.

Consumers who experience signs of skin injury (eg, pain, swelling, or blistering) following application of these products should discontinue their use and seek immediate medical attention. When recommending these pain relievers, healthcare providers should counsel patients about their appropriate use and the risk of burns.

Further information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm319353.htm.

Influenza Virus Vaccine 2012-2013

The 2012-2013 influenza virus vaccine contains the same H1N1 virus as in the 2011-2012 vaccine, but different H3N2 and B viruses. The vaccine strains approved for this season in the United States are as follows: A/California/7/2009 (H1N1)-like virus, A/Victoria/361/2011 (H3N2)-like virus, and B/Wisconsin/1/2010-like virus. Because immunity to influenza virus declines over time, and because two of the three strains of the virus are different this year than last, persons should be vaccinated every year even if vaccinated during the previous season.

In addition, a variant influenza A virus (H3N2v) is currently circulating in pigs and infecting humans. Immunization with the 2012-2013 seasonal influenza vaccine is not expected to provide protection against this virus. Symptoms of H3N2v are generally similar to those of seasonal influenza infections. Unfortunately, standard tests used to detect influenza virus cannot differentiate between H3N2v virus from seasonal influenza A (H3N2) virus and there is a potential for false negatives with antigen detection tests. Clinicians who suspect probable H3N2v virus should contact their local or state health department for additional testing for H3N2v at a state public health laboratory. A link to recent swine exposure (within 1 week) of symptom onset should be considered a probable H3N2v case. Antiviral treatment of H3N2v influenza is the same as seasonal influenza.

For additional information refer to the following websites:

FDA approves vaccines for the 2012-2013 influenza season: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315365.htm

CDC, Interim Information about Human Infections with H3N2v Virus: http://www.cdc.gov/flu/swineflu/h3n2v-clinician.htm

FDA Issues Safety Recommendation Regarding Sildenafil (Revatio®) Use in Children and Adolescents

The Food and Drug Administration (FDA) is recommending to healthcare providers and their medical care organizations that Revatio® (sildenafil) not be used to treat pulmonary arterial hypertension (PAH) in pediatric patients (1-17 years of age) due to a dose-dependent increased mortality risk observed in a long-term (≤ 7 years) study. The Sildenafil in Treatment-Naive Children, Aged 1?17 Years, With Pulmonary Arterial Hypertension (STARTS-1, 2), a randomized, double-blind, international, multicenter, placebo-controlled, parallel-group trial, included 234 pediatric patients (1-17 years, weight ≥8 kg) with PAH (mild-to-moderate symptoms), evaluated 3 doses (low, medium, and high) of sildenafil on long-term mortality (Barst, 2012). Patients were randomized according to weight into the 3 dosage levels with doses administered 3 times daily:

Low dose: Weight >20 kg: 10 mg per dose

Medium dose:

Weight ≥8-20 kg: 10 mg per dose

Weight >20-45 kg: 20 mg per dose

Weight >45 kg: 40 mg per dose

High dose:

Weight ≥8-20 kg: 20 mg per dose

Weight >20-45: 40 mg per dose

Weight >45 kg: 80 mg per dose

Low-, medium-, and high-dose levels were based upon desired steady state concentrations of 47, 140, and 373 ng/mL respectively; these concentrations are expected to inhibit 53%, 77%, and 90% of phosphodiesterase type 5 activity in vitro.

An increased risk of death was observed after 2 years of therapy and appeared to be dose-dependent with the highest risk in the high-dose group after ≥3 years of treatment (20% vs 9%, and 14% in the low- and medium-dose group); most deaths (74%) occurred in patients with idiopathic and hereditary PAH. The most frequent causes of death in the trial were pulmonary hypertension and heart failure which are also the most common causes of death in patients with PAH. Results did not show that low-dose sildenafil was effective at improving exercise ability.

A new warning stating the use of Revatio® is not recommended in pediatric patients has been added to the labeling. Revatio® is indicated for the treatment of PAH by relaxing the blood vessels in the lungs to reduce blood pressure and is approved to improve exercise ability and delay clinical worsening of PAH in adult patients (WHO Group I). The FDA is requiring Pfizer, the manufacturer of Revatio®, to evaluate its effect on the risk of death in adults with PAH.

Patients and caregivers are advised to not change the dose or stop taking Revatio® without talking with their healthcare provider. Healthcare providers were reminded that use of this product, particularly long-term use, in children is an off-label indication, is not approved by the FDA, and is not recommended.

For additional information, refer to http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm

Barst RJ, Ivy DD, Gaitan G, et al, "A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Na?ve Children With Pulmonary Arterial Hypertension," Circulation, 2012, 125(2):324-34.

Labeling Revised with Stronger Cardiovascular Warnings and Recommendations (May 2012) Updated

The U.S. Food and Drug Administration (FDA) completed its review of a report of a patient who died after the first dose of fingolimod (Gilenya®). Clinical trial and postmarketing data for the drug were also reviewed, including reports of patients who died of cardiovascular events or unknown causes. Although the FDA could not definitively conclude that fingolimod was related to any of the deaths, it remains concerned about the drug's cardiovascular effects after administration of the first dose. The FDA continues to recommend monitoring for signs of bradycardia for at least 6 hours after the first dose, and additionally recommends hourly pulse and blood pressure measurements for all patients initiating therapy. Electrocardiogram (ECG or EKG) testing should be performed prior to dosing and at the end of the observation period, and cardiovascular monitoring should continue until any symptoms resolve. In addition, extended cardiovascular monitoring (>6 hours) is recommended in patients who are at higher risk for or who may not tolerate bradycardia; extended monitoring should include continuous ECG monitoring overnight. High-risk patients may include those who:

- develop severe bradycardia (HR <45 bpm) after the first dose of fingolimod

- have certain pre-existing conditions where bradycardia would be poorly tolerated

- have QT prolongation prior to fingolimod initiation or during the monitoring period

- take other medications that can slow the heart rate or atrioventricular conduction

- take other medications that prolong the QT interval or can cause torsade de pointes

Based on the FDA's findings, fingolimod (Gilenya®) is now contraindicated in patients with certain preexisting or recent (within the past 6 months) heart conditions or stroke, or in those who are taking certain antiarrhythmic medications. Similar to the FDA, Health Canada has announced that the Canadian product monograph has been updated with stronger recommendations regarding cardiovascular monitoring with initial dosing and use in patients with pre-existing cardiovascular disease. Further information may be found at:

U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm

Canada: http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/gilenya_hpc-cps-eng.php

Campath® Being Withdrawn From Market to be Relaunched as Lemtrada™

Sanofi is withdrawing its leukemia therapy Campath® (alemtuzumab) from the U.S. market to prepare for a relaunch (under the name Lemtrada™) at a lower dose to treat relapsing-remitting multiple sclerosis (MS). The withdrawal from the commercial market, designed to prevent the off-label use of Campath® in the MS indication, will be effective September 4, 2012. After this date, Campath® will remain accessible free of charge through the Campath® Distribution Program for the treatment of B-cell chronic lymphocytic leukemia. Regulatory applications for Lemtrada? were filed with the U.S. Food and Drug Administration (FDA) in June and, if approved, the product could be launched in 2013.

For additional information, please refer to http://www.campath.com.

FDA Warns of Codeine Use in Children After Tonsillectomy and/or Adenoidectomy

The FDA has issued a Drug Safety Communication after reviewing reports of children who developed serious adverse effects, including death, after receiving codeine in the usual dosage range for pain relief following tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. Three deaths occurred in children that had evidence of a genetic variation (?ultrarapid metabolizers?) which results in faster and more complete conversion of codeine to morphine, possibly leading to overdose or death. The estimated incidence of this genetic variation is ~1-7 per 100 people, but may be higher in some ethnic groups.

Healthcare professionals should be aware of the risks associated with the administration of codeine or codeine-containing drugs in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnea and should use the lowest effective dose for the least amount of time on an as-needed basis. Parents and caregivers who observe signs of overdose in a child such as unusual sleepiness, confusion, or difficult or noisy breathing should stop codeine administration and seek medical attention immediately.

Further information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm313631.htm#.

Risk of Seizures with Dalfampridine Therapy

The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals about the risk of seizure in patients with multiple sclerosis initiated on dalfampridine (Ampyra™). The FDA recently evaluated postmarketing reports of adverse events and noted an elevated risk of seizure; the majority of seizures occured within days to weeks after initiation of the recommended dose in patients with no history of seizures. The FDA is also updating the Ampyra™ labeling to clarify recommendations that renal function be assessed in patients before starting the drug and monitored at least annually during treatment. In patients who miss a dose, double or extra doses should not be administered as that may increase seizure risk.

For more information, see http://www.fda.gov/Drugs/DrugSafety/ucm312846.htm

Canadian Labeling Adds New Contraindication in Patients with Idiopathic Pulmonary Fibrosis (IPF)

GlaxoSmithKline, Inc, in conjunction with Health Canada, is informing healthcare professionals that patients with idiopathic pulmonary fibrosis (IPF) should not receive ambrisentan (Volibris®). Ambrisentan is not indicated for this condition, and was found to be ineffective in a randomized clinical trial evaluating efficacy for IPF. Furthermore, higher rates of pulmonary compromise, respiratory hospitalizations, and death were reported with ambrisentan (90 events, 27%) compared to placebo (28 events, 17%). Ambrisentan should be discontinued in any patients receiving treatment for IPF.

Additional information can be found at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/volibris_hpc-cps-eng.php

QT Prolongation with Ondansetron

Previously, in September 2011, the U.S. Food and Drug Administration (FDA) notified healthcare professionals about an ongoing safety review of the risk of QT prolongation with ondansetron. At that time, the FDA required GlaxoSmithKline (manufacturer of Zofran®) to conduct an in-depth study on the effects of ondansetron on the QT interval. Recent preliminary study results suggest that a single intravenous dose of ondansetron (Zofran®) 32 mg may prolong the QT interval, which could predispose patients to development of torsade de pointes. Those most at risk include patients with congenital long QT syndrome, heart failure, bradyarrhythmias, electrolyte abnormalities (ie, hypokalemia, hypomagnesemia), and concomitant use of other QT-prolonging medications. GlaxoSmithKline has announced changes to ondansetron labeling to remove the 32 mg single intravenous dose. Updated labeling will also state that ondansetron 0.15 mg/kg can be administered to patients with chemotherapy-induced nausea and vomiting every 4 hours for 3 doses, but no single intravenous dose should exceed 16 mg. The labeling for oral ondansetron will not be changed.

Further information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm310219.htm?source=govdelivery.

FDA Warns of Seizure Risk with Cefepime

The FDA is reminding health care providers about the need to adjust the dosage of cefepime in patients with renal impairment. Cases of nonconvulsive status epilepticus have been associated with the use of cefepime, primarily in patients with renal impairment who did not receive appropriate dosage adjustments; however, some of the cases occurred in patients who appropriately received dosage adjustment according to their degree of renal impairment.

To minimize the risk of seizures, healthcare providers should adjust the dosage of cefepime in patients with creatinine clearance =60 mL/minute. If seizure associated with cefepime therapy does occur, consider discontinuing cefepime or making appropriate adjustment in dosage, as necessary, based on renal function. The label is being revised to highlight this risk.

Further information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm309661.htm.

Pentacel® Shortage Dosing Guidelines

The Center for Disease Control and Prevention (CDC) has issued guidelines for vaccinating children during the Pentacel® and Daptacel® shortage. Sanofi Pasteur expects a shortage of these vaccines during the summer of 2012.

Guidelines may be found on the following CDC website: http://www.cdc.gov/vaccines/vac-gen/shortages/downloads/pentacel-guidance.pdf

Reports of Severe Hypocalcemia Including Fatalities, Health Canada Issues Notice

Amgen Canada Inc, in conjunction with Health Canada, has issued notice to healthcare professionals regarding reports of severe symptomatic hypocalcemia (including fatalities) in patients receiving denosumab (XGEVA®). Severe hypocalcemia with symptoms including altered mental status, tetany, seizures and QTc prolongation has been reported at an estimated incidence of 1% to 2%. During clinical trials, the incidence of severe hypocalcemia (corrected serum calcium <7 mg/dL) was ~3%. The Canadian product monograph will be updated with this important safety information.

To reduce the risk of severe hypocalcemia, healthcare professionals are reminded to:

- Correct pre-existing hypocalcemia prior to initiating denosumab therapy.

- Identify patients at high risk of developing hypocalcemia, such as patients with severe renal impairment and/or receiving dialysis.

- Supplement with calcium and vitamin D unless hypercalcemia is present.

- Monitor calcium levels during therapy.

- If severe hypocalcemia occurs, assess the risk versus benefit of continued treatment.

Further information may be found at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/xgeva_hpc-cps-eng.php.

Hospira Carpuject® Prefilled Cartridges Alert

The Food and Drug Administration (FDA) is alerting healthcare providers of a potential safety risk with as many as 280 lots of 15 different Carpuject® prefilled cartridges that may be overfilled by at least twice the expected amount, which may result in overdose. The company has identified the cause as a manufacturing issue and has implemented corrective actions. Products should be visually inspected upon dispensing and prior to administration. If overfill is detected, the unit should not be used and should be returned to the manufacturer.

For additional information, including a complete list of affected products, please refer to the following websites:

http://www.hospira.com/Files/ClinicalBulletin/Final%20Carpuject%20Product%20List%20and%20Images.pdf

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm305236.htm?source=govdelivery

FDA Revises Monitoring and Contraindications

The U.S. Food and Drug Administration (FDA) completed its review of a report of a patient who died after the first dose of fingolimod (Gilenya®). Clinical trial and postmarketing data for the drug were also reviewed, including reports of patients who died of cardiovascular events or unknown causes. Although the FDA could not definitively conclude that fingolimod was related to any of the deaths, it remains concerned about the drug's cardiovascular effects after administration of the first dose. The FDA continues to recommend monitoring for signs of bradycardia for at least 6 hours after the first dose, and additionally recommends hourly pulse and blood pressure measurements for all patients initiating therapy. Electrocardiogram (ECG or EKG) testing should be performed prior to dosing and at the end of the observation period, and cardiovascular monitoring should continue until any symptoms resolve. In addition, extended cardiovascular monitoring (>6 hours) is recommended in patients who are at higher risk for or who may not tolerate bradycardia; extended monitoring should include continuous ECG monitoring overnight. High-risk patients may include those who:

- develop severe bradycardia (HR <45 bpm) after the first dose of fingolimod

- have certain pre-existing conditions where bradycardia would be poorly tolerated

- have QT prolongation prior to fingolimod initiation or during the monitoring period

- take other medications that can slow the heart rate or atrioventricular conduction

- take other medications that prolong the QT interval or can cause torsade de pointes

Based on the FDA?s findings, fingolimod (Gilenya®) is now contraindicated in patients with certain preexisting or recent (within the past 6 months) heart conditions or stroke, or in those who are taking certain antiarrhythmic medications.

For more information, refer to http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm.

FDA Review of Long-term Bisphosphonate Efficacy for Osteoporosis

In response to serious postmarketing adverse reactions, including atypical femur fractures, osteonecrosis of the jaw, and esophageal cancer, and a paucity of long-term efficacy data, the FDA conducted a systematic review of long-term bisphosphonate therapy for osteoporosis. To date, randomized controlled trials have shown that bisphosphonate therapy is effective in preventing fractures in trials of 3- to 4-years duration. Therefore, to examine long-term efficacy, three long-term extension trials (involving postmenopausal women) ranging in a duration of treatment from 6-10 years were used in the FDA?s analysis. Based on the available long-term clinical trial data, the FDA was unable to identify subgroups of patients who are more likely to benefit from therapy beyond 3-5 years. Continuation of treatment should be based on individual assessment of risks, benefits, and preferences of patients and their physicians.

Until further data are available, the data suggests patients at low risk for fracture (eg, younger patients without a fracture history and bone mineral density [BMD] approaching normal) may be good candidates for discontinuation of therapy after 3-5 years. Patients at increased risk, such as older patients with a history of fracture and a BMD in the osteoporotic range, may benefit from continued therapy.

Further investigation into the risks and benefits of long-term therapy, the usefulness of markers of bone turnover or BMD in determining duration or interruption of therapy, and surveillance or fracture risk after therapy discontinuation are needed.

For additional information, please refer to http://www.nejm.org/doi/pdf/10.1056/NEJMp1202619.

Health Canada Issues Notice Regarding Hypersensitivity and Infusion Reactions

GlaxoSmithKline Inc, in conjunction with Health Canada, has notified healthcare practitioners that belimumab Canadian product monograph has been updated in response to reports of serious (including fatal) hypersensitivity and infusion-related reactions observed with belimumab administration. Hypersensitivity reactions with a delayed onset of up to several hours (eg, 4 hours) after belimumab administration have been reported. The manufacturer notes that during clinical trials, similar reactions reported in ~1% of patients, were observed more often during or shortly after administration.

Healthcare providers are being reminded of the following:

- The risk of a reaction may be increased in patients with multiple drug allergies or significant hypersensitivity. Reactions occur most often with the first two infusions and decrease with subsequent infusions.

- Therapy should be prescribed, managed, and administered by qualified healthcare providers.

- Monitor patients during and for an appropriate amount of time following administration of belimumab (keeping in mind the potential for delayed-onset reactions).

- Stop belimumab infusion and initiate appropriate medical management in the event of a severe reaction.

Further information may be found at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/benlysta_hpc-cps-eng.php

Important Drug Interaction Between Victrelis™ (Boceprevir) and Ritonavir-Boosted HIV Protease Inhibitor Regimens (Update) April 2012

The U.S. Food and Drug Administration (FDA) has updated the drug interaction section of the Victrelis™(boceprevir) prescribing information, as a result of a drug interaction study reported in a February 2012 FDA Drug Safety Communication. It is now recommended that boceprevir not be coadministered with certain ritonavir-boosted HIV protease inhibitors because of the potential to reduce the effectiveness of HCV or HIV treatment. Ritonavir-boosted HIV protease inhibitors include ritonavir-boosted Reyataz® (atazanavir), ritonavir-boosted Prezista® (darunavir), and Kaletra® (lopinavir/ritonavir).

Patients should not stop taking any of their HCV or HIV medicines without consulting their healthcare provider. Patients infected with both chronic HCV and HIV on boceprevir while taking antiretroviral therapy containing one of these ritonavir-boosted protease inhibitors should be closely monitored for treatment response (no HCV virus detected in the blood) and for potential HCV or HIV virologic rebound. Victrelis™ is not FDA-approved for the treatment of patients coinfected with HIV and HCV.

For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm291144.htm

FDA Announces New Warning and Contraindication for Aliskiren-Containing Products April 2012

The FDA has issued a new warning and contraindication concerning the concurrent use of the direct renin inhibitor aliskiren (including Tekturna®, Tekturna HCT®, Amturnide™, Tekamlo™, Valturna®) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with diabetes or renal impairment. These drug combinations are now contraindicated in patients with diabetes and should be avoided in patients with moderate-to-severe renal impairment (Clcr <60 mL/minute). Labels for the aliskiren-containing drugs are being updated based on preliminary data from the ALTITUDE trial. The trial was stopped early after an increased incidence of renal impairment, hypotension, and hyperkalemia were observed in patients receiving combination therapy. There also was a numerically higher number of deaths and strokes noted in patients receiving aliskiren. The FDA is continuing its evaluation to see if there is truly an increased risk of stroke or death in this population. Finally, due to the results of this study, the combination product Valturna® (aliskiren/valsartan), will no longer be marketed after July 2012.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm300889.htm?source=govdelivery.

Potential Increased Risk of Bladder Cancer with Pioglitazone (Actos®) (Health Canada Review) April 2012

Health Canada, in conjunction with Takeda Canada, Inc, has completed a review of pioglitazone and an associated increased risk of bladder cancer. Based on available data, it is determined that there is a potential increased risk of bladder cancer with the use of pioglitazone and pioglitazone-containing combinations. The Canadian pioglitazone product monograph has been updated to include a contraindication in patients with active bladder cancer, a history of bladder cancer, or with uninvestigated macroscopic hematuria. Macroscopic hematuria should be investigated prior to pioglitazone initiation. Risk factors for bladder cancer (age, smoking, family history, chemical exposure, and treatment with certain antineoplastic agents or radiation therapy) should be assessed prior to initiation of pioglitazone. Patients currently receiving pioglitazone treatment should be advised to seek medical attention if macroscopic hematuria, dysuria, or urinary urgency develop during pioglitazone treatment.

For additional information, refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/actos_3_hpc-cps-eng.php

Drospirenone-Containing Oral Contraceptives: FDA Update on Increased Risk of Blood Clots April 2012

The U.S. Food and Drug Administration (FDA) has finalized its review of epidemiological data, and concluded there may be an increased risk (up to threefold) of blood clots compared to other progestin-containing oral contraceptives. However, the studies did not provide consistent estimates of comparative risk with other progestin-containing products, nor did they account for potentially meaningful patient characteristics (that may have influenced risk). The results of these data, including acknowledgment of studies showing no increased risk, have been added to the labeling of drospirenone-containing contraceptive products.

Additional information can be found at http://www.fda.gov/Drugs/DrugSafety/ucm299305.htm.

Exparel®: Medication Safety Error March 2012

The Institute for Safe Medication Practices (ISMP) has issued an alert concerning a potential route of administration safety error for Exparel® (bupivacaine liposome injectable suspension). ISMP is warning that Exparel® may be confused with propofol in operating rooms and other surgical areas due to their similar white, milky appearance when prepared in unlabeled syringes. Exparel® is a local anesthetic to be infiltrated into a surgical wound to produce postsurgical analgesia. It is not intended for systemic use. Propofol is used systemically during surgical procedures, as a sedative during procedures, or for patients undergoing mechanical ventilation. If Exparel® is accidentally administered intravenously, adverse cardiac effects such as atrioventricular block, ventricular arrhythmias, and cardiac arrest may result. Although no reports of this error have been received, it is recommended that prepared syringes be labeled and vials be separated and that directions for treatment of bupivacaine toxicity be available in areas where Exparel® is used.

For additional information, please refer to http://www.ismp.org/NAN/files/NAN-20120318.pdf.

U.S. Revises Previous QT Interval-related Recommendations for Citalopram Label March 2012

The U.S. Food and Drug Administration (FDA) is revising previously recommended dosing and warning information for citalopram. The revised recommendations are as follows:

- Although citalopram should be avoided, if possible, in patients with conditions known to have a risk of QT prolongation, electrolyte and/or more frequent ECG monitoring should be done if citalopram is used in these patients.

- Use in patients with congenital long QT syndrome was previously contraindicated; however, those who require treatment with citalopram (ie, no other alternative) may derive benefit from a low dose of citalopram. Therefore, use has been changed to "not recommended" in this patient group.

- In patients >60 years of age, the maximum recommended dose of citalopram is 20 mg/day.

- If a patient is found to have persistent prolongation (>500 msec) of QTc measurements, citalopram should be discontinued.

For more information, refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm297624.htm.

Canadian Dabigatran Etexilate (Pradax®) Product Monograph Updated with New Recommendations March 2012

Boehringer Ingelheim (Canada) LTD, in conjunction with Health Canada, is notifying healthcare professionals of updated labeling for dabigatran etexilate (Pradax®). The updates were prompted by postmarketing reports of serious bleeding associated with use in patients at a high risk of bleeding, elderly patients, or patients with renal impairment.

The following is a summary of the new recommendations:

• Due to the risk for bleeding when used in patient with renal impairment:
• - Renal function should be determined in all patients prior to initiation to exclude use in any patient with severe impairment (Canadian labeling contraindicates use in patients with Clcr <30 mL/minute).
• - During therapy, renal function should be assessed in any situation when a decline in renal function is suspected or likely (eg, hypovolemia, dehydration, concomitant use with medications potentially affecting renal function).
• - If therapy is used in any elderly patient (>75 years of age) or in any patient with moderate renal impairment (Clcr 30-50 mL/minute), assess renal function routinely at a minimum of once per year.
• Use is not recommended in patients with prosthetic heart valves or those with hemodynamically significant rheumatic valvular heart disease since it is unknown whether or not dabigatran provides adequate anticoagulation for these conditions.

Healthcare professionals should be cognizant of the bleeding risk associated with dabigatran therapy and avoid its use in any patient at high risk of bleeding. All patients receiving therapy should be monitored for signs/symptoms of bleeding or anemia. If severe bleeding is suspected, therapy should be discontinued and the source of bleeding investigated.

For additional information, please refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/pradax_hpc-cps-eng.php.

Risk of Muscle Weakness in Patients with Myasthenia Gravis - Updated March 2012

Health Canada is notifying healthcare professionals and patients of an increased risk (rare) of exacerbated muscle weakness and potential need for ventilatory support in patients with myasthenia gravis taking fluoroquinolones. Use of fluoroquinolones is not recommended in patients with myasthenia gravis. Canadian manufacturers have either updated or will be updating their product monographs to include this additional safety information. This information is included as a Boxed Warning in the U.S. and now Canadian product labels for these products.

For additional information, refer to the following websites:

http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_147-eng.php

http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/fluoroquinolone_hpc-cps-eng.php

Association of Domperidone with Serious Cardiac Arrhythmias and Sudden Cardiac Death March 2012

Health Canada is notifying healthcare professionals of recent epidemiologic studies showing that the use of domperidone may be associated with serious ventricular arrhythmias and sudden cardiac death (cardiac arrest). The risk of cardiac adverse effects was highest in patients taking >30 mg of domperidone daily (adjusted OR 11.4; 95% CI: 1.99-65.2) and in those patients over the age of 60 years (adjusted OR: 1.64; 95% CI: 1.31-2.05). Healthcare professionals are advised to:

- Initiate and maintain all patients (including those with Parkinson's disease) on the lowest possible domperidone dose.

- Increase dose based on the risk versus benefit of possible serious cardiac adverse effects.

- Use caution in patients with existing prolongation of cardiac conduction intervals (particularly QTc), patients taking drugs that prolong the QT interval or that inhibit CYP3A4 (use with ketoconazole is contraindicated), and in patients with cardiac disease (ie, congestive heart failure) or significant uncorrected electrolyte disturbances.

Patients should stop taking domperidone and seek medical attention immediately if they experience dizziness, palpitations, seizures, or other signs or symptoms of an abnormal heart rhythm.

For more information, please refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/domperidone_hpc-cps-eng.php

HMG-CoA Reductase Inhibitors and Protease Inhibitors: New Contraindications and Dose Limitations March 2012

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals of updates to the prescribing information regarding use of HMG-CoA reductase inhibitors with protease inhibitors. Use of some of these medications together may increase the risk of myopathy or the more serious rhabdomyolysis, which can damage the kidneys and lead to kidney failure (sometimes fatal). The updates include new contraindications (lovastatin, simvastatin), warnings (atorvastatin), and maximum dose restrictions for specific HMG-CoA reductase inhibitors (atorvastatin, rosuvastatin) when combined with specific protease inhibitors used for the treatment of human immunodeficiency virus (HIV) or hepatitis C virus (HCV).

Lovastatin, simvastatin: Protease inhibitors (including boceprevir and telaprevir) are contraindicated with either lovastatin or simvastatin

Rosuvastatin: With atazanavir ± ritonavir or lopinavir + ritonavir: Rosuvastatin maximum daily dose of 10 mg

Atorvastatin:

With darunavir + ritonavir or fosamprenavir ± ritonavir or saquinavir + ritonavir: Atorvastatin maximum daily dose of 20 mg

With lopinavir + ritonavir: Use lowest daily atorvastatin dose; monitor closely

With nelfinavir: Atorvastatin maximum daily dose of 40 mg

With telaprevir or tipranavir + ritonavir: Avoid concurrent use

Other HMG-CoA reductase inhibitors were reviewed, but did not have adjustments to dosing.

For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm.

HMG-CoA Reductase Inhibitors: Liver Enzyme Monitoring Requirements Removed and Warning Updates February 2012

The U.S. Food and Drug Administration (FDA) has approved important labeling changes for HMG-CoA reductase inhibitors.

Routine monitoring of liver enzymes has been removed from the drug labeling. The incidence of serious liver injury associated with the currently marketed HMG-CoA reductase inhibitors is very low and routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury, but may cause interruptions in therapy for patients with isolated increases in ALT levels, placing them at risk for cardiovascular events. Baseline liver function tests are still recommended prior to initiation of HMG-CoA Reductase Inhibitor therapy.

Based upon review of postmarketing events through the AERS database and clinical trials, updated details regarding cognitive adverse events and glycemic regulation have been added to the labels. Although rare, reversible memory impairment (including confusion, forgetfulness, amnesia, and memory loss) can occur with HMG-CoA reductase inhibitors. These cognitive symptoms have been reported at variable times during therapy (1 day to years after initiation) and are reversible with discontinuation; resolution usually occurs within ~3 weeks. Cases have not been associated with fixed or progressive dementia; nor have they been associated with age, specific HMG CoA reductase inhibitor, dose or concomitant medication use.

Additionally, HMG-CoA reductase inhibitors have been associated with increases in glycosylated hemoglobin and fasting plasma glucose. Subgroup analyses of randomized, controlled, clinical trials, an observational study, and meta-analyses have observed an association between new onset diabetes and the use of an HMG CoA reductase inhibitor.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm.

Fatality Reported Within 24 Hours of Initial Administration of Fingolimod (Gilenya®) [December 2011] - Updated February 2012

Health Canada has issued notice to Canadian healthcare providers regarding an ongoing safety review of fingolimod (Gilenya®) following reports of serious adverse events including 11 deaths worldwide. Four of the deaths involved serious heart-related events (3 heart attacks, 1 heart rhythm disturbance) and 7 remain unexplained. Previously, the U.S. Food and Drug Administration (FDA), had issued a similar safety communication in regards to the reported death of a patient with multiple sclerosis within 24 hours of receiving an initial fingolimod dose. In this case, the patient had been monitored for 6 hours (event-free) after receiving the dose and had also received metoprolol and amlodipine. Neither the FDA nor Health Canada has concluded a causal relationship at this time, and are continuing to investigate the findings. Further information will be communicated by the respective regulatory agencies as it becomes available.

Healthcare providers are being advised to:

- Prescribe fingolimod according to recommendations within the manufacturer labeling

- Obtain a baseline ECG (if not recently done) prior to initiating therapy in patients at increased risk for bradyarrhythmias

- Carefully monitor during therapy initiation; use caution in patients with underlying cardiovascular disease, low heart rate, history of syncope, or receiving concurrent drug therapy that may increase the risk for bradycardia

- Monitor for signs/symptoms of bradycardia for 6 hours after the initial dose; follow the same procedure in patients resuming therapy after treatment interruption of >2 weeks

- Ensure patient understands signs/symptoms of bradycardia and when to seek care

- Report adverse events involving fingolimod to the FDA MedWatch program

Patients receiving fingolimod should be advised not to discontinue treatment without discussing with their healthcare provider.

Further information may be found at the following websites:

U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm284355.htm

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2012/2012_28-eng.php

Doxil® Shortage: Availability of Product Alternative February 2012

In response to the ongoing Doxil® (doxorubicin liposomal) shortage, the U.S. Food and Drug Administration (FDA) is allowing for the temporary importation and distribution of Sun Pharma's doxorubicin (liposomal) products, Lipodox™ and Lipodox 50™ within the U.S. during the critical Doxil® shortage. Lipodox™ and Lipodox 50™ are available as a 20 mg/10 mL and 50 mg/25 mL single use vial (same concentrations as in the U.S.), respectively. Product may be obtained by calling 888-835-2237. Refer to the Lipodox™ and Lipodox 50™ prescribing information for additional information.

Information on the FDA's decision is available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm292721.htm.

Possible Increased Risk of Clostridium Difficile-Associated Diarrhea (CDAD) with Proton Pump Inhibitor Use: Update February 2012

The U.S. Food and Drug Administration (FDA) and Health Canada have announced that proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD). The FDA reviewed reports of PPI-associated CDAD from the FDA Adverse Event Reporting System and from the medical literature. The association of PPI use and CDAD varied among studies, ranging from a risk of 1.4-2.75 higher in those exposed to a PPI compared to those without PPI exposure. Many of the cases reported involved patients who were elderly, had chronic and/or underlying conditions, or were taking broad-spectrum antibiotics - all of which could have increased the risk of CDAD. Health Canada has also been assessing study data on an ongoing basis. In spite of potential predisposition to CDAD, or other limitations to study design, association with PPI use could not be ruled out and patients with these risk factors may have more serious outcomes from CDAD associated with PPI use. The FDA is working with manufacturers to include information regarding the increased risk of CDAD with use of PPIs in their prescribing information and is also evaluating the risk of CDAD in users of histamine H2 receptor blockers. Health Canada also notes that the possible association between PPIs and CDAD is noted in their PPI product labeling.

The following advice is provided by the FDA and Health Canada to assist healthcare professionals in the management of patients receiving PPIs:

- Consider a diagnosis of CDAD in PPI users that have persistent diarrhea.

- Advise patients to get immediate care from a healthcare professional if they experience persistent watery stools, bloody diarrhea, abdominal pain or tenderness, nausea, loss of appetite, or fever while taking PPIs.

- Use the lowest dose and shortest duration of PPI therapy appropriate for the condition being treated.

For more information, refer to the following websites:

U.S.:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm290838.htm

http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2012/2012_23-eng.php

Cardiac Risks Associated with Vandetanib February 2012

Health Canada, in conjunction with AstraZeneca Canada, has issued notice to Canadian healthcare providers regarding serious cardiac adverse events associated with vandetanib (Caprelsa®) use. Vandetanib may prolong the QT interval; torsade de pointes and sudden death have been reported. Both the U.S. and Canadian manufacturer labels include boxed warnings regarding these serious adverse events. Use of vandetanib for the treatment of medullary thyroid cancer should take into consideration these risks with the potential benefits of use. Vandetanib is only available in the U.S. and Canada under restricted distribution programs.

For additional information, refer to the following Health Canada website at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/index-eng.php.

Important Drug Interaction Between Victrelis™ (Boceprevir) and Ritonavir-Boosted HIV Protease Inhibitor Regimens February 2012

The U.S. Food and Drug Administration (FDA) and Merck and Company are alerting patients and healthcare professionals of an important drug interaction between the hepatitis C virus (HCV) protease inhibitor Victrelis&tade; (boceprevir) and certain ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors (PIs) (atazanavir, lopinavir, darunavir). When using boceprevir in combination with ritonavir and one of the three HIV PIs, the drug concentrations of both regimens may be decreased and patients may be at risk for HCV and/or HIV virologic rebound. The safety and efficacy of boceprevir in patients coinfected with HIV and HCV have not been established and use is not recommended by the manufacturer.

In a pharmacokinetic study in healthy volunteers, concomitant administration of boceprevir and ritonavir in combination with atazanavir, darunavir, or with lopinavir/ritonavir (Kaletra®) resulted in reduced exposures of both the HIV medicines and boceprevir. Boceprevir with ritonavir reduced the mean trough concentrations of concomitant atazanavir, darunavir, or lopinavir/ritonavir by 43% to 59 %, the AUC by 34% to 44 %, and the Cmax by 25% to 36%. The AUC of boceprevir with ritonavir-boosted atazanavir was unchanged; however, boceprevir AUC was decreased by 45% with lopinavir/ritonavir and by 32% with ritonavir-boosted darunavir.

The FDA and the manufacturer are advising patients to speak with their healthcare provider as soon as possible if they have any concerns and should not stop taking any of their medications. Patients infected with both HIV and HCV who are on boceprevir concurrently with a ritonavir-boosted PI should be monitored closely for virologic rebound. The FDA will be updating the Victrelis&tade; prescribing information to include more information regarding these drug interactions. The manufacturer has also issued a Dear Healthcare Professional letter to help communicate the interaction study findings.

For additional information, refer to the following websites:

http://www.fda.gov/Drugs/DrugSafety/ucm291119.htm

http://www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdfhttp://www.fda.gov/Drugs/DrugSafety/ucm290510.htm

Possible Increased Risk of Clostridium Difficile?Associated Diarrhea (CDAD) with Proton Pump Inhibitor Use February 2012

The U.S. Food and Drug Administration (FDA) has announced that proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridium difficile?associated diarrhea (CDAD). The FDA reviewed reports of PPI-associated CDAD from the FDA Adverse Event Reporting System and from the medical literature. The association of PPI use and CDAD varied among studies, ranging from a risk of 1.4-2.75 higher in those exposed to a PPI compared to those without PPI exposure. Many of the cases reported involved patients who were elderly, had chronic and/or underlying conditions, or were taking broad-spectrum antibiotics - all of which could have increased the risk of CDAD. In spite of potential predisposition to CDAD, association with PPI use could not be ruled out and patients with these risk factors may have more serious outcomes from CDAD associated with PPI use. The FDA is working with manufacturers to include information regarding the increased risk of CDAD with use of PPIs in their prescribing information and is also evaluating the risk of CDAD in users of histamine H2 receptor blockers.

The following advice is provided by the FDA to assist healthcare professionals in the management of patients receiving PPIs:

- Consider a diagnosis of CDAD in PPI users that have persistent diarrhea.

- Advise patients to get immediate care from a healthcare professional if they experience persistent watery stools, abdominal pain, and fever while taking PPIs.

- Use the lowest dose and shortest duration of PPI therapy appropriate for the condition being treated.

For more information, refer to the following websites:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm290838.htm

http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm

Decreased Clinical Cure Rates and Increased Mortality in Ventilator-Associated Pneumonia (VAP) January 2012

Janssen Inc., in conjunction with Health Canada, is alerting healthcare professionals regarding the premature termination, due to safety concerns identified during interim analyses, of a noninferiority study investigating the use of a fixed 7-day course of doripenem (1 g every 8 hours administered over 4 hours) versus a fixed 10-day course of imipenem and cilastatin (1 g every 8 hours administered over 1 hour) in adult patients with ventilator-associated pneumonia (VAP). Patients randomized to treatment with doripenem showed a higher 28-day all-cause mortality rate (21.5 % vs 14.8%) and a lower clinical cure rate (45.6% vs 56.8%) when compared to patients treated with imipenem and cilastatin. In Canada, doripenem is currently approved for the treatment of healthcare associated pneumonia (including VAP) at doses less than those used in this clinical trial (500 mg every 8 hours administered over 1 or 4 hours for 7-14 days). The Canadian product monograph will be updated to reflect the results from this Phase 3 VAP trial.

For more information, please refer to

Fatalities Associated with Intrathecal Bortezomib Administration January 2012

Janssen Inc, in conjunction with Health Canada, is alerting healthcare professionals of deaths associated with inadvertent intrathecal administration of bortezomib. Three cases of accidental intrathecal administration resulting in death have been reported; all three patients were scheduled to receive intrathecal chemotherapy at the same time as I.V. bortezomib. In Canada, bortezomib is approved for I.V. administration only. Clinicians are encouraged to schedule any intrathecal chemotherapy at a different time than the scheduled bortezomib therapy. Additional recommendations include the use of different connectors for intravenous and intrathecal medications and clear labeling with the product name and intended route of administration.

In the U.S., bortezomib is approved for I.V. or SubQ administration only; intrathecal administration of bortezomib is contraindicated.

For additional information, please refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/velcade_hpc-cps-eng.php.

Citalopram: Reports of Dosage-Related QT-Interval Prolongation and Subsequent Arrhythmia Prompt Reduction in Maximum Recommended Dosage - Updated January 2012

The U.S. Food and Drug Administration (FDA) and Health Canada have announced that citalopram doses >40 mg/day should not be used due to dosage-related prolongation of the QT interval and subsequent risk of cardiac arrhythmia, including torsade de pointes. Dosages >40 mg/day have not been shown to be more effective in treating depression during clinical trials. Patients with heart failure, bradyarrhythmia, or those receiving concomitant medications known to prolong the QT interval should be considered for more frequent ECG monitoring due to the heightened risk of developing torsade de pointes. Patients with a predisposition for hypokalemia or hypomagnesemia are also at increased risk of torsade de pointes. Serum potassium and magnesium should be normalized prior to citalopram administration and monitored as clinically appropriate. Patients with hepatic impairment, elderly patients, poor CYP2C19 metabolizers, or patients taking cimetidine (or other CYP2C19 inhibitors) should not receive citalopram doses >20 mg/day due to the potential for increased citalopram serum concentrations and increased risk of QT-interval prolongation and subsequent torsade de pointes. Citalopram should not be administered to patients with congenital QT-prolongation syndrome.

Patients should be instructed to continue current doses of citalopram and consult their healthcare provider if taking doses >40 mg/day. Patients who experience episodes of irregular heartbeat, shortness of breath, dizziness, or fainting while taking citalopram should seek immediate medical care.

For more information:

U.S. healthcare professionals:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm269481.htm

http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm#data

Canadian healthcare professionals:

http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/celexa_2_hpc-cps-eng.php

Health Canada Issues Update Regarding the Use of Aliskiren (Rasilez®) Following Discontinuation of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints (ALTITUDE) Trial January 2012

Novartis Canada, in conjunction with Health Canada, is alerting healthcare providers regarding updated safety information following further review of an interim analysis of the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints) study. This worldwide study of 8606 patients with type 2 diabetes and renal impairment intended to evaluate if aliskiren-containing products, when given in addition to conventional therapies (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), could reduce the risk of cardiovascular and renal events. The manufacturer terminated the study upon review of interim data and findings that use of aliskiren was of unlikely benefit and that concomitant use of aliskiren with ACE inhibitors or ARBs was associated with an increased risk of nonfatal stroke, hyperkalemia, hypotension, and renal complications. Concomitant use of aliskiren-containing products with ACE inhibitors or ARBs in diabetic patients is now contraindicated in Canada; the manufacturer's labeling will be updated in 2012.

Healthcare providers should discontinue aliskiren-containing products in diabetic patients also receiving an ACE inhibitor or ARB and should consider alternative antihypertensive treatment if appropriate. Diabetic patients receiving an ACE inhibitor or ARB should not be started on aliskiren-containing products. Patients receiving aliskiren as monotherapy or in combination with other antihypertensives should be advised not to discontinue treatment without discussing with their healthcare provider.

Further information may be found at:

http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/rasilez_hpc-cps-eng.php

http://novartis.ca/

Risk Factor Identified for Progressive Multifocal Leukoencephalopathy Associated with Natalizumab January 2012

The U.S. Food and Drug Administration (FDA) is alerting clinicians and the public to a newly identified risk factor for the development of progressive multifocal leukoencephalopathy (PML) associated with natalizumab (Tysabri®). A positive test result for anti-JC virus (JCV) antibodies is a risk factor for the development of PML. Additional risk factors include a longer duration of treatment (especially >2 years) and a history of immunosuppressant medication use (eg, mitoxantrone, azathioprine, methotrexate, cyclophosphamide or mycophenolate mofetil). Patients demonstrating all three risk factors have an estimated PML risk of 11/1000. As of January 4, 2012, the FDA is aware of 201 confirmed worldwide cases of PML among ~96,582 patients related to the use of natalizumab.

Anti-JCV antibody status is determined by performing an anti-JCV antibody detection test (eg, Stratify JCV Antibody ELISA test); a positive result indicates prior exposure to JCV. Consider testing prior to natalizumab treatment (or during treatment if status is unknown). When assessing the risk for PML using anti-JCV antibody status, a positive test at any time is considered a risk factor regardless of prior or future test results. The risks and benefits of continued natalizumab treatment should be weighed in a patient with a history of a positive anti-JCV antibody test. Patients with a negative result may still be at risk for PML as new JCV infection or false negative result are possible; periodic retesting may be warranted.

Natalizumab treatment should be discontinued immediately at the first sign or symptom of PML (eg, progressive weakness on one side of the body, limb clumsiness, visual disturbance, changes in thinking, memory, personality or orientation). Patients should be counseled to contact their prescriber if symptoms occur. Adverse events should be reported to the FDA through the MedWatch program.

For additional information refer to http://www.fda.gov/Drugs/DrugSafety/ucm288186.htm#data.

New Cases of Progressive Multifocal Leukoencephalopathy (PML) and Pulmonary Toxicity Associated with Brentuximab Vedotin (Adcetris™) January 2012

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of labeling changes (including a new Boxed Warning and contraindication) for brentuximab vedotin (Adcetris™) based on the emergence of additional cases of PML associated with the use of brentuximab, and a higher incidence of pulmonary toxicity when brentuximab is used in combination with bleomycin.

The additional cases of PML were identified in patients who had received 3-8 cycles of brentuximab and had also received prior multiple chemotherapy and radiation, and were determined positive for the JC virus. At the time of reporting, these additional cases were not fatal, but the patients' conditions were deteriorating. Healthcare providers should advise patients to report any signs of possible PML which can occur weeks to months after initiation of therapy. These symptoms can include changes in mood, memory, cognition, motor incoordination and/or weakness, speech and/or visual disturbances. Brentuximab should be held with symptoms suggestive of PML, and immediately discontinued upon confirmation of PML diagnosis.

In a separate Hodgkin's lymphoma trial comparing brentuximab added to ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) with brentuximab added to AVD (doxorubicin, vinblastine and dacarbazine), the occurrence of pulmonary toxicity was 40% in the brentuximab/ABVD (with bleomycin) group compared to a literature-based frequency of up to 25% for other bleomycin-containing regimens. No cases of pulmonary toxicity have been documented with brentuximab in combination with AVD. Pulmonary toxicities reported with brentuximab in combination with ABVD consisted of cough, dyspnea, and pulmonary infiltration. Brentuximab is now contraindicated with concurrent use of bleomycin due to the risk for pulmonary injury.

Additional information can be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm287710.htm?source=govdelivery.

Confusion Between Durezol® (difluprednate ophthalmic emulsion) and the Topical Wart Remover Durasal™ (salicylic acid, 26%)December 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of the potential confusion between the FDA-approved ophthalmic corticosteroid emulsion Durezol® (difluprednate) and the unapproved topical wart remover Durasal™ (salicylic acid, 26%). Serious injury has resulted from the inadvertent administration of salicylic acid in the eye and several cases of near-miss events have been reported due to product name similarity. Healthcare providers should be diligent in specifying the product necessary and pharmacists should be vigilant when filling prescriptions for ophthalmic Durezol® to avoid potential confusion.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm285235.htm.

Fatality Reported Within 24 Hours of Initial Administration of Fingolimod (Gilenya®)December 2011

The U.S. Food and Drug Administration (FDA), has issued a safety communication in regards to the reported death of a patient with multiple sclerosis within 24 hours of receiving an initial fingolimod dose. In this case, the patient had been monitored for 6 hours (event-free) after receiving the dose and had also received metoprolol and amlodipine. The FDA has not concluded a causal relationship at this time and is continuing to investigate the case; further information will be communicated by the FDA as it becomes available.

Healthcare providers are being advised to:

- Prescribe fingolimod according to recommendations within the manufacturer labeling

- Obtain a baseline ECG (if not recently done) prior to initiating therapy in patients at increased risk for bradyarrhythmias

- Carefully monitor during therapy initiation; use caution in patients with underlying cardiovascular disease, low heart rate, history of syncope, or receiving concurrent drug therapy that may increase the risk for bradycardia

- Monitor for signs/symptoms of bradycardia for 6 hours after the initial dose; follow the same procedure in patients resuming therapy after treatment interruption of >2 weeks

- Ensure patient understands signs/symptoms of bradycardia and when to seek care

- Report adverse events involving fingolimod to the FDA MedWatch program

Patients receiving fingolimod should be advised not to discontinue treatment without discussing with their healthcare provider.

Further information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm284355.htm.

Bisphosphonates: Health Canada Issues Update Regarding Atypical Femur Fractures December 2011

Health Canada has issued an update to Canadian healthcare professionals in regards to its review of bisphosphonate drugs and the risk for atypical femur fractures. The regulatory agency has determined that bisphosphonate use is associated with a slightly increased risk for these uncommon fractures, but considers the benefit of therapy to outweigh the extremely small risk. The Canadian product monographs for bisphosphonates are being updated accordingly.

Canadian healthcare professionals are being reminded to be aware of this possible risk for fracture and to evaluate and rule out femur fracture in patients reporting new hip, thigh, or groin pain. Patients receiving bisphosphonate therapy should not discontinue therapy without consulting a healthcare professional and should be encouraged to report new or unusual hip, thigh, or groin pain.

Further information may be found at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_172-eng.php.

Multaq® (Dronedarone) and Permanent Atrial Fibrillation (U.S. information) December 2011

The U.S. Food and Drug Administration (FDA) has completed its safety review of data from the PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) trial and the ATHENA trial (the trial supporting approval in nonpermanent atrial fibrillation [AF]). The FDA has determined that dronedarone increases the risk of serious cardiovascular events (death, stroke and heart failure) in patients with permanent AF.

The PALLAS trial, involving patients with permanent AF, was terminated early due to an increased incidence of cardiovascular events in dronedarone-treated patients compared to patients receiving placebo. Final results for the PALLAS trial revealed a hazard ratio of 1.94 for total deaths (95% CI: 0.99-3.79), a hazard ratio of 3.26 for death from arrhythmia or sudden death (95% CI: 1.06-10), a hazard ratio of 2.32 for stroke (95% CI: 1.11-4.88), and a hazard ratio of 1.81 for hospitalization for heart failure (95% CI: 1.10-2.99). The ATHENA trial, involving patients with nonpermanent AF, was also reassessed to determine if negative cardiovascular outcomes were increased. The final analysis of the ATHENA trial did not reveal an increased risk of cardiovascular death, stroke or heart failure in these patients.

The manufacturer's labeling for Multaq® has been revised to include the following recommendations:

- Dronedarone should not be used in patients with AF who cannot or will not be converted into normal sinus rhythm. Patients with permanent AF treated with dronedarone have double the risk of cardiovascular death, stroke, and heart failure.

- ECG monitoring should be performed at least once every 3 months. Dronedarone should be discontinued if the patient is in AF or, if clinically indicated, the patient should be cardioverted.

- Dronedarone is indicated to decrease the risk of hospitalization for AF in patients in sinus rhythm with a history of paroxysmal or persistent AF (ie, nonpermanent AF).

- Patients receiving dronedarone should receive appropriate antithrombotic therapy.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm283933.htm.

SSRI Use During Pregnancy and Potential Risk of Persistent Pulmonary Hypertension of the Newborn (PPHN) December 2011

The U.S. Food and Drug Administration (FDA) has issued updated safety information regarding selective serotonin reuptake inhibitor (SSRI) use during pregnancy and the potential risk of persistent pulmonary hypertension of the newborn (PPHN). The FDA has reviewed additional studies evaluating this risk which have shown conflicting results. The FDA has concluded that based on available data, it is unclear whether SSRI use during pregnancy causes PPHN. Updates to product labeling, which will include the additional data and conflicting results, are forthcoming.

The FDA initially released communication regarding this potential risk in July 2006 following the results of a single study which found a sixfold increase of PPHN in neonates born to mothers who received an SSRI at >20 weeks gestation. As a result of the finding, product labeling was updated to include the risk of PPHN and SSRI use in late pregnancy. However, since 2006, additional studies have been published. To date, 2 studies (including the study from 2006) have suggested an increased risk for PPHN due to SSRI use during pregnancy, while 3 studies have not found an association.

The FDA is offering the following recommendations for healthcare professionals:

- At present, healthcare professionals should not alter their current clinical practice of treating depression during pregnancy.

- Healthcare professionals and patients must weigh the small potential risk of PPHN which may be associated with SSRI use during pregnancy against the substantial risks associated with either no treatment or undertreating depression during pregnancy.

- Untreated depression during pregnancy may result in poor birth outcomes (eg, low birth weight, preterm delivery, poor prenatal care).

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm283375.htm.

Dose Limitation Revised for Simvastatin (Zocor®) When Administered Concomitantly with Amiodarone December 2011

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals of revised dose recommendations regarding the concomitant use of simvastatin and amiodarone. The FDA is now recommending a maximum simvastatin dose of 20 mg/day in patients receiving concomitant amiodarone.

The current recommendation represents a change from a previous recommendation (communicated by the FDA in June 2011) to limit the dose of simvastatin to 10 mg when coadministered with amiodarone. This previous recommendation was erroneous as there were no pharmacokinetic or clinical trial data to support that dose limitation.

Manufacturer's labeling for Zocor® and Vytorin® (ezetimibe and simvastatin) was updated in October 2011 to reflect the most current recommendation. Of note, Simcor® (niacin and simvastatin) prescribing information, dated June 2011, lists coadministration with amiodarone as a contraindication.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm283137.htm.

Safety Review of Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) December 2011

The U.S. Food and Drug Administration (FDA) issued updated information regarding the safety of medications for attention-deficit/hyperactivity disorder (ADHD) in adults. The communication was prompted by the results of two epidemiologic studies which failed to show an increased risk of serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), and stroke, in adults who received certain medications for ADHD.

The retrospective, population-based cohort studies involved 443,198 adults (aged 25-64 years), of which 150,359 received certain ADHD medications and were matched to 292,839 nonusers (1 user to 2 nonusers). Exposure was based on electronic pharmacy records of filled prescriptions at various study sites. Current ADHD use was a median of 0.33 years and follow-up was a median of 1.3 years per person. The results found no evidence of an increased risk of MI, SCD, or stroke associated with the use of ADHD medications. Specifically, the adjusted rate ratio (RR) of serious cardiovascular events for current use compared with nonuse was 0.83 (95% CI: 0.72-0.96) (Habel, 2011).

Previously, in November 2011, the FDA communicated safety information following results of a study in children and young adults exposed to certain ADHD medications which also failed to show an association of adverse cardiovascular events (SCD, MI, and stroke) and ADHD use in that population. That retrospective cohort study included >1 million patients (aged 2-24 years) and >2 million person-years of follow-up. When compared to patients who did not receive ADHD medications, neither current (adjusted hazard ratio: 0.75; 95% CI: 0.31-1.85) or former (adjusted hazard ratio: 1.03; 95% CI: 0.57-1.89) users of ADHD medications experienced an increased rate of serious cardiovascular events (Cooper, 2011).

ADHD medications involved in these safety reviews were atomoxetine, dexmethylphenidate, dextroamphetamine, dextroamphetamine and amphetamine, lisdexamfetamine, methamphetamine, methylphenidate, and pemoline (no longer marketed).

Product labeling should continue to be followed. In general, stimulant medications and atomoxetine should not be used in patients with serious heart problems or in patients who should avoid increased blood pressure or heart rate; monitor patients for blood pressure or heart rate changes.

For more information, please refer to the following websites:

December, 2011 (adult information): http://www.fda.gov/Drugs/DrugSafety/ucm279858.htm

November, 2011 (children and young adult information): http://www.fda.gov/Drugs/DrugSafety/ucm277770.htm

DEA Places Carisoprodol into Schedule IV Category December 2011

The Drug Enforcement Administration (DEA) has placed carisoprodol, and its salts, isomers, or salts of isomers, into a Schedule IV category of the Federal Controlled Substance Act. This decision will become effective January 11, 2012.

Of note, several U.S. states have previously treated carisoprodol as a controlled substance according to their state laws.

For more information on the final ruling, please refer to http://www.gpo.gov/fdsys/pkg/FR-2011-12-12/pdf/2011-31542.pdf.

Multaq® (Dronedarone) and Permanent Atrial Fibrillation - Updated December 2011

Sanofi-aventis Canada, in conjunction with Health Canada, has notified healthcare professionals concerning updates made to the dronedarone Canadian product monograph. Revisions are due to an increased risk of death, stroke, and hospitalization due to heart failure in a trial evaluating dronedarone (compared to placebo) in patients with permanent atrial fibrillation. The Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) trial was halted early after negative cardiovascular outcomes were noted in preliminary results. There are also postmarketing reports of increased pulmonary injury (including interstitial lung disease and pulmonary fibrosis) associated with dronedarone use.

The following changes have been made to the dronedarone Canadian product monograph:

- Dronedarone is now indicated for the treatment of paroxysmal or persistent atrial fibrillation in patients in sinus rhythm or those in whom cardioversion is intended.

- Dronedarone is contraindicated in patients with permanent atrial fibrillation; dronedarone therapy should be discontinued in patients who develop permanent atrial fibrillation during therapy. It is also contraindicated in patients with a history of, or current heart failure (of any NYHA functional class), left ventricular systolic dysfunction, select conduction abnormalities or a history of liver or lung dysfunction associated with amiodarone use.

- Cautions have been added for patients who develop or have worsening heart failure during therapy, those who have preexisting coronary artery disease, and in the elderly with multiple comorbidities.

- Monitoring recommendations now include an ECG at least every 6 months and periodic renal and pulmonary function assessments.

The updated Canadian labeling should be consulted prior to prescribing and/or dispensing dronedarone.

For further information, please refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/multaq_3_hpc-cps-eng.php.

Avastin®: Rate of Ovarian Failure Increased in Premenopausal Women November 2011

Hoffman-La Roche Limited, in conjunction with Health Canada, has issued notice to Canadian healthcare professionals regarding an increased incidence of ovarian failure in premenopausal women treated with bevacizumab (Avastin®). In a phase III study of colon cancer patients, the incidence of ovarian failure was 39% in premenopausal patients receiving bevacizumab concomitantly with chemotherapy versus ~3% in those receiving chemotherapy alone. Ovarian function recovered in ~86% of affected women following discontinuation of bevacizumab. Chemotherapy is a risk factor for ovarian failure; however, when bevacizumab is used as an adjuvant treatment, the risk is higher. Avastin® Canadian product monograph has been updated to include this new important safety information.

Further information may be found at http:// hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/avastin_6_hpc-cps-eng.php.

Avastin®: FDA Removes Breast Cancer Indication from the Product Labeling Updated - November 2011

On November 18, 2011, the U.S. Food and Drug Administration (FDA) announced that it is removing the metastatic breast cancer indication from bevacizumab (Avastin®) labeling, citing a lack of demonstrated safety and efficacy in metastatic breast cancer. After reviewing data from several clinical trials, the FDA determined that use of bevacizumab in patients with metastatic breast cancer did not prolong overall survival, quality of life, or provide a sufficient benefit in slowing disease progression to outweigh significant risks associated with treatment (eg, severe hypertension, hemorrhage, myocardial infarction, heart failure, GI perforation).

Updates to the product labeling (for the removal of the metastatic breast cancer indication) are forthcoming.

Bevacizumab (Avastin®) continues to be an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).

Information from the FDA regarding this issue may be found at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280536.htm.

Avastin®: Rate of Ovarian Failure Increased in Premenopausal Women - November 2011

Hoffman-La Roche Limited, in conjunction with Health Canada, has issued notice to Canadian healthcare professionals regarding an increased incidence of ovarian failure in premenopausal women treated with bevacizumab (Avastin®). In a phase III study of colon cancer patients, the incidence of ovarian failure was 39% in premenopausal patients receiving bevacizumab concomitantly with chemotherapy versus ~3% in those receiving chemotherapy alone. Ovarian function recovered in ~86% of affected women following discontinuation of bevacizumab. Chemotherapy is a risk factor for ovarian failure; however, when bevacizumab is used as an adjuvant treatment, the risk is higher. Avastin® Canadian product monograph has been updated to include this new important safety information.

Further information may be found at http:// hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/avastin_6_hpc-cps-eng.php.

Labeling Updated Due to Lack of Morbidity and Mortality Benefit in Patients with Type 2 Diabetes Mellitus - November 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals (HCPs) about labeling changes made to fenofibric acid (Trilipix®) after reviewing data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial. Specifically, the updated labeling includes information on the lack of a demonstrable benefit in reducing the risk of a heart attack, stroke, or cardiovascular death when combined with statin therapy in patients with type 2 diabetes mellitus. Additionally, in a subgroup analysis, an increase in cardiovascular events was seen in women. The clinical significance of this finding is unclear. Of note, the dose of fenofibrate used in the ACCORD trial (160 mg) was equivalent to 135 mg of fenofibric acid. The FDA has chosen to apply this labeling change to Trilipix®, which is the only fibric acid derivative approved for concurrent use with a statin; however, these findings would also apply to fenofibrate. Previously, labeling changes were also made to both fenofibrate and fenofibric acid regarding the lack of a cardiovascular benefit following review of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. In summary, these two clinical trials have concluded that neither fenofibrate monotherapy nor the addition of fenofibrate to simvastatin reduce cardiovascular disease morbidity and mortality in patients with type 2 diabetes. The FDA is requiring the manufacturer of Trilipix® to conduct a clinical trial to determine if there is a benefit of combined therapy with a statin in patients at high risk of cardiovascular disease.

HCPs should weigh the benefits and risks of fenofibric acid or fenofibrate when considering prescribing this medication. Patients on fenofibric acid or fenofibrate should continue therapy and discuss risks, benefits, and any additional concerns with a HCP.

Further information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm279185.htm.

Storage and Handling Alert for Pradaxa®, Updated - November 2011

The prescribing information of Pradaxa® has been updated by the manufacturer, Boehringer Ingelheim, to allow storage of opened bottles for up to 4 months, when properly stored. Previously, opened bottles had to be used within 30 days. Dabigatran capsules should still be stored and dispensed in the original manufacturer's bottle or blister pack until administration to avoid loss of potency and degradation due to moisture exposure.

Dispensing in pharmacy bottles other than the original container, storage in a pill organizer, or repackaging into unit dose form are not recommended. Patients should be instructed to store in the original manufacturer's packaging away from moisture and excessive heat or cold and to only have 1 bottle open at any given time. Bottles should be closed immediately after opening and dated with an expiration date 4 months after initial opening.

Alternatively, pharmacies may supply patients with blister packs of dabigatran to circumvent this problem with instructions not to puncture or remove from blister pack until time of administration.

For additional information, please refer to the updated prescribing information available at http://www.pradaxa.com..

Potential for Patient Harm Associated with Brand Name Confusion - November 2011

Health Canada is notifying healthcare professionals (HCPs) and patients of the potential for patient harm associated with brand name confusion between Pradax™ (dabigatran etexilate) and Plavix® (clopidogrel) in verbal and written forms. Five cases of wrong medication error, including 1 case of patient harm, have been reported in Canada since January of 2011. Administration of dabigatran instead of clopidogrel, or vice versa, may result in increased risk of bleeding or thromboembolic events.

Healthcare professionals are encouraged to refer to these medications by generic nomenclature (in addition to or in place of the brand name). Additionally, HCPs should spell the medication name for verbal medication orders. Medication errors associated with brand name confusion between Pradax™ and Plavix® or serious/unexpected adverse reactions should be reported to the manufacturers or Health Canada.

Further information may be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/plavix_2_hpc-cps-eng.php.

Risk of Muscle Weakness in Patients with Myasthenia Gravis

Health Canada is notifying healthcare professionals and patients of an increased risk (rare) of muscle weakness in patients with myasthenia gravis when taking fluoroquinolones. The Canadian manufacturers will be updating the prescribing information for these products to include this additional safety information. This information is already included as a Boxed Warning in the U.S. prescribing information of these products.

For additional information, refer to http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_147-eng.php.

Safety Review of Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) - November 2011

The U.S. Food and Drug Administration (FDA) is updating the public regarding the safety of medications for attention-deficit/hyperactivity disorder (ADHD) in children and young adults. The results from a recently completed study failed to show an association between certain medications for ADHD and adverse cardiovascular events, which included sudden cardiac death, acute myocardial infarction, and stroke. This retrospective cohort study included >1 million patients (aged 2-24 years) and >2 million person-years of follow-up. When compared to patients who did not receive ADHD medications, neither current (adjusted hazard ratio: 0.75; 95% CI: 0.31-1.85) or former (adjusted hazard ratio: 1.03; 95% CI: 0.57-1.89) users of ADHD medications experienced an increased rate of serious cardiovascular events (Cooper, 2011). Medications included in the safety review were atomoxetine, dexmethylphenidate, dextroamphetamine, dextroamphetamine and amphetamine, lisdexamfetamine, methamphetamine, methylphenidate, and pemoline (no longer marketed). Results from studies involving adult patients aged 25-64 years exposed to ADHD medications are forthcoming.

Product labeling should continue to be followed. In general, stimulant medications and atomoxetine should not be used in patients with serious heart problems or in patients who should avoid increased blood pressure or heart rate; monitor patients for blood pressure or heart rate changes.

For more information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm277770.htm.

Extension of Expiration Dating - October 2011

Pfizer, Inc has announced that the expiration date of one lot of antivenin, Lot Number 4030026 (formerly manufactured by Wyeth Pharmaceuticals), has been extended to October 31, 2012; institutions should retain any remaining inventory of Lot No. 4030026. Clinicians should note that due to supply concerns, Pfizer, Inc supplies product only to direct customers on a replacement or emergency basis. To obtain antivenin, Pfizer, Inc may be reached at 800-666-7248; alternatively, clinicians may contact their local Poison Control Center at 800-222-1222 for assistance in locating antivenin. In the event licensed antivenin cannot be secured, an investigational imported antivenin may be available under an Investigational New Drug (IND) protocol with informed consent; for more information contact a local Poison Control Center at 800-222-1222 or the U.S. Food and Drug Administration (FDA) at 800-835-4709 (business hours) or 301-796-8240 (nonbusiness hours).

Discontinuation of Botulinum Pentavalent (ABCDE) Toxoid Vaccine - October 2011

Effective November 30, 2011, botulinum pentavalent (ABCDE) toxoid vaccine will no longer be provided by the CDC for vaccination of workers at risk for occupational exposure to botulinum. The vaccine has been provided under an Investigational New Drug (IND) application from the CDC since 1965. For workers who have already begun the primary series, the vaccine will continue to be available under the IND application until May 31, 2012. Although no alternate vaccine is currently available in the U.S., a replacement vaccine is under development by the Department of Defense Chemical Biological Medical Systems Joint Project Management Office.

For additional information, refer to http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6042a3.htm?s_cid=mm6042a3_w

Drospirenone-Containing Oral Contraceptives: Potential Increased Risk of Blood Clots; Update - October 2011

The FDA has issued updated information concerning the potential for an increased risk of venous thromboembolism (VTE) in women using drospirenone-containing oral contraceptives. The FDA has reviewed the preliminary results of a large FDA-funded epidemiologic study designed to evaluate the association of blood clots with various hormonal contraceptive products. The preliminary results have indicated an ~1.5-fold increase in VTE risk in patients receiving drospirenone-containing contraceptives compared to patients receiving other hormonal contraceptives. The FDA has still not come to a conclusion, but has continued concern with this potential increased VTE risk.

In addition to the FDA funded study, the FDA has reviewed a total of six published epidemiologic studies evaluating this risk of VTE, including two published in 2011. These studies have shown conflicting results. Two postmarketing studies did not reveal any differences in women receiving drospirenone-containing contraceptives and products containing levonorgestrel or other progestins. Conversely, a higher VTE risk was observed in women receiving drospirenone-containing contraceptives compared to women receiving levonorgestrel-containing contraceptives in two studies (from 2009), which revealed a 1.5- to 2-fold higher risk, and two studies (published in 2011), which revealed a 2- to 3- fold higher risk. Of note, the studies have only evaluated the risk of contraceptives containing drospirenone and ethinyl estradiol 0.03 mg, and have not included any contraceptives containing drospirenone and ethinyl estradiol 0.02 mg (a lower dose of estrogen).

The FDA will conduct a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, on December 8, 2011, to present and discuss the risks and benefits of drospirenone-containing contraceptives. Information, including a link to the final report, may be found at http://www.fda.gov/Drugs/DrugSafety/ucm277346.htm. Until any further safety information is communicated, healthcare professionals should:

- Follow the recommendations in drospirenone-containing oral contraceptive product labeling

- Discuss known risks and benefits of drospirenone-containing oral contraceptives with patients prior to prescribing

- Educate patients on signs/symptoms of DVT and PE and instruct them to seek medical attention immediately if any symptoms develop

- Report any adverse events involving drospirenone-containing oral contraceptives to the FDA MedWatch Program

For additional information, including a list of drospirenone-containing oral contraceptives, refer to http://www.fda.gov/Drugs/DrugSafety/ucm273021.htm.

Xigris®: Worldwide Market Withdrawal - October 2011

Eli Lilly and Company is withdrawing drotrecogin alfa from worldwide markets following results from the PROWESS-SHOCK study. The study, a large international trial, failed to demonstrate a statistically significant reduction in 28-day all cause mortality with drotrecogin alfa in patients with septic shock. While the market withdrawal process is ongoing, treatment with drotrecogin alfa should be discontinued in patients who are currently receiving it and no new patients should be initiated on treatment. All remaining drotrecogin alfa should be returned to the supplier where the product was purchased. The manufacturer is in the process of notifying clinical trial investigators.

Further information may be found at the following websites:

Manufacturer: http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=617602

FDA: http://www.fda.gov/Drugs/DrugSafety/ucm277114.htm

Health Canada http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_142-eng.php

Zyvox®: Update on Serious CNS Reactions Reported with Specifically Implicated Serotonergic Psychiatric Medications Such as SSRIs and SNRIs - October 2011

Health Canada, in conjunction with Eli Lilly Canada Inc, is alerting healthcare professionals of increased blood pressure (10-20 mm Hg) and increased heart rate (10-20 bmp) associated with atomoxetine. These increases were noted in a recent analysis of multiple trials in children; a similar increase has already been observed in adults. As a result of this analysis, the following recommendations have been made for the atomoxetine Canadian product monograph:

• Use is contraindicated in patients with symptomatic cardiovascular diseases, moderate-to-severe hypertension, or severe cardiovascular disorders in which the condition would be expected to deteriorate with clinically-relevant blood pressure or heart rate increases.
• Atomoxetine should be used cautiously in patients with underlying medical conditions which may be exacerbated with increases in blood pressure or heart rate (eg, hypertension, cardiovascular disease, cerebrovascular disease) and in patients with congenital or acquired long QT syndrome or with a family history of QT prolongation.
• Screen patients for pre-existing or underlying cardiovascular or cerebrovascular conditions prior to treatment initiation and monitor patients during treatment.
• Assess heart rate and blood pressure prior to treatment, following dose increases, and periodically during treatment to detect clinically-relevant increases in heart rate or blood pressure, especially during the first few months of treatment.

For additional information, refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/strattera_2_hpc-cps-eng.php.

Zyvox®: Update on Serious CNS Reactions Reported with Specifically Implicated Serotonergic Psychiatric Medications Such as SSRIs and SNRIs - October 2011

The U.S. Food and Drug Administration (FDA) has acknowledged that drugs used for psychiatric treatment possess differing degrees of pro-serotonergic activity. Therefore, the FDA is not explicitly implicating psychiatric medications outside of the SSRIs and SNRIs at this time, as there appears to be insufficient evidence to define a comparable risk. Medications belonging to the tricyclic and MAOI classes, as well as other psychiatric medications, are listed in the updated bulletin as a precautionary measure, but without explicit wording to avoid concomitant use.

An updated list of medications to avoid or exercise caution with can be found at http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm.

Sprycel®: Reports of Serious Pulmonary Arterial Hypertension (PAH): Update - October 2011

The Food and Drug Administration (FDA) is advising healthcare professionals not to use jet injector devices for the administration of influenza vaccines intended for intradermal or intramuscular administration. For additional information, refer to http://www.fda.gov/BiologicsBloodVaccines/Vaccines/QuestionsaboutVaccines/ucm276773.htm

Sprycel®: Reports of Serious Pulmonary Arterial Hypertension (PAH): Update - October 2011

The Food and Drug Administration (FDA) and Health Canada have notified healthcare professionals and the public regarding reports of serious pulmonary arterial hypertension (PAH) in patients treated with dasatinib. From June 2006 to June 2011, sixty cases of pulmonary hypertension (PH) were reported worldwide in patients receiving dasatinib, including 24 PAH cases (12 of which were confirmed by right heart catheterization). In some cases, patients had been receiving dasatinib for over 12 months. Concomitant medications or comorbidities were often associated with PAH during dasatinib therapy. No fatalities have been reported.

Patients should be evaluated for cardiopulmonary disease prior to and during dasatinib therapy. Alternative causes of dyspnea (eg, pleural effusion, pulmonary edema, anemia, lung infiltration) should be ruled out prior to initiating invasive diagnostic procedures. If severe symptoms (eg, dyspnea, fatigue, fluid retention, hypoxia) occur during treatment, dasatinib should be withheld until PAH evaluation is complete. If PAH is confirmed, dasatinib should be permanently discontinued. Symptoms improved in some PAH patients after dasatinib treatment was stopped.

Further information may be found at:

U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm275176.htm

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/sprycel_hpc-cps-eng.php

Extension of Expiration Dating - October 2011

Pfizer, Inc has announced that the expiration date of one lot of antivenin, Lot Number 4030026 (formerly manufactured by Wyeth Pharmaceuticals), has been extended to October 31, 2011. Clinicians should note that due to supply concerns, Pfizer, Inc supplies product only to direct customers on a replacement or emergency basis. To obtain antivenin, Pfizer, Inc may be reached at 800-666-7248; alternatively, clinicians may contact their local Poison Control Center at 800-222-1222 for assistance in locating antivenin. In the event licensed antivenin cannot be secured, an investigational imported antivenin may be available under an Investigational New Drug (IND) protocol with informed consent; for more information contact a local Poison Control Center at 800-222-1222 or the U.S. Food and Drug Administration (FDA) at 800-835-4709 (business hours) or 301-796-8240 (nonbusiness hours).

Health Canada Issues Updated Recommendations Regarding Use With Proton Pump Inhibitors - September 2011

Health Canada has issued notice to Canadian healthcare professionals regarding new recommendations for concomitant use of clopidogrel (Plavix®) with proton pump inhibitors (PPIs). PPIs interfere with the conversion of clopidogrel to its active metabolite although the extent of interaction varies depending on the PPI. Clopidogrel Canadian product labeling was previously updated in 2009 with recommendations that discouraged use with PPIs due to concerns that PPIs would decrease clopidogrel's antithrombotic effects. Based on more recent data, the product labeling has been updated. For patients requiring PPI therapy, the labeling now recommends the use of PPIs that do not interact strongly with clopidogrel (eg, pantoprazole) and avoiding the use of PPIs (eg, omeprazole) that strongly or moderately decrease clopidogrel's efficacy.

Patients receiving clopidogrel and who are taking or considering PPI therapy should be advised to continue clopidogrel therapy and to discuss therapeutic options with their healthcare provider. PPIs available in Canada include dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.

Further information may be found at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_125-eng.php

Marketing Suspension Lifted in Canada - September 2011

Bayer Canada, in conjunction with Health Canada, has issued notice that the previous temporary marketing suspension of aprotinin (Trasylol®) in Canada has been lifted effective immediately. Marketing of aprotinin in Canada was previously suspended in 2007 due to safety concerns of increased mortality observed with aprotinin in the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study. Upon further review, Health Canada has concluded that due to baseline differences in risk factors among aprotinin treated subjects and those treated with other antifibrinolytics (ie, aminocaproic acid and tranexamic acid) in several nonrandomized studies, these data neither establish nor refute an association between aprotinin use and increased mortality. Although the BART study, a prospective multicenter, blinded, randomized, controlled clinical trial, reported a higher consistently negative mortality trend associated with aprotinin as compared to other antifibrinolytics, it was not powered for the secondary endpoint of all-cause mortality. Of note, the trial was discontinued early because of the higher rate of death in patients receiving aprotinin. Regardless, Health Canada states this could be due to statistical chance and does not establish or refute an association.

Prior to initiating aprotinin therapy, clinicians are advised to carefully weigh benefits versus risk associated with its use. In Canada, aprotinin is indicated for prevention of perioperative blood loss and the need for blood transfusion in patients who are at increased risk for blood loss and blood transfusions in association with cardiopulmonary bypass in coronary artery bypass graft (CABG) surgery. Aprotinin Canadian product monograph includes a boxed warning regarding the increased mortality rates reported in some studies, potential risks for renal dysfunction, appropriate anticoagulation monitoring, and risk of anaphylactic reactions.

Further information may be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/trasylol_3_nth-aah-eng.php

Ongoing Safety Review Regarding Risk of QT prolongation - September 2011

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals and patients of the ongoing review and risk of QT prolongation, including the development of torsades de pointes, associated with ondansetron use. Those most at risk include patients with underlying cardiac conditions (eg. congenital long QT syndrome), electrolyte abnormalities (eg hypokalemia, hypomagnesemia), and concomitant use of other QT-prolonging medications.

The FDA is requiring GlaxoSmithKline (manufacturer of Zofran®) to conduct an in-depth study on the effects of ondansetron on the QT interval. Results of this study are expected in mid-2012. In the interim, the Zofran® prescribing information will be updated to include additional warnings (including avoiding use in patients with congenital long QT syndrome) and monitoring requirements for the use of ondansetron in patients considered at risk for QT prolongation.

Further information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm271913.htm

GnRH Agonists: Canadian Labeling Updated to Include Increased Risk of Cardiovascular Disease in Males - September 2011

Health Canada has issued notice to Canadian healthcare professionals and patients that the product labeling for Gonadotropin-Releasing Hormone (GnRH) agonists (eg, goserelin, leuprolide, buserelin, triptorelin, histrelin) has been updated with warnings regarding possible increased risks for cardiovascular events (eg, MI, stroke) in males receiving GnRH agonist therapy for prostate cancer. Although the risk for adverse events appears to be low, healthcare providers are advised to weigh known benefits/risks of GnRH agonists and patient risk factors prior to initiating therapy and to carefully monitor for signs/symptoms of cardiovascular disease during therapy. Patients should be advised to continue with therapy until discussing treatment options with their healthcare provider.

The U.S. prescribing information for these agents has been previously updated with this information.

Further information may be found at

U.S.: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230334.htm

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_122-eng.php

Tumor Necrosis Factor-alpha (TNFa) Blockers: Risk of Infection from Legionella and Listeria - September 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of an update to the Boxed Warning for the entire class of tumor necrosis factor-alpha (TNFa) blockers including Remicade® (infliximab), Enbrel® (etanercept), Humira® (adalimumab), Cimzia® (certolizumab pegol), and Simponi® (golimumab). The Boxed Warning will include the risk of infection from two bacterial pathogens, Legionella and Listeria.

For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm270977.htm

Zoledronic Acid (Reclast®): Reports of Kidney Failure - September 2011

The U.S. Food and Drug Administration (FDA) has announced that zoledronic acid, marketed as Reclast®, is contraindicated in patients with a creatinine clearance >35 mL/minute or with evidence of acute renal impairment. Cases of renal failure requiring dialysis or leading to death have occurred following zoledronic acid administration. Patients at greatest risk include those with underlying moderate-to-severe renal impairment, concurrent use of nephrotoxic or diuretic medications, or severe dehydration prior to or after zoledronic acid administration. Others with increased risk include patients with renal impairment or dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic use. The risk of renal failure also increases with age for those with underlying renal impairment. Appropriate screening to identify risk factors is recommended prior to administration of zoledronic acid. Additionally, renal function should be assessed before therapy in all patients and monitored intermittently after therapy in at-risk patients.

Further information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm270199.htm.

Asenapine (Saphris®): Serious Allergic Reactions - September 2011

The U.S. Food and Drug Administration (FDA) has announced that cases of serious allergic reactions have been reported with asenapine use. A type I allergic reaction (eg, anaphylaxis, angioedema, dyspnea, hypotension, tachycardia, swollen tongue, wheezing, or rash) occurring with asenapine use has been reported in 52 patients. Some allergic reactions occurred following the first dose of medication. Patients with a known hypersensitivity to asenapine should not receive this medication. All patients receiving asenapine should be counseled regarding signs and symptoms of a serious allergic reaction and advised to seek immediate medical attention if signs or symptoms of a reaction occur.

Further information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm270243.htm