Special Alerts

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

Influenza Virus Vaccine (Inactivated): Increased Risk of Febrile Seizures in Children - August 2011

The Centers for Disease Control and Prevention (CDC) has announced that young children appear to be at increased risk of febrile seizures when given the pneumococcal conjugate vaccine (PCV 13) at the same time as the inactivated influenza virus vaccine (TIV). The risk appears to be greatest from ages 12-23 months. Because febrile seizures are typically benign and occur in 2% to 5% of all young children, the ACIP does not recommend a delay in administration of either vaccine or altering the vaccine schedule in any manner due to the potential risk of infection.

For additional information, refer to the following CDC website: http://www.cdc.gov/vaccines/pubs/vis/tiv-pcv-note.htm

Dasatinib (Sprycel®): Reports of Serious Pulmonary Arterial Hypertension (PAH) - August 2011

Bristol-Myers Squibb Canada, in collaboration with Health Canada, has 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. No cases have been reported in Canada.

Prior to starting dasatinib, patients should be evaluated for cardiopulmonary disease. If severe symptoms (eg, dyspnea, fatigue) 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 on Health Canada?s website at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/sprycel_hpc-cps-eng.php

Citalopram: Reports of Dosage-Related QT-Interval Prolongation and Subsequent Arrhythmia Prompt Reduction in Maximum Recommended Dosage - August 2011

The U.S. Food and Drug Administration (FDA) has 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, >60 years of age, poor CYP2C19 metabolizers, or taking cimetidine 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 may refer to the following websites:

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

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

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

The U.S. Food and Drug Administration (FDA) and Health Canada have notified healthcare professionals and the public of 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 trial, the Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS), was halted early after negative cardiovascular outcomes were noted in preliminary results. Both the FDA and Health Canada are currently reviewing the cardiovascular-related safety for dronedarone; the FDA is also reviewing data to determine if these issues also apply to populations within the FDA-approved indications for dronedarone. In the meantime, dronedarone should not be prescribed to patients with permanent atrial fibrillation; dronedarone therapy should be discontinued in patients who develop permanent atrial fibrillation during therapy. Patients should not stop taking dronedarone (for permanent or nonpermanent atrial fibrillation) without discussing with their health care professional.

For further information, please refer to:

U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_101-eng.php

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/multaq_2_hpc-cps-eng.php

Finasteride: Rare Reports of Breast Cancer in Men - August 2011

Health Canada is notifying patients and healthcare providers of rare reports of breast cancer in males taking either the 1 mg or 5 mg formulations of finasteride (Propecia®; Proscar®). The 5 mg dose was associated with a majority of the cases reported. Although the cause of the male breast cancer cannot be explicitly linked to finasteride therapy at this time, the labeling for finasteride products has been updated to include information on the potential risk.

Patients taking finasteride should immediately report any breast changes (eg, breast enlargement, lumps, tenderness, pain, or nipple discharge) to their healthcare provider.

For additional information, refer to http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_110-eng.php.

Fluconazole: Birth Defects Associated with Long-Term, High-Dose Use - August 2011

The U.S. Food and Drug Administration (FDA) is communicating to patients and healthcare professionals that the long-term use of fluconazole at high doses (400-800 mg/day) during the first trimester of pregnancy may be associated with an increased risk of birth defects. As a result, the pregnancy category for fluconazole has been changed from category C to category D for indications other than vaginal candidiasis. However, because the risk of birth defects is not associated with a single, low dose (150 mg) of fluconazole for vaginal candidiasis, the pregnancy risk category for this indication remains category C.

Healthcare professionals should counsel patients on the risk of birth defects with fluconazole use; patients should notify their healthcare professionals if they are or become pregnant during treatment with fluconazol.

For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm266468.htm.

Acetaminophen: New Maximum Dose Recommendation for Some Tylenol® OTC Products - July 2011

McNeil Consumer Healthcare has announced the maximum daily dose of single-ingredient acetaminophen Extra Strength Tylenol® OTC products will be lowered from 4 g/day to 3 g/day on product packages beginning in the fall of 2011. Additionally, the dosing frequency will change from 1 g every 4-6 hours to 1 g every 6 hours. Of note, the labeling of Regular Strength Tylenol® and other McNeil OTC acetaminophen-containing products is expected to have similar labeling revisions beginning sometime in 2012.

According to Cadence Pharmaceuticals, the sole manufacturer of injectable acetaminophen (Ofirmev®), the maximum dose of Ofirmev® will remain 4 g/day for adults and children weighing at least 50 kg.

Additional information can be found at:

http://www.tylenol.com/page2.jhtml?id=tylenol/news/newdosing.inc

http://investors.cadencepharm.com/releasedetail.cfm?ReleaseID=595145

Linezolid (Zyvox®): Serious CNS Reactions Reported with Concomitant Use of Serotonergic Psychiatric Medications - July 2011

The U.S. Food and Drug Administration (FDA) has issued a safety announcement regarding the potential for serotonin syndrome to develop in patients receiving linezolid (Zyvox®) and psychiatric medications with serotonergic effects including, SSRIs, SNRIs, tricyclic and MAOI antidepressants, and other medications with proserotonergic properties. Linezolid has been shown to inhibit monoamine oxidase A and may lead to increased levels of serotonin in the brain when combined with serotonergic psychiatric medications. For a complete list of medications not to be used with linezolid, please refer to the link below.

The FDA has received reports of serious CNS reactions with these combinations, thus prompting additional warnings to be added to the labels of linezolid and the respective psychiatric medications. Use of linezolid in life-threatening infections (eg, vancomycin-resistant Enterococcus faecium (VRE), nosocomial pneumonia and complicated skin infections caused by MRSA) should prompt immediate discontinuation of any serotonergic medication with close monitoring for CNS adverse effects for 2 weeks (5 weeks if discontinuing fluoxetine), or for 24 hours after the last linezolid dose. For nonemergent use of linezolid, discontinue serotonergic medication(s) at least 2 weeks (5 weeks with fluoxetine) prior to initiating linezolid therapy. Serotonergic psychiatric medications should not be initiated in any patient on linezolid, but can be started 24 hours after the last dose of the antibiotic.

Patients should notify their healthcare provider if they are taking any serotonergic psychiatric medications and reminded not to discontinue these medications without advice from their healthcare practitioner. Patients should be instructed to recognize the signs of CNS toxicity (eg, mental changes, muscle twitching, shivering, incoordination) and to report these symptoms immediately to their healthcare provider.

Additional information, including a list of medications to avoid can be found at: http://www.fda.gov/Drugs/DrugSafety/ucm265305.htm.

Varenicline: Labeling Changes Due to Risk of Cardiovascular Events; Updated - July 2011

The U.S. Food and Drug Administration (FDA) has announced revisions to the labeling for varenicline (Chantix ®) which include updated information regarding therapeutic efficacy versus risk of cardiovascular events in patients who have cardiovascular disease. Based on an analysis of a randomized clinical trial of 700 smokers (350 patients per treatment arm) with cardiovascular disease, cardiovascular events were reported more frequently in patients taking varenicline than in patients treated with placebo. Incidence of these events in varenicline compared to placebo groups were as follows: angina pectoris (13 vs 7), nonfatal myocardial infarctions (4 vs 1), need for coronary revascularization (7 vs 2), and new diagnosis of peripheral vascular disease or admission for a procedure for the treatment of peripheral vascular disease (4 vs 2). Varenicline was not studied in patients with unstable cardiovascular disease or in patients experiencing recent events (<2 months) prior to treatment.

The FDA is continuing to evaluate the cardiovascular safety of varenicline and is requiring the manufacturer to conduct a meta-analysis of randomized, placebo-controlled trials. The FDA will provide an update when additional information is available. Health Canada has also announced an ongoing review of varenicline (Champix®) and the potential for an increased risk of cardiovascular events in patients with cardiovascular disease.

The FDA has also reviewed vareniciline use for smoking cessation in patients with chronic obstructive pulmonary disease (COPD) and no new safety concerns were identified. Clinicians should be aware that the risk of smoking is an independent and major risk factor for the development of cardiovascular disease. Data from the analyses of use in patients with cardiovascular disease revealed a greater than twofold chance of remaining abstinent within 1 year of varenicline treatment compared to placebo (19% vs 7%). Healthcare professionals must weigh the potential risks and benefits of varenicline use in smokers with cardiovascular disease.

For additional information, please refer to the following websites:

U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm259161.htm#safety

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_84-eng.php

Metoclopramide: Health Canada Updates Labeling (Tardive Dyskinesia) - July 2011

Health Canada is notifying healthcare providers that the metoclopramide product monograph is being updated to include stronger warnings regarding the risk for tardive dyskinesia, a movement disorder characterized by uncontrollable muscle movements, generally facial (tongue, face, mouth, and jaw) movements. The risk for metoclopramide-associated tardive dyskinesia is increased with longer treatment durations and in the elderly, particularly in elderly females.

For more information, please refer to http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_99-eng.php

Oseltamivir (Tamiflu®): Labeling Updated Due to Change in Oral Suspension Concentration - July 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals about labeling changes being made to oseltamivir (Tamiflu®) oral suspension to reduce the likelihood of medication errors. The changes to the product label include:

- A reduction in the concentration from 12 mg/mL to 6 mg/mL; this new concentration will reduce the froth generated when shaken therefore providing a more accurate measurement.

- A change in the measurements on the oral dosing device from milligrams (mg) to milliliters (mL).

- A change in the dosing table for oseltamivir (Tamiflu®) to include a column for the volume (mL) based on the new currently available 6 mg/mL concentration.

- Revised compounding instructions for pharmacies to prepare a 6 mg/mL oral suspension from oseltamivir (Tamiflu®) capsules in the event of a shortage of the commercially available suspension.

The manufacturer, Genentech, has instituted a voluntary Take Back Program to remove the 12 mg/mL concentration from the marketplace and program participation is encouraged; however, the FDA wants to alert healthcare professionals that both concentrations may remain on the market and until the current stock of oseltamivir (Tamiflu®) 12 mg/mL oral suspension expires, patients could potentially receive either concentration. To reduce potential errors, the FDA is encouraging prescribers to take additional safety measures when prescribing, such as writing both the strength (6 mg/mL) and volume (mL) in addition to the dose in milligrams (mg) on all prescriptions for oseltamivir (Tamiflu&ref;) oral suspension.

Additional information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm262432.htm

Valproate Products: Impaired Cognitive Development Observed in Children Exposed In Utero to Valproate - July 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals that children born to mothers who received valproic acid products (Depakene®, Stavzor?), valproate sodium (Depacon®), or divalproex sodium (Depakote®), may have impaired cognitive development. The FDA announcement was prompted by epidemiologic studies which showed that children exposed in utero in women who received valproate throughout their pregnancy had lower cognitive test scores compared to children exposed in utero to other antiepileptic agents. In particular, one of the largest of these studies, a prospective cohort study conducted in the U.S. and the United Kingdom, showed a lower Differential Ability Scale (D.A.S.) score in children 3 years of age with prenatal exposure to valproate (92 [95% CI, 88-97]) compared to children with prenatal exposure to lamotrigine (101 [95% CI, 98-104]), carbamazepine (98 [95% CI, 95-102]), or phenytoin (99 [95% CI, 94-104]) monotherapy. The D.A.S. measures cognitive development in children 2.5-17 years of age, and has a mean score of 100 (SD=15).

In light of the results, the FDA is requiring the prescribing information for valproate products to include the risk of lower cognitive test scores in children with fetal valproate exposure. The FDA is also reminding practitioners to inform women of childbearing potential the risks associated with its use during pregnancy, including the known teratogenic effects. Any woman who becomes pregnant while receiving valproate is encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334).

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

Bevacizumab: FDA Proposal for Removal of the Breast Cancer Indication from the Product Labeling - Updated - June 2011

In December, 2010, the U.S. Food and Drug Administration (FDA) announced that it was recommending removal of the metastatic breast cancer indication from bevacizumab (Avastin®) labeling, citing a lack of demonstrated safety and efficacy in breast cancer. After reviewing data from four clinical trials, the FDA determined that use of bevacizumab in breast cancer patients did not prolong overall survival 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). Following the announcement by the FDA, Genetech, the manufacturer of Avastin®, contested the recommendation and requested a public hearing on the issue.

On June 29, 2011, the FDA announced the completion of the public hearing. However, both the FDA and Genentech are to provide additional written submission by July 28, 2011. The issue is open for public comment until July 28, 2011. Once the docket is closed, the FDA commissioner will review and make a final decision.

Regardless of the FDA decision for the metastatic breast cancer indication, bevacizumab will remain on the market for the other FDA-approved indications, including metastatic colorectal cancer, glioblastoma, nonsmall cell lung cancer (nonsquamous histology), and metastatic renal cell cancer.

Information from the FDA regarding this issue may be found at http://www.fda.gov/Drugs/DrugSafety...

Varenicline: Labeling Changes Due to Risk of Cardiovascular Events Update- June 2011

The U.S. Food and Drug Administration (FDA) has announced a requirement for the manufacturer of varenicline to revise the labeling to include updated information regarding the risk of cardiovascular events in patients who have cardiovascular disease. Based on an analysis of a randomized clinical trial of 700 smokers with cardiovascular disease, cardiovascular events including angina pectoris, nonfatal myocardial infarctions, need for coronary revascularization, and new diagnosis of peripheral vascular disease or admission for a procedure for the treatment of peripheral vascular disease were reported more frequently in patients taking varenicline than in patients treated with placebo.

The FDA is continuing to evaluate the cardiovascular safety of varenicline and is requiring the manufacturer to conduct a meta-analysis of randomized, placebo-controlled trials. The FDA will provide an update when additional information is available.

Health Canada has also announced an ongoing review of varenicline (Champix®) and the potential for an increased risk of cardiovascular events in patients with cardiovascular disease.

Clinicians should be aware that the risk of smoking is an independent and major risk factor for the development of cardiovascular disease. Health care professionals must weigh the potential risks and benefits of varenicline use in smokers with cardiovascular disease.

For additional information, please refer to the following websites:

U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm259161.htm#safety

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_84-eng.php

Erythropoiesis-Stimulating Agents (ESAs): Dosing Recommendations Modified - June 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of revisions made to the prescribing information for the ESAs, epoetin alfa (Epogen®, Procrit®) and darbepoetin (Aranesp®), which include changes to the Boxed Warning, Warnings/Precautions, and Dosage/Administration sections of the labeling. The revised dosing modifications recommend more conservative dosing in patients with chronic kidney disease (CKD). The revisions were prompted by data in patients with CKD indicating an increased risk of cardiovascular events with ESA use. The ESA labels now include a warning that, in controlled trials, CKD patients experienced an increased risk of death, serious adverse cardiovascular reactions, and stroke when administered ESAs to a target hemoglobin >11 g/dL. To date, no clinical trial has identified a target hemoglobin level, ESA dose, or dosing guide that does not increase these risks.

ESA labels now recommend practitioners consider initiating ESA treatment in CKD patients when the hemoglobin is <10 g/dL. The target hemoglobin previously recommended in the labeling (target range of 10-12 g/dL in CKD patients) has been removed. There is currently no target hemoglobin recommended in the product labeling of ESAs. Instead the recommendation is to individualize dosing and use the lowest ESA dose necessary to decrease the need for red blood cell (RBC) transfusions, and to adjust the dose as appropriate.

The FDA is also providing the following additional information for healthcare professionals:

When treating CKD patients:

• ESAs dosed to a target hemoglobin >11 g/dL increase the risk of serious adverse cardiovascular events, without providing any proven additional patient benefit. No target hemoglobin level, ESA dose, or dosing guide has been studied that does not increase these risks.
• An ESA medication guide should be given to every patient (or patient representative) when an ESA is dispensed.
• Monitor hemoglobin levels at least weekly until stable when initiating or adjusting ESA therapy, then at least monthly.
• Patients not responding adequately over a 12-week escalation period are unlikely to have an improved response by further increasing the ESA dose, and the risks may be increased.

When treating CKD patients not receiving dialysis:

• Consider initiating ESA therapy only when the hemoglobin is <10 g/dL and both of the following are true:
  • The rate at which the hemoglobin declines indicates the likelihood of RBC transfusions being required.
  • Decreasing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.
• If hemoglobin is >10 g/dL, decrease or interrupt the ESA dose and use the lowest dose of ESA sufficient to decrease the need for RBC transfusions.

When treating CKD patients on dialysis:

• Initiate ESA treatment when hemoglobin is <10 g/dL.
• If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the ESA dose.

Additional information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm260641.htm

Acetaminophen: Transition of Pediatric Liquid Products to Standard Concentration - June 2011

Based on recommendations provided by the Food and Drug Administration (FDA), all over-the-counter (OTC) pediatric single-ingredient acetaminophen liquid products will transition to a single concentration of 160 mg/5 mL; the transition has already begun and will continue into 2012. The concentration of acetaminophen infant drops (previously 80 mg/0.8 mL) will now be the same as children's acetaminophen products (160 mg/5 mL) and as a result, new dosing on a volume-per-weight (or volume-per-age) basis will apply. The recommended mg/kg dose is unaffected and continues to be 10-15 mg/kg/dose.

Healthcare professionals should be aware that during this transition, acetaminophen infant drop products with both the new and old concentrations may be available on pharmacy shelves. Parents may continue to use either product, but should verify concentration and use according to labeled dosing directions. Healthcare professionals should verify product concentration prior to providing dosing information.

Additional information can be found at http://www.tylenolprofessional.com/index.html

Varenicline: Labeling Changes Due to Risk of Cardiovascular Events - June 2011

The U.S. Food and Drug Administration (FDA) has announced a requirement for the manufacturer of varenicline to revise the labeling to include updated information regarding the risk of cardiovascular events in patients who have cardiovascular disease. Based on an analysis of a randomized clinical trial of 700 smokers with cardiovascular disease, cardiovascular events including angina pectoris, nonfatal myocardial infarctions, need for coronary revascularization, and new diagnosis of peripheral vascular disease or admission for a procedure for the treatment of peripheral vascular disease were reported more frequently in patients taking varenicline than in patients treated with placebo.

The FDA is continuing to evaluate the cardiovascular safety of varenicline and is requiring the manufacturer to conduct a meta-analysis of randomized, placebo-controlled trials. The FDA will provide an update when additional information is available.

Clinicians should be aware that the risk of smoking is an independent and major risk factor for the development of cardiovascular disease. Health care professionals must weigh the potential risks and benefits of varenicline use in smokers with cardiovascular disease.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm259161.htm#safety

Pioglitazone (Actos®): Ongoing Safety Review: Potential Increased Risk of Bladder Cancer (Update) - June 2011

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals and patients that it is reviewing data from an ongoing, 10-year epidemiological study evaluating if pioglitazone (Actos®) is associated with an increased risk of bladder cancer. In a five-year interim analysis, patients taking pioglitazone for more than one year appeared to be at an increased risk of bladder cancer. The overall risk of bladder cancer was not increased in pioglitazone users, but an increased risk of bladder cancer was associated with patients who had the highest cumulative pioglitazone dose or the longest pioglitazone exposure. The FDA is also aware of an epidemiological study conducted in France which suggests an increased risk of bladder cancer associated with pioglitazone use. The FDA recommends not using pioglitazone in patients who have active bladder cancer and to use caution in patients with a prior history of bladder cancer since the risk of recurrence induced by pioglitazone is unknown.

The FDA will continue to evaluate data from the ongoing, 10-year epidemiological study as well as review findings from the French epidemiologic study. The Agency will update the public when it has additional information.

Any adverse events involving pioglitazone should be reported to the FDA MedWatch program (http://www.fda.gov/MedWatch/report.htm).

For additional information, refer to http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm.

Antipsychotics: Newborn Extrapyramidal and Withdrawal Symptoms with Third Trimester Exposure (Update) - June 2011

The U.S. Food and Drug Administration (FDA) and Health Canada have updated or are in the process of updating the pregnancy sections of their respective prescribing information for antipsychotics to contain detailed information about nonteratogenic effects following maternal use during pregnancy. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms; EPS) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor. These effects vary in severity and may be self-limiting (subsiding within hours or days) or require hospitalization. In the cases reported to the FDA, concomitant use of other medications (known to precipitate withdrawal symptoms) may have contributed to the effects, although in some cases, antipsychotic medication use was the only contributing factor for the EPS and withdrawal symptoms.

Women who are taking antipsychotics should not stop them if they become pregnant (abrupt discontinuation is not recommended), but should notify their healthcare provider. Women taking antipsychotics who intend to become pregnant should discuss treatment concerns with their healthcare provider. Any adverse effects noted in newborns should be reported in the U.S. to the FDA's Medwatch program (1-800-332-1088 or https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm) or in Canada to Health Canada's Canada Vigilance Program (1-866-234-2345 or http://www.hc-sc.gc.ca/dhp-mps/medeff/index-eng.php).

For additional information, please refer to:

U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm#aihp

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_78-eng.php

Risperidone and Ropinirole: Sound-Alike/Look-Alike Alert - June 2011

The U.S. Food and Drug Administration (FDA) issued a statement alerting healthcare practitioners and patients to the potential for medication errors when prescribing and dispensing risperidone (Risperdal®) or ropinirole (Requip®) due to product similarities. Errors have occurred when patients have received the incorrect medication. In some cases the error has lead to patient hospitalization. Confusion between the products includes sound-alike/look-alike characteristics of both the brand and generic names, similarities in container labeling and carton package, illegible handwriting on written prescriptions, and overlapping dosage strengths, forms, and intervals.

The FDA has requested that the manufacturers use "tall man" lettering on container labels and packaging for both brand and generic products. In addition, the FDA has requested that the generic manufacturers change labels and packaging to provide additional visual differentiation between the products.

Healthcare professionals are encouraged to clearly print prescriptions, spell drug name when prescribing over the telephone, provide the medical indication on the prescription, and separate storage of risperidone and ropinirole.

Patients should be counseled on the purpose of their medication and be encouraged to check the name of the medication and appearance of the tablets every time the medication is filled. Patients should talk to their pharmacist or other healthcare professional with any questions.

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

Liraglutide: Risk of Acute Pancreatitis, Thyroid C-Cell Tumors - June 2011

Novo Nordisk, the manufacturer of liraglutide (Victoza®), reminded health care professionals of the important risks associated with use. Liraglutide causes dose- and duration-dependent thyroid C-cell tumors in animal studies; the relevance in humans is not known. Use is contraindicated in patients with a history of or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2). Patients with thyroid nodules should be evaluated by an endocrinologist. Monitoring serum calcitonin levels is of questionable benefit; if elevated, refer for further evaluation. Liraglutide has also been reported to cause pancreatitis in clinical studies; conclusive evidence has not been established. Monitor for unexplained persistent severe abdominal pain with or without vomiting; if pancreatitis is suspected, discontinue use. Use caution in patients with a history of pancreatitis. Because of these risks, use is not recommended as first-line therapy in patients inadequately controlled on diet and exercise alone.

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

Five Alpha-Reductase Inhibitors (5-ARI): Increased Incidence of High-Grade Prostate Cancers - June 2011

The U.S. Food and Drug Administration (FDA) has notified healthcare providers about new safety information regarding the increased risk of being diagnosed with a more aggressive prostate cancer in patients taking 5-ARIs (eg, dutasteride, finasteride, and combinations containing a 5-ARI). Two large trials (Kaplan, 2009; Andriole, 2010) evaluated finasteride and dutasteride, respectively, in prostate cancer prevention. Results of both trials suggested that although the overall risk of being diagnosed with prostate cancer was low, the risk of a more aggressive prostate cancer diagnosis (Gleason Score [GS] 8-10) was increased. In the finasteride trial the incidence of GS 8-10 prostate cancer was 1.8% in the active treatment group versus 1.1% in the placebo group. Similarly in the dutasteride trial the risk of GS 8-10 prostate cancer diagnosis was higher in the active treatment group compared to placebo (0.9 % vs 0.6%). Although neither study demonstrated a statistical increase in risk, there was a trend that requires further evaluation.

The FDA is making the following suggestions for clinicians:

- Prior to initiating therapy with a 5-ARI, evaluate and rule out other urological etiologies including prostate cancer.

- 5-ARIs may reduce prostate-specific antigen (PSA) values by 50% within 6 months of initiation, although individual patients may experience varying decreases.

- Any confirmed increase in PSA in a patient maintained on a 5-ARI may be suggestive of prostate cancer and should be evaluated even if the PSA is within the normal range.

- 5-ARIs are not FDA-approved for prevention of prostate cancer.

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

Simvastatin (Zocor®), Ezetimibe and Simvastatin (Vytorin®), Niacin and Simvastatin (Simcor®): New Safety and Dosing Information - June 2011

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals of updated prescribing information for Zocor®, Vytorin® and Simcor® in response to published research evaluating efficacy and safety of high-dose simvastatin (80 mg daily) compared to low-dose (20 mg daily) (SEARCH Collaborative Group, 2010). Although high-dose simvastatin lowered LDL cholesterol an average of 13.5 mg/dL (0.35 mmol/L) more than low dose, there was no significant difference between the 2 doses in major vascular event reduction. Confirmed cases of myopathy, including rhabdomyolysis, were significantly greater in the high-dose group (0.9% versus 0.03%; CI 6.5-109). In the high-dose group there were 7 confirmed cases of rhabdomyolysis (defined as CPK >40 times the upper limit of normal (ULN) with evidence of end-organ damage (eg, doubling of plasma creatinine)) and another 7 with CPK levels >40 times ULN.

In addition to classic risk factors for statin-associated myopathy, other risk factors for simvastatin-related myopathy include the first 12 months of use, specific drug interactions known to increase simvastatin concentrations, and genetic predisposition. As a result of the updated prescribing information, only patients that have been taking simvastatin 80 mg for >12 months without evidence of muscle damage may remain on this dose. New prescriptions for simvastatin-containing products and patients currently taking simvastatin-containing products should be limited to doses of <80 mg. Patients who are not achieving LDL goal while on simvastatin 40 mg should be switched to another LDL-lowering agent capable of achieving patient specific LDL goal.

For additional information, refer to http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm

Rituximab (Rituxan®): Fatal Infusion Related Reactions in patients with Rheumatoid Arthritis (RA) - June 2011

Hoffmann-La Roche Limited, in collaboration with Health Canada, has notified healthcare professionals and the public of four fatalities that may be associated with rituximab infusions. The fatalities occurred in patients receiving rituximab for the treatment of RA.

Review of safe administration practices may be helpful in preventing further events. Premedicate (analgesic/antipyretic, antihistamine, and glucocorticoid) patients 30 minutes prior to the rituximab infusion, have resuscitation equipment immediately available when rituximab is administered, monitor closely during infusion and immediately stop the infusion with suspected anaphylaxis or other severe hypersensitivity or infusion reactions, and closely monitor patients with pre-existing cardiac conditions or those with previous cardiopulmonary adverse events after completion of the infusion.

It is not known if the patients with fatal infusion reactions were properly premedicated, although all RA patients should receive methylprednisolone 100 mg I.V. 30 minutes prior to the initiation of each rituximab infusion (in addition to acetaminophen and diphenhydramine).

Further information may be found on Health Canada's website at http://hc-sc.gc.ca/dhp-mps/medeff/advisories...

Angiotensin II Receptor Blockers (ARBs) and Cancer Risk - June 2011

The U.S. Food and Drug Administration (FDA) has notified healthcare providers of the results from an ongoing review of ARB use and cancer risk. In June 2010, a published meta-analysis of 5 clinical trials reported a statistically significant increased risk of developing cancer in patients who received treatment with ARBs compared to those who did not. The FDA has completed a meta-analysis of 31 trials to further investigate the association between ARB use and cancer risk. The results of the FDA meta-analysis, along with other available data, have found no evidence for an increased risk of cancer with ARB use.

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

Drospirenone-Containing Oral Contraceptives: Potential Increased Risk of Blood Clots - May 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals and patients of two recently published studies evaluating if there is an increased risk of developing venous thromboembolism (VTE) in women taking drospirenone-containing oral contraceptives compared to women taking oral contraceptives containing levonorgestrel. The results of these studies showed a 2-3 times greater risk of VTE development for drospirenone-containing compared to levonorgestrel-containing oral contraceptives. Four previously published studies have shown conflicting results. Two postmarketing studies did not find an increased risk of VTE; two additional studies did find an increased risk of VTE in women taking drospirenone-containing oral contraceptives. The FDA is currently evaluating the results of the two most recent studies and will continue to assess the risks versus benefits of drospirenone-containing oral contraceptives. Additionally, the FDA will be evaluating the results of a larger trial designed to assess thromboembolic risk in 800,000 women taking oral contraceptives, including drospirenone-containing products, and will communicate any new safety recommendations after reviewing the trial data.

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....

Rosiglitazone (Avandia®): Modification of the Risk Evaluation and Mitigation Strategy (REMS) - May 2011

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals and patients that access to rosiglitazone (Avandia®) and rosiglitazone-containing medicines (Avandamet®, Avandaryl®) will be restricted as part of a modification to the current risk evaluation and mitigation strategy (REMS) program. The modified REMS program, known as the Avandia-Rosiglitazone Medicines Access Program, will include a medication guide and a restricted access and distribution program.

The Avandia-Rosiglitazone Medicines Access Program restricts access to rosiglitazone-containing medicines to the following group of patients:

- Patients currently clinically benefitting from rosiglitazone.

- Patients with type 2 diabetes who cannot achieve adequate disease management with other antidiabetic agents or who are not willing to use pioglitazone-containing medications after consulting with their healthcare provider.

In order to prescribe and receive rosiglitazone-containing medicines, the prescriber and patient must be enrolled in the Avandia-Rosiglitazone Medicines Access Program. For enrollment, healthcare providers are required to review the rosiglitazone medicine prescribing information (including the medication guide), and complete an enrollment form. After November 18, 2011, GlaxoSmithKline will withdraw all rosiglitazone-containing products from the current supply chain and product will no longer be available in retail pharmacies. At that time, rosiglitazone-containing medicines will only be available through specially certified pharmacies participating in the program. Additional information on the program, including enrollment information, is available at http://www.fda.gov/downloads/Drugs/DrugSafety/....

For additional information, refer to http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm.

Adenosine: Safety Concern Regarding Compatibility of Prefilled Needleless Glass Syringes with Needleless I.V. Access Systems - May 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of reports of compatibility problems when prefilled needleless glass syringes are used with needleless I.V. access systems, specifically prefilled glass syringes containing amiodarone or adenosine. The syringes may malfunction, break, or become clogged when connecting to the needleless I.V. access system. In addition, the I.V. tubing or needleless connector may become damaged, thereby, requiring reestablishment of I.V. access and delaying the administration of potentially lifesaving medication.

The FDA is recommending that healthcare organizations that currently stock prefilled needleless glass syringes of amiodarone or adenosine consider stocking these medications in vials or prefilled plastic syringes as a back-up measure.

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

Dolasetron: Anzemet® I.V. injection Withdrawn from Canadian Market - April 2011

Sanofi-Aventis Canada, Inc, in conjunction with Health Canada, is notifying Canadian healthcare providers that dolasetron 20 mg/mL injection will be withdrawn from the Canadian market as of May 10, 2011. This withdrawal is due to an association with QTc prolongation which may result in serious arrhythmias. The injectable product is no longer indicated for the prevention of nausea and vomiting associated with chemotherapy. (Use for this indication was recently contraindicated in the United States.)

Oral dolasetron is still available and may be used as indicated. However, caution should be used in patients at risk for arrhythmias, such as those with renal impairment, the elderly, those with underlying heart conditions, existing heart rate or rhythm problems, and concomitant use of medications known to affect heart rate or electrolytes.

Additional information may be found on the Health Canada website: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/index-eng.php

American Regent Potassium Phosphates Injection and Particulate Matter - April 2011

American Regent, Inc notified healthcare providers of particulate matter observed in potassium phosphates USP, 5 mL single dose vials (the affected lot, Lot #0048, has been recalled). All other lots and sizes have been visually reinspected, and no particular matter has been identified. However, as a precaution and until further notice, American Regent is recommending all potassium phosphate products be inspected and filtered prior to use.

Products in which particulate matter is present in the vial on visual inspection should not be used.

The following procedure should be followed when using all remaining lots of American Regent potassium phosphates injection: Prior to use, withdraw the required volume of potassium phosphates injection using a 5 micron filter. Remove the filter and attach a standard needle prior to adding the solution to a larger volume of I.V. fluid (must dilute further prior to I.V. administration). Visually inspect the final admixture. Do not use if particulate matter is present. Use a 0.22-micron in-line filter during administration to the patient (use a 1.2 micron in-line filter for lipid-containing admixtures)

If particulates are observed upon visual inspection, contact the American Regent Professional Services Department at 877-788-3232 or by email at www.inquiry@americanregent.com.

Refer to the American Regent website for additional information, http://www.americanregent.com/NewsEvents.aspx.

Lansoprazole ODT by Teva Pharmaceuticals: Clogged Syringes and Feeding Tubes - April 2011

The U.S. Food and Drug Administration (FDA) has received reports of blocked or clogged oral syringes and feeding tubes (both gastric and jejunostomy tubes) following administration of a prepared suspension using lansoprazole delayed release oral disintegrating tablets (ODT) manufactured by Teva pharmaceuticals. This product may also be packaged and labeled with the following: Sharp Corporation, Cardinal Health, and Quality Packaging Specialist, Inc. According to the reports, the tablets may not completely disintegrate after water is added or may dissolve initially, but later form clumps. These clumps may adhere to the walls of oral syringes and feeding tubes. Emergency medical assistance to unclog or remove and replace feeding tubes has been required in some cases.

Teva Pharmaceuticals has voluntarily withdrawn lansoprazole delayed release ODT from distribution; however, the product may be in stock in pharmacies or other facilities, or in patients' possession.

Due to the reports, the FDA is recommending that:

- Healthcare professionals evaluate their stock and not dispense the Teva product to patients who will administer the medication through an oral syringe and/or feeding tube; another lansoprazole ODT product produced by a different manufacturer should be dispensed instead. Patients taking the tablets by mouth may still receive the product.

- Patients/caregivers should be informed not to administer the Teva product via an oral syringe and/or feeding tube; if patients cannot take the Teva-manufactured product orally, they should contact their healthcare professional for an alternative product.

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

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

Olmesartan: Studies Suggesting Possible Increased Risk of Death in Patients with Type 2 Diabetes - Updated April 2011

In June 2010, the U.S. Food and Drug Administration (FDA) alerted healthcare providers of an ongoing safety review of olmesartan and its potential to increase the risk of death when used for blood pressure management in patients with type 2 diabetes.

The FDA announced that it would evaluate data from two studies: ROADMAP (The Randomized Olmesartan and Diabetes Microalbuminuria Prevention Study) and ORIENT (The Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial). Both studies were randomized, double-blind, placebo-controlled trials consisting of patients with type 2 diabetes receiving olmesartan therapy to slow the development of kidney disease. An unexpected finding in both trials was an increased number of deaths due to cardiovascular events (eg, heart attack, stroke) in patients receiving olmesartan compared to placebo. In ROADMAP, cardiovascular deaths occurred in 15 patients receiving olmesartan compared to 3 patients receiving placebo. In ORIENT, cardiovascular deaths occurred in 10 patients receiving olmesartan compared to 3 patients receiving placebo.

In April 2011, following the review of the results of the ROADMAP and ORIENT trials, the FDA has determined that the benefits of olmesartan therapy continue to outweigh potential risks, when used as prescribed for the treatment of hypertension. Olmesartan is not recommended for the prevention or delay of microalbuminuria development in diabetic patients. Daiichi Sankyo, the manufacturer of Benicar®, has agreed to perform additional studies, in collaboration with the FDA, to obtain more data about the risks/benefits of olmesartan.

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

Immune Globulin, Subcutaneous (Vivaglobin®): Risk of Thrombotic Events Associated with Use - Updated April 2011

The Food and Drug Administration (FDA) and Health Canada have notified healthcare professionals of postmarketing reports of thrombotic events with use of Vivaglobin®. Vivaglobin® is approved for use as a subcutaneous infusion (the only route approved in the U.S. and Canadian labeling). A risk of thrombosis following intravenous administration of immune globulin products has previously been established; however, these recent postmarketing reports involving Vivaglobin ® indicate that there is some degree of risk associated with subcutaneous administration. Inadvertent administration of Vivaglobin® intravenously may be associated with an even higher risk for thrombotic events. Risk factors associated the recent postmarketing reports have included pre-existing cardiovascular disorders, prior thrombotic event, obesity, oral estrogen use, hyperlipoproteinemia, in-dwelling catheter, and immobility. In addition, patients with multiple cardiac risk factors, hypercoagulable disorders, and hyperviscosity may also be at increased risk of thrombosis following use of immune globulin products. The manufacturer of Vivaglobin®, CSL Behring, has conducted in-house research testing and determined that there is procoagulant activity in Vivaglobin®. The clinical significance of this finding is unknown.

In light of these postmarketing reports, the FDA and Health Canada are making the following recommendations: Vivaglobin® should only be administered via subcutaneous infusion (as described in the prescribing information) at the minimum rate practicable. Vivaglobin® should not be administered intravenously. Patients should be informed of the sign/symptoms of thrombotic events (eg, shortness of breath, pain, swelling of a limb, focal neurological deficits).

Additional information may be found at:

U.S.: http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm246863.htm

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

Tumor Necrosis Factor (TNF) Blockers, Azathioprine, and/or Mercaptopurine: Reports of Hepatosplenic T-Cell Lymphoma (HSTCL) - April 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals and the public of continued reports of a rare malignancy, Hepatosplenic T-Cell Lymphoma (HSTCL), occurring in patients receiving TNF blockers (eg, adalimumab, certolizumab pegol, etanercept, golimumab), azathioprine, and/or mercaptopurine. HSTCL is an aggressive form of a rare white blood cell cancer that is usually fatal. These reports have occurred predominately in adolescents and young adults being treated with these agents for Crohn's disease or ulcerative colitis; however, some case reports occurred in patients treated for psoriasis (one report) or rheumatoid arthritis (two reports). In addition, most of the reported cases of HSTCL have occurred in patients treated with a combination of immunosuppressant agents (including TNF blockers, azathioprine, mercaptopurine), although there have been reports of HSTCL in patients receiving azathioprine or mercaptopurine monotherapy.

The FDA is recommending prescribers discuss with patients the increased risk of HSTCL development, particularly in adolescents and young adults, when prescribing these and other immunosuppressant therapies. Healthcare professionals should monitor for the emergence of malignancies during therapy with TNF blockers, azathioprine, and/or mercaptopurine. Patients should be educated on the signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss) during use. The FDA is also reminding healthcare professionals that patients with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis may be more likely to develop lymphoma compared to the general U.S. population, which can make assessing the additional risk of immunosuppressant use difficult to determine.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm250913.htm

Lenalidomide (Revlimid®): Ongoing Safety Review Regarding Potential for Secondary Malignancies - April 2011

The Food and Drug Administration (FDA) has announced an ongoing safety review of lenalidomide to investigate the potential for an increased risk of developing secondary malignancies. The review was prompted by the results of controlled clinical trials, conducted in and outside of the U.S., which showed an increased incidence of new malignancies in patients who received lenalidomide compared to those who did not. In addition, preliminary outcome data following long-term treatment with lenalidomide also revealed a higher incidence of certain secondary malignancies, particularly acute myelogenous leukemia (AML) and B-cell lymphomas.

Lenalidomide is an analogue of thalidomide, therefore the FDA is also reviewing thalidomide data to determine if thalidomide is also associated with a potential risk of secondary malignancies.

The FDA will communicate recommendations, if any, once its review is complete. At present, there are no recommendations from the FDA for healthcare practitioners to delay, modify, or restrict the use of lenalidomide. Patients should not stop taking lenalidomide unless told to do so by their healthcare provider.

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

Benzocaine Topical Products and Risk of Methemoglobinemia - April 2011

The U.S. Food and Drug Administration (FDA) has issued a statement regarding continued reports of topical benzocaine products causing methemoglobinemia. Methemoglobinemia is a serious and potentially fatal condition in which the amount of oxygen carried through the blood stream is greatly reduced. Signs and symptoms may include pale, gray or blue colored skin, lips, and nail beds; headache; lightheadedness; shortness of breath; fatigue; and rapid heart rate. Symptoms usually appear within minutes to hours of applying benzocaine, and may occur with the first application or prolonged use. The majority of reports have been in children ≤2 years of age receiving benzocaine products for teething pain. The following products have been reported to cause methemoglobinemia:

- Sprays used during medical procedures to numb the mucous membranes of the mouth and throat; as little as a single spray has been implicated.

- Gels and liquids (all strengths) sold over-the-counter to relieve pain from teething, canker sores, or irritation of the mouth and gums.

The FDA recommends:

- Benzocaine products should not be used on children <2 years of age, except under the advice and supervision of a healthcare professional.

- Adult consumers who use benzocaine gels or liquids to relieve pain in the mouth should follow the recommendations in the product label.

- Consumers should store benzocaine products out of the reach of children.

Of note, labels of marketed benzocaine sprays are not currently required as of yet to warn about the risk of methemoglobinemia. The FDA is continuing to evaluate safety data related to benzocaine products and will inform the public when additional information is available.

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

http://www.fda.gov/Safety/MedWatch/SafetyInformation...

http://www.fda.gov/Drugs/DrugSafety/ucm250040.htm

Dabigatran Etexilate: Storage and Handling Alert - March 2011

The U.S. Food and Drug Administration (FDA) has alerted healthcare professionals and the public regarding updated dabigatran storage and handling recommendations. Dabigatran capsules should 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. According to the manufacturer, an opened bottle must be used within 30 days. However, the FDA is currently reviewing data supporting extension of stability to 60 days. Although final review is incomplete, the FDA is recommending that the product be used within 60 days according to this information. Additionally, the manufacturer is evaluating stability beyond 60 days.

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 60 days 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 http://www.fda.gov/Safety/MedWatch/Safety....

Possible Increased Risk of Fractures (Hip, Wrist, and Spine) with Proton Pump Inhibitor (PPI) Use - Updated March 2011

The U.S. Food and Drug Administration (FDA) has announced that over-the-counter (OTC) labeling for proton pump inhibitors (PPI) will not be required to carry an osteoporosis or fracture warning at this time. In May 2010, the FDA had revised all prescription and OTC labels for PPIs with information regarding an increase in the risk of fractures (hip, wrist, and spine) based on several epidemiologic studies. The greatest risk for these fractures was in patients who received high doses or used them for ≥1 year. The majority of the patients in the epidemiologic studies were ≥50 years of age with the risk of fractures being limited to this age group. The FDA has now concluded that short-term, low dose PPI use is unlikely to increase fracture risk.

The FDA has recommended that healthcare providers continue to prescribe, and patients continue to use these products as described within their labeling. In addition, healthcare providers should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. Patients who continue to receive PPIs and who are at risk for osteoporosis, should receive vitamin D and calcium supplementation and have their bone status monitored and managed according to current practice standards. Patients should not stop taking their proton pump inhibitor unless told to do so by their healthcare provider.

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

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrug...

http://www.fda.gov/Safety/MedWatch/SafetyInformation...

Dronedarone and Severe Liver Injury - Updated March 2011

The U.S. Food and Drug Administration (FDA) and Health Canada have notified healthcare professionals and patients about rare reports of dronedarone (Multaq®) causing severe liver injury, including acute liver failure leading to liver transplant in two patients. Information regarding the potential risk of liver injury is being added to the U.S. and Canadian labeling of dronedarone.

Healthcare professionals should consider periodically monitoring serum liver enzymes and bilirubin, especially during the first 6 months of therapy. If liver injury is suspected, dronedarone therapy should be discontinued and liver enzymes and bilirubin should be measured. Appropriate treatment should be started and dronedarone therapy should not be reinitiated if liver injury is confirmed. Patients should be advised to discuss any signs or symptoms of hepatic injury with a healthcare professional.

Further information may be found at:

U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm

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

Immune Globulin, Subcutaneous (Vivaglobin®): Risk of Thrombotic Events Associated with Use - March 2011

The Food and Drug Administration (FDA) is notifying healthcare professionals of postmarketing reports of thrombotic events with use of Vivaglobin®. Vivaglobin® is approved for use as a subcutaneous infusion (the only FDA-approved route). A risk of thrombosis following intravenous administration of immune globulin products has previously been established; however, these recent postmarketing reports involving Vivaglobin ® indicate that there is some degree of risk associated with subcutaneous administration. Inadvertent administration of Vivaglobin® intravenously may be associated with an even higher risk for thrombotic events. Risk factors associated the recent postmarketing reports have included pre-existing cardiovascular disorders, prior thrombotic event, obesity, oral estrogen use, hyperlipoproteinemia, in-dwelling catheter, and immobility. In addition, patients with multiple cardiac risk factors, hypercoagulable disorders, and hyperviscosity may also be at increased risk of thrombosis following use of immune globulin products. According to the FDA, the manufacturer of Vivaglobin®, CSL Behring, has conducted in-house research testing and determined that there is procoagulant activity in Vivaglobin®. The clinical significance of this finding is unknown.

In light of these postmarketing reports, the FDA is making the following recommendations: Vivaglobin® should only be administered via subcutaneous infusion (as described in the prescribing information) at the minimum rate practicable. Vivaglobin® should not be administered intravenously. Patients should be informed of the sign/symptoms of thrombotic events (eg, shortness of breath, pain, swelling of a limb, focal neurological deficits).

Additional information may be found at http://www.fda.gov/BiologicsBloodVaccines....

Lopinavir/Ritonavir (Kaletra®): Serious Health Problems Seen in Preterm Neonates Given Lopinavir/Ritonavir Oral Solution - March 2011

The Food and Drug Administration (FDA) is notifying healthcare professionals of serious cardiac, renal, or respiratory problems reported in preterm neonates receiving lopinavir/ritonavir oral solution. Lopinavir/ritonavir oral solution contains ethanol and propylene glycol. Ethanol competitively inhibits propylene glycol metabolism, which may lead to propylene glycol toxicity due to impaired elimination in neonates (full-term or preterm). Preterm neonates are at an increased risk of adverse events from propylene glycol toxicity, including cardiotoxicity (complete AV block, bradycardia, cardiomyopathy), lactic acidosis, CNS depression, respiratory complications, acute renal failure and death.

The oral solution should not be used in the immediate postnatal period (including full-term neonates <14 days old or preterm neonates until 14 days after their due date) unless the benefits clearly outweigh risks. If used, neonates should be closely monitored for increases in serum osmolality and serum creatinine, and other signs of propylene glycol toxicity (eg, CNS depression, seizures, cardiac arrhythmias, hemolysis); symptoms should be distinguished from neonatal sepsis. In addition, parents and caregivers should be instructed to contact their healthcare professional immediately if their baby appears too sleepy or if their breathing has changed during therapy with lopinavir/ritonavir oral solution. Lopinavir/ritonavir product labeling has been updated to reflect these new warnings.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm246002.htm.

Ambrisentan (Letairis®): Boxed Warning Pertaining to Hepatotoxicity to be Removed From Product Labeling - March 2011

The Food and Drug Administration (FDA) announced that the product labeling for Letairis® will no longer contain hepatic injury information in the boxed warning. The FDA also concluded that routine monthly monitoring of serum liver enzymes is no longer necessary, and shipment of Letairis® through the Letairis Education and Access Program (LEAP) will no longer be contingent upon these tests being performed. This decision follows the FDA's review of all available data, including clinical trials and postmarketing reports, which indicated that the risk for hepatic injury in ambrisentan-treated patients is consistent with the general pulmonary artery hypertension (PAH) population, and is similar to placebo-treated patients during clinical trials with ambrisentan.

The FDA is reminding healthcare professionals that although monthly liver enzyme testing is no longer required, clinicians should continue to perform liver enzyme testing when clinically appropriate. Therapy should be discontinued if signs/symptoms of hepatic injury appear, if serum liver aminotransferases >5 times ULN are observed, or if aminotransferases are increased in the presence of bilirubin >2 times ULN. Of note, the warning against ambrisentan use in moderate and severe hepatic impairment is unchanged.

For additional information, please refer to http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm245848.htm.

Proton Pump Inhibitors (PPIs): Long-term Use May be Associated With Hypomagnesemia - March 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare providers and patients that long-term use of proton pump inhibitors (PPIs) may be associated with hypomagnesemia. Some of the reported cases of hypomagnesemia occurred after 3 months of use, but most occurred in patients using PPIs for longer than 1 year. The mechanism for this adverse effect is not clearly defined.

Healthcare providers should consider obtaining serum magnesium levels prior to beginning long-term PPI therapy, especially in patients taking concomitant digoxin, diuretics, or other drugs known to cause hypomagnesemia; and periodically thereafter. Although magnesium supplementation may correct hypomagnesemia, discontinuation of the PPI may be necessary to correct and maintain normal magnesium levels. Typically, according to the case reports, magnesium levels returned to normal within 1 week of stopping the PPI. Hypomagnesemia can cause serious adverse events including tetany, tremors, seizures, QT prolongation, and cardiac arrhythmias. Patients should not stop PPI therapy without first discussing with a healthcare professional.

The FDA is requiring all manufacturers of prescription PPI products to update the package labeling to include the potential risk of hypomagnesemia. Since OTC PPIs are only approved for short-term use, the package labeling for these products will not be updated. However, healthcare professionals should be aware of the risk of hypomagnesemia if OTC PPIs are used longer than the approved use.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm245011.htm.

Abacavir: Update on the Risk of Myocardial Infarction - March 2011

In July 2008, the U.S. Food and Drug Administration (FDA) notified healthcare professionals of a possible increased risk of myocardial infarction (MI) in patients taking nucleoside reverse transcriptase inhibitors (NRTIs), including abacavir, based on observational study data. Subsequently, the FDA completed a meta-analysis of 26 abacavir randomized clinical trials conducted between 1996 and 2010. Although several observational studies and one randomized controlled trial showed an increased risk of MI, the FDA has concluded there is not an increased risk of MI with abacavir use based on the overall meta-analysis.

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm245164.htm.

Warfarin (Jantoven®): Recall Due to Mislabeled Bottle - Updated February 2011

Upsher-Smith Laboratories has initiated a voluntary recall of Jantoven® warfarin sodium tablets. The precautionary recall was prompted after a single bottle labeled with 3 mg tablets (tan colored tablets) was found to actually contain the 10 mg strength tablets (white colored tablets). The risk of administering a 10 mg strength tablet in place of the intended 3 mg strength tablet could potentially result in life-threatening hemorrhage.

As an additional precautionary measure, Upsher-Smith Laboratories has expanded its previously announced recall to include additional products and lots produced on the same line during a similar period of time.

For the most recent information, including the products recalled, please refer to http://www.upsher-smith.com.

Antipsychotics: Newborn Extrapyramidal and Withdrawal Symptoms with Third Trimester Exposure - February 2011

The U.S. Food and Drug Administration (FDA) has updated the pregnancy section of the prescribing information for antipsychotics to contain detailed information about nonteratogenic effects following maternal use during pregnancy. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms; EPS) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor. These effects vary in severity and may be self-limiting (subsiding within hours or days) or require hospitalization. In the cases reported to the FDA, concomitant use of other medications (known to precipitate withdrawal symptoms) may have contributed to the effects, although in some cases, antipsychotic medication use was the only contributing factor for the EPS and withdrawal symptoms.

Women who are taking antipsychotics should not stop them if they become pregnant (abrupt discontinuation is not recommended), but should notify their healthcare provider. Women taking antipsychotics who intend to become pregnant should discuss treatment concerns with their healthcare provider. Any adverse effects noted in newborns should be reported to the FDA's Medwatch program (1-800-332-1088 or https://www.accessdata.fda.gov/scripts/...).

For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm#aihp

Terbutaline: Serious Maternal Adverse Reactions When Used for Preterm Labor - February 2011

The U.S. Food and Drug Administration (FDA) is requiring the addition of a boxed warning related to the unlabeled use of terbutaline for the prevention of preterm labor. These labeling changes are due to the potential for maternal death and serious heart problems, including increased heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema, and myocardial ischemia.

The FDA reviewed postmarketing reports of maternal death and serious cardiovascular adverse events associated with the obstetric use of terbutaline and have identified 16 maternal deaths and 12 maternal cases of serious cardiovascular events reported. These cases involved both inpatient and outpatient use of oral, subcutaneous, and/or intravenous terbutaline. Based on this information, the FDA has concluded that the risk of serious events outweighs any potential benefit to pregnant women receiving prolonged treatment (>48-72 hours) with terbutaline injection. Oral terbutaline should not be used for prevention or any treatment of preterm labor because it has not been shown to be effective and has similar safety concerns. These label changes are consistent with statements from the American College of Obstetricians and Gynecologists (ACOG) on management of preterm labor.

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

Antipyrine and Benzocaine Otic Solution (Auralgan®): Forced Withdrawal from U.S. Market - February 2011

All available lots of Auralgan® otic solution have been seized by U.S. Marshals at the request of the U.S. Food and Drug Administration (FDA). The product was seized because it does not have FDA approval and its labeling does not contain adequate instructions for appropriate use.

This action is a part of the 2006 FDA initiative to get unapproved drugs to either obtain FDA approval or be removed from the market.

For further details, please refer to http://www.fda.gov/NewsEvents/Newsroom...

Methylene Blue: Risk of Serotonin Syndrome when Administered in Combination with Serotonin Reuptake Inhibitors - February 2011

Health Canada has issued important safety information notifying practitioners of updates to the methylene blue Canadian prescribing information. These changes are a result of several case reports of serotonin toxicity in association with the use of injectable methylene blue in patients exposed to selective serotonin reuptake inhibitors (SSRIs) or other drugs with serotonin reuptake inhibition properties (eg, duloxetine, venlafaxine, clomipramine). Recent research has shown that methylene blue has structural properties similar to monoamine oxidase inhibitors (MAOI). Revisions to the prescribing information will include the following points:

- Serotonin syndrome (agitation or diaphoresis, or hypertonia accompanied with fever, and tremor, hyperreflexia, or clonus) has been reported when methylene blue was administered intravenously at concentrations as low as 1 mg/kg in patients also receiving other medications with serotonin reuptake inhibition properties. Several of these cases required admission to the intensive care unit.

- Carefully consider concurrent use of methylene blue with a serotonin reuptake inhibitor; allow a washout period of at least 4-5 half lives of the serotonin reuptake inhibitor prior to intravenous methylene blue use.

For further detail regarding these changes, please refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/...

Rosiglitazone (Avandia®): Addition of a Risk Evaluation and Mitigation Strategy (REMS) - Updated February 2011

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals and patients that the use of rosiglitazone (Avandia®) will now be restricted to patients already being treated with rosiglitazone and in patients with type 2 diabetes mellitus whose disease cannot be adequately managed with other antidiabetic medications and who are unable or unwilling to take pioglitazone (Actos®). The new restrictions are in response to data suggesting an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with rosiglitazone. At this time, the FDA will require GlaxoSmithKline, the manufacturer of Avandia®, to develop a restricted access program under a risk evaluation and mitigation strategy (REMS); the REMS is expected to be approved by Spring 2011. Physicians prescribing rosiglitazone will have to attest to and document their patients' eligibility; patients prescribed the drug will have to review statements describing the cardiovascular safety concerns associated with rosiglitazone and acknowledge they understand the risks. Patients currently taking rosiglitazone and benefiting from the drug may continue to use the medication if they choose to do so.

Health Canada has added similar restrictions for rosiglitazone, which is now only indicated in patients with type 2 diabetes where other medications are either inappropriate (due to intolerance or to contraindications) or do not result in adequate glycemic control (as monotherapy or in combination). Prior to initiation of rosiglitazone, there must be adequate documentation that the patient meets the eligibility criteria for rosiglitazone treatment, patients must be counseled on the risks (including cardiovascular) of treatment with rosiglitazone, and have written informed consent from the patient for treatment with rosiglitazine. Additionally, the Canadian Product Monographs for rosiglitazone and combination products containing rosiglitazone have been updated to reflect the restrictions and new boxed warnings have been added.

For additional information, refer to:

U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm241411.htm

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff...

CDC Recommendations for the Use of Antivirals for Influenza - Februrary 2011

The Centers for Disease Control and Prevention (CDC) has issued recommendations for the use of antivirals for the control and prevention of influenza. Amantadine and rimantadine are not effective for the treatment or prevention of the currently circulating strains of influenza A virus. Oseltamivir or zanamivir should be used when an antiviral agent is needed. Based on information from the IDSA, rimantadine may be useful in order to control outbreaks in institutions under certain conditions: if influenza A virus subtyping is unavailable and oseltamivir resistant viruses are circulating, rimantadine may be used in combination with oseltamivir if zanamivir cannot be used (Harper 2009).

CDC recommendations may change as more information on antiviral susceptibilities and effectiveness becomes available. For the most recent recommendations and information from the CDC, please refer to Seasonal Influenza (Flu) "Antiviral Drugs, Information for Healthcare Professionals" at http://www.cdc.gov/flu/professionals/antivirals/index.htm.

Influenza Virus Vaccine (2010-2011 Season): Fluzone® and Risk of Febrile Seizures - January 2011

The U.S. Food and Drug Administration (FDA) and Centers for Disease Control (CDC) have observed increased reports of febrile seizures associated with the use of Fluzone® (trivalent inactivated influenza [TIV] vaccine; Sanofi Pasteur, Inc). Reports of febrile seizures have increased in children <2 years of age; however, no long-term adverse effects have been noted. There have been no increased reports of febrile seizures in patients >2 years of age after vaccination with TIV or live attenuated influenza vaccine (FluMist®). Further investigations are being conducted to determine if there is an association between influenza vaccination and febrile seizures; however, Fluzone® is still the recommended vaccine for infants and children 6-23 months of age for the 2010-2011 flu season.

Additional information may be found at http://www.fda.gov/BiologicsBloodVaccines...

Dronedarone and Severe Liver Injury - January 2011

The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals and patients about rare reports of dronedarone (Multaq®) causing severe liver injury, including acute liver failure leading to liver transplant in two patients. Information regarding the potential risk of liver injury is being added to the labeling of dronedarone (Warnings, Precautions, and Adverse Reactions sections).

Healthcare professionals should consider periodically monitoring serum liver enzymes and bilirubin, especially during the first 6 months of therapy. If liver injury is suspected, dronedarone therapy should be discontinued and liver enzymes and bilirubin should be measured. Appropriate treatment should be started and dronedarone therapy should not be reinitiated if liver injury is confirmed. Patients should be advised to discuss any signs or symptoms of hepatic injury with a healthcare professional.

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

Acetaminophen: Change in Maximum Content of Prescription Products and Labeling Changes - January 2011

The Food and Drug Administration (FDA) is asking manufacturers to limit the strength of acetaminophen in prescription products to 325 mg per dosage unit. Drug manufacturers will have until January 14, 2014 to comply with the FDA's request. The dosing instructions of prescription acetaminophen products will not change. For example, the instructions of 1-2 tablets every 4-6 hours for a combination product of acetaminophen 500 mg with an opioid can still be used for a combination product of acetaminophen 325 mg with an opioid.

The FDA is also notifying healthcare professionals of labeling changes for all prescription products that contain acetaminophen. A Boxed Warning will be required on all prescription acetaminophen products to describe the potential risk of severe liver injury. Additionally, the FDA has asked manufacturers to add a Warning regarding the potential for allergic reactions, including anaphylaxis.

Healthcare professionals should advise patients:

- not to exceed 4 g/day of acetaminophen

- not to take multiple acetaminophen-containing products (including over-the-counter products)

- not to consume alcohol while taking acetaminophen-containing products

- that severe liver injury and cases of hypersensitivity reactions (including anaphylaxis) have occurred with the use of acetaminophen

- to report taking more acetaminophen than directed

- to report any adverse events that may have occurred with the use of acetaminophen

Further information may be found at: http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm

Morphine Sulfate Oral Solution: Labeling Changes Due to Reports of Accidental Overdose - January 2011

The Food and Drug Administration (FDA) and Roxane Laboratories have notified healthcare professionals of accidental overdoses with morphine sulfate oral solutions leading to adverse events and deaths. In most of these cases, morphine sulfate oral solutions ordered in milligrams (mg) were mistakenly interchanged for milliliters (mL) of the product. To reduce the risk of medication errors, the labeling of the high potency morphine sulfate (100 mg/5 mL [20 mg/mL]) oral solution has been changed.

The following labeling changes have been implemented:

- A boxed warning has been added to the prescribing information noting that morphine sulfate oral solution is available in 10 mg/5 mL, 20 mg/5 mL, and 100 mg/5 mL concentrations. The 100 mg/5 mL (20 mg/mL) concentration is indicated for use in opioid-tolerant patients only.

- A warning stating "Only for use in patients who are opioid tolerant" is highlighted on the product label for the 100 mg/5 mL (20 mg/mL) strength. Fatal respiratory depression may occur if the high potency morphine sulfate oral solution (100 mg/5 mL [20 mg/mL]) is administered to patients not previously exposed to opioids.

- In an effort to distinguish between the 20 mg per mL and the 20 mg per 5 mL morphine sulfate oral solutions, the strength of the high potency morphine sulfate oral solution is now presented as 100 mg/5 mL followed by a less prominently displayed concentration of 20 mg/mL. Additionally, the drug name, strength, and concentration are displayed in white lettering on a red background and a bright yellow background is used on multiple sides of the product.

- The 30 mL and 120 mL morphine sulfate (100 mg/5 mL [20 mg/mL]) oral solutions are packaged with a calibrated oral syringe for accurate dose measurements and should be dispensed with the prescription. Correct use of the oral syringes should be discussed with the patient.

- A reminder is presented to dispense the enclosed Medication Guide with each prescription.

Finally, prescriptions should be written clearly for morphine sulfate oral solutions. The concentration of morphine sulfate oral solution should be used; morphine sulfate should be written out, not abbreviated; and the intended dose of morphine in milligrams (mg) with the corresponding volume in milliliters (mL) should be written out in the prescription directions. For example: Morphine sulfate oral solution 100 mg/5 mL (20 mg/mL) 15 mg (0.75 mL) orally every 4 hours as needed.

For additional information, please refer to the following FDA websites:

http://www.fda.gov/Safety/MedWatch/SafetyInformation...

http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation...

Sodium Bicarbonate: American Regent Recall of 7.5% and 8.4% Single-Dose 50 mL Vials - December 2010

American Regent and the U.S. Food and Drug Administration (FDA) notified healthcare providers of a national voluntary recall of Sodium Bicarbonate Injection, USP, 7.5% 50 mL single-dose vials and 8.4% 50 mL single-dose vials. Some vials of the affected lots contain particulates. Potential adverse events after intravenous administration include damage to blood vessels in the lung, localized swelling, and granuloma formation. Healthcare providers should not use these products in the lot numbers identified above and should immediately quarantine any product for return.

Further information (including lots affected) is available on the following websites:

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

http://www.fda.gov/Safety/Recalls/ucm238227.htm

Somatropin: Ongoing Safety Review of the Santé Adulte GH Enfant (SAGhE) Study - December 2010

The U.S. Food and Drug Administration (FDA) is informing the public of a French observational (SAGhE) study's results describing a small increased risk of death in adults who were treated with recombinant human growth hormone (somatropin) during childhood for certain types of short stature (eg, idiopathic growth hormone deficiency, idiopathic or gestational short stature). The study population included people who received somatropin between 1985 and 1996 and whose vital status and cause of death were determined through September 2009. There were 93 observed deaths in the somatropin group versus 70 expected deaths in the general French population. The data suggests an increase in mortality due to bone tumors and cardiovascular events (eg, subarachnoid or intracerebral hemorrhage) in the somatropin group. The risk of death was reported to be increased when higher than recommended doses of somatropin were used.

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has initiated a safety review but confirms that there is no immediate concern. Prescribers are reminded to strictly follow the indications for use and approved doses. The FDA is currently reviewing available information on the potential risk as well. The FDA and European Medicines Agency are recommending that patients continue this medication unless their healthcare providers discontinue the treatment.

Further information may be found at:

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

Europe: http://www.ema.europa.eu/ema/index.jsp?curl=pages...

Dolasetron: Parenteral Administration Increases Risk Of Torsades de Pointes; Labeling Updated With New Contraindication - December 2010

The U.S. Food and Drug Administration (FDA) has announced that injectable dolasetron (Anzemet®) is now contraindicated for use in the prevention of chemotherapy induced nausea and vomiting (CINV) in pediatric and adult patients, due to an increased risk for development of torsades de pointes. Patients at increased risk include those with underlying cardiac abnormalities and/or existing rate/rhythm problems. The FDA has determined that limitations of previous data which suggested dolasetron could cause QT prolongation failed to clearly establish the degree of this effect.

Results of a manufacturer sponsored randomized, placebo and active comparator controlled crossover study of healthy adults demonstrated significant QT prolongation with intravenous dolasetron (100 mg and 300 mg [supratherapeutic] doses). Compared to placebo, a maximum mean change in QTcF (95% upper confidence bound) of 14.1 (16.1) msec was observed with 100 mg dolasetron and 36.6 (38.6) msec with 300 mg dolasetron. PR and QRS intervals were also prolonged. Dolasetron appears to have a dose-dependent effect on the QT, PR, and QRS intervals. Predictions of QT prolongation in the pediatric population were simulated based upon known intravenous dolasetron pharmacokinetics and demonstrated an increase in the QTcF interval by a mean (90% CI) of 22.5 msec (21.1-23.9 msec) for the CINV recommended dose (1.8 mg/kg).

Oral dolasetron may still be used to prevent CINV due to a decreased risk of developing an arrhythmia; however, a stronger warning about the potential risk is being added to its labeling. Oral dolasetron is also indicated for use in the prevention of postoperative nausea and vomiting (PONV). Injectable dolasetron may still be used for the treatment and prevention of PONV as lower doses are required for PONV and are less likely to cause arrhythmia; however, patients at higher risk for developing arrhythmia should not receive intravenous or oral dolasetron (eg, those with congenital long QT syndrome). Additional monitoring (ie, ECG, potassium and magnesium concentrations) is necessary for patients with heart failure, bradycardia, the elderly, those with renal impairment, and those at risk of developing hypokalemia or hypomagnesemia during treatment with dolasetron. If abnormal, potassium and magnesium concentrations should be corrected prior to and during treatment with dolasetron.

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

Bevacizumab: FDA Recommends Removal of Breast Cancer Indication from the Product Labeling - December 2010

The U.S. Food and Drug Administration (FDA) has announced that it is recommending removal of the metastatic breast cancer indication from bevacizumab (Avastin®) labeling, citing a lack of demonstrated safety and efficacy in breast cancer. After reviewing data from four clinical trials, the FDA has determined that use of bevacizumab in breast cancer patients does not prolong overall survival and does not 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).

The manufacturer (Genentech) has not agreed to voluntarily remove the breast cancer indication at this time. Therefore, the FDA has issued permission for the manufacturer to request a public hearing within 15 days, should Genentech wish to contest the FDA's decision. Failure of Genentech to request a hearing within the allotted time will result in the FDA proceeding forward with the removal of the indication. The FDA has stated it is open to working with Genentech to conduct further studies to possibly identify a certain population of patients with breast cancer that might benefit from therapy.

At present, in regards to bevacizumab therapy, the FDA is further emphasizing that:

- The drug is not being removed from the market and that the current recommendations do not affect other approved indications (eg, colon, kidney, brain, and lung cancers).

- Breast cancer patients will still have access to therapy until a final decision has been made.

- Clinicians currently treating patients with metastatic breast cancer should use their medical judgment in regards to continuing treatment with bevacizumab or considering alternative therapies.

Further information may be found at http://www.fda.gov/NewsEvents/Newsroom....

Benzonatate: Accidental Ingestion and Fatal Overdose In Children; FDA Issues Warning - December 2010

The U.S. Food and Drug Administration (FDA) has issued a warning in regards to accidental ingestion and potentially fatal overdose of benzonatate (Tessalon®) in children <10 years of age. Though benzonatate overdose has been reported in adults and adolescents, all accidental ingestions reported to the FDA to date, have occurred in children <10 years, and in some cases, have been reported following ingestion of as few as 1 or 2 capsules in children <2 years. Signs and symptoms of overdose (restlessness, tremors, convulsion, coma, cardiac arrest) may occur within 15-20 minutes after ingestion. Fatalities in children have been reported within hours of accidental ingestion. Benzonatate is not approved for use in children <10 years of age.

Healthcare providers are advised to:

• Prescribe benzonatate only in sufficient quantities for relief of cough.
• Dispense the drug in child resistant containers.
• Be aware of the signs/symptoms of overdose and of their potentially rapid onset.

Healthcare professionals should advise patients on or how to:

• Proper storage (child-resistant container kept away out of children's reach) and disposal of any unused drug upon discontinuation of therapy.
• Contact the Poison Control Center at 1-800-222-1222 and seek immediate medical attention following accidental ingestion by a child.
• Proper dosage and administration including instructions regarding missed doses.

The product labeling is being revised by the FDA. Further information is available at http://www.fda.gov/Drugs/DrugSafety/ucm236651.htm.

Sitaxentan: Idiosyncratic Liver Toxicity: Manufacturer Announces Voluntary Withdrawal From Canadian Market - December 2010

(Thelin®) from the Canadian market and is discontinuing clinical studies of the drug worldwide. The announcement comes after clinical trial and postmarketing data have identified an increased risk of potentially life-threatening idiosyncratic liver toxicity. The manufacturer is recommending that healthcare providers no longer prescribe sitaxentan and to transition patients to alternative therapies as soon as clinically feasible. Patients should be advised to not stop taking sitaxentan until they consult with their healthcare providers.Further information may be found at http://www.pfizer.ca/en/media_centre/news_releases...

Propoxyphene: Withdrawal from the U.S. and Canadian Markets - Updated December 2010

Xanodyne Pharmaceuticals Inc, the manufacturer of Darvon® (propoxyphene) and Darvocet® (propoxyphene and acetaminophen), in conjunction with the U.S. Food and Drug Administration (FDA), has agreed to withdraw both products from the U.S. market. This decision is the result of a recent safety study which demonstrated an increased risk of potentially serious and fatal cardiac rhythm abnormalities with propoxyphene. The FDA has requested that all generic manufacturers of propoxyphene-containing products also voluntarily withdraw their products from the market as well. Due to the same safety concerns prompting the U.S. withdrawal, Paladin Labs, Inc, in collaboration with Health Canada, is voluntarily withdrawing NDarvon-N® (dextropropoxyphene) from the Canadian market. Prescribers are advised to no longer prescribe propoxyphene-containing products. Patients should contact their healthcare provider to discuss alternative pain management.

For further details, please refer to:

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

Canada: http://hc-sc.gc.ca/dhp-mps/medeff...

Propoxyphene: Withdrawal from the U.S. Market - November 2010

Xanodyne Pharmaceuticals Inc, the manufacturer of Darvon® (propoxyphene) and Darvocet® (propoxyphene and acetaminophen), in conjunction with the U.S. Food and Drug Administration (FDA), has agreed to withdraw both products from the U.S. market. This decision is the result of a recent safety study which demonstrated an increased risk of potentially serious and fatal cardiac rhythm abnormalities with propoxyphene. The FDA has requested that all generic manufacturers of propoxyphene-containing products also voluntarily withdraw their products from the market as well. Prescribers are advised to no longer prescribe propoxyphene-containing products. Patients should contact their healthcare provider to discuss alternative pain management.

For further details, please refer to: http://www.fda.gov/Safety/MedWatch/SafetyInformation...

Rosiglitazone (Avandia®): Addition of a Risk Evaluation and Mitigation Strategy (REMS) - Updated November 2010

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals and patients that the use of rosiglitazone (Avandia®) will now be restricted to patients with type 2 diabetes mellitus whose disease cannot be adequately managed with other antidiabetic medications and who are unable to take pioglitazone (Actos®). The new restrictions are in response to data suggesting an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with rosiglitazone. At this time, the FDA will require GlaxoSmithKline, the manufacturer of Avandia®, to develop a restricted access program under a risk evaluation and mitigation strategy (REMS). Physicians prescribing rosiglitazone will have to attest to and document their patients' eligibility; patients prescribed the drug will have to review statements describing the cardiovascular safety concerns associated with rosiglitazone and acknowledge they understand the risks. Patients currently taking rosiglitazone and benefiting from the drug may continue to use the medication if they choose to do so.

Health Canada has added similar restrictions for rosiglitazone, which is now only indicated in patients with type 2 diabetes where other medications are either inappropriate (due to intolerance or to contraindications) or do not result in adequate glycemic control (as monotherapy or in combination). Prior to initiation of rosiglitazone, there must be adequate documentation that the patient meets the eligibility criteria for rosiglitazone treatment, patients must be counseled on the risks (including cardiovascular) of treatment with rosiglitazone, and have written informed consent from the patient for treatment with rosiglitazine. Additionally, the Canadian Product Monographs for rosiglitazone and combination products containing rosiglitazone have been updated to reflect the restrictions and new boxed warnings have been added.

For additional information, refer to:

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

Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/...

Diphtheria and Tetanus Toxoids, and Acellular Pertussis Vaccine: Use of Tdap in People ≥ 65 Years of Age - November 2010

There are reports of increased cases of pertussis (also known as whooping cough) circulating in the United States. From January to November 2, 2010, > 6,400 cases of pertussis (including 10 infant deaths) were reported throughout California; this is the most number of cases reported in 60 years. Michigan has also reported an increase in cases beginning at the end of 2008 and continuing through 2010. Pertussis infection can cause serious illness in infants, children, and adults. Immunization is recommended to prevent transmission of this disease.

The diphtheria, tetanus toxoids, and acellular pertussis vaccines are currently approved to provide immunization against pertussis, as well as diphtheria and tetanus. Two types of vaccine are available in the United States: DTaP which is used to provide active immunization in children from age 6 weeks through 6 years of age; and Tdap which is used to provide booster immunization in older children and adults. Tdap (Adacel®, Boostrix®) contains lower amounts of diphtheria toxoid and pertussis antigens than DTaP and cannot be used for primary immunization.

In adults 19-64 years of age, a single dose of Tdap is recommended to replace a single dose of Td if the last dose of Td was ≥ 10 years earlier (not for multiple administrations; recommendations are for the replacement of a single dose of Td only). The Advisory Committee on Immunization Practices (ACIP) recommends immunization of adults who anticipate close contact with children < 12 months of age to protect them against pertussis transmission; Tdap should be administered at least 2 weeks prior to beginning close contact. However, Tdap is currently not FDA approved for use in adults ≥65 years of age. The ACIP proposed a recommendation for use of Tdap in people ≥65 years at their October 27-28, 2010 meeting. Guidelines for use in this population are pending. Providers may choose to give Tdap in persons 65 years and older if the clinician and patient agree that the benefits of the off-label use of the vaccine exceed the risk. This may be especially important during a community outbreak and/or if caring for an infant. The safety of Tdap in persons 65 years and older is likely the same as in persons 18-64 years of age.

Refer to the Recommended Adult (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5901a5.htm) and Child (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5851a6.htm) Immunization Schedules for complete guidance on the use of Tdap and DTaP.

Also refer to the following CDC websites for additional information on pertussis and the use of Tdap in older adults:

Pertussis (whooping cough): http://www.cdc.gov/pertussis/index.html, last updated 8/27/10

Pertussis Outbreaks - Questions and Answers http://www.cdc.gov/pertussis/outbreaks-faqs.html, last updated 8/26/10

Pertussis: Summary of Vaccine Recommendations http://www.cdc.gov/vaccines/vpd-vac/pertussis/recs-summary.htm, last updated 8/16/10

Statement Released Regarding Clopidogrel-Proton Pump Inhibitor (PPI) Interaction - November 2010

The American College of Cardiology Foundation, in conjunction with the American College of Gastroenterology and the American Heart Association, has issued a consensus document regarding the concomitant use of PPIs and thienopyridines, specifically clopidogrel.

The following highlighted recommendations are discussed within this consensus statement:

• Clopidogrel alone, aspirin alone, and their combination are associated with an increased risk of GI bleeding.
• Risk of GI bleeding increases as the number of risk factors increase (eg, prior GI bleeding, advanced age, concurrent use of anticoagulants).
• PPIs are appropriate in patients with multiple risk factors for GI bleeding who are also receiving antiplatelet therapy (eg, clopidogrel).
• Although pharmacokinetic and pharmacodynamic studies have demonstrated varying effects of PPIs on the extent of clopidogrel metabolic conversion to the active metabolite, no evidence has established clinically meaningful differences in outcomes.
• A clinically-significant interaction cannot be excluded in subgroups who are poor metabolizers of clopidogrel.
• Until solid evidence exists to support staggering PPIs with clopidogrel, the dosing of PPIs should not be altered.

Healthcare professionals must evaluate the risks and benefits of concomitant use of PPIs and thienopyridines, considering both the cardiovascular and GI complications. For more information, healthcare professionals may refer to the following website: http://content.onlinejacc.org/cgi/reprint/...

Saquinavir (Invirase®): U.S. Prescribing Information Updated to Include Risk of Abnormal Heart Rhythms - Updated November 2010

The U.S. Food and Drug Administration (FDA) has notified healthcare providers of recent updates to the prescribing information for saquinavir (Invirase®). The labeling changes, including new contraindications, are related to the potential for prolonged QT or PR intervals with saquinavir administered with ritonavir. Prolonged QT interval (potentially leading to torsade de pointes) and prolonged PR interval (potentially leading to heart block) have been observed with the FDA-approved saquinavir/ritonavir combination. Patients with preexisting cardiac conduction abnormalities, cardiomyopathies, or ischemic heart disease may be at increased risk.

The recent labeling updates were prompted by an FDA review, initiated in February 2010, of a clinical study evaluating the effects of saquinavir/ritonavir on the QT interval. The randomized, crossover study used a placebo, an active control of moxifloxacin, the FDA-approved regimen of saquinavir 1000 mg/ritonavir 100 mg twice daily, and a supratherapeutic regimen of saquinavir 1500 mg/ritonavir 100 mg twice daily. The study demonstrated a dose-dependent effect of saquinavir/ritonavir on the QTc and PR intervals.

U.S. healthcare professionals are advised by the FDA to:

- Note the additional contraindications for saquinavir in patients with congenital or acquired QT prolongation, refractory hypokalemia or hypomagnesemia, or concomitant use of medications that both increase saquinavir plasma concentrations and prolong the QT interval. Saquinavir is also contraindicated in patients with complete AV block (without implanted ventricular pacemakers) or those at high risk of complete AV block.

- Prior to initiation of therapy, an electrocardiogram (ECG) should be performed. Patients with a QT interval >450 msec should not receive saquinavir/ritonavir. In patients with a QT interval <450 msec, a second ECG after 3-4 days of therapy is suggested. If QT interval is >480 msec or if QT prolongation exceeds pretreatment value by >20 msec, saquinavir/ritonavir should be discontinued.

A medication guide, also communicating the risk of abnormal heart rhythms, is available and required for patient distribution. Patients should be instructed to contact a healthcare provider immediately if they experience symptoms of an abnormal heart rate/rhythm.

Of note, Health Canada has issued "Dear HealthCare Professional" letters (April 2010, October 2010) to Canadian practitioners regarding updates made to the Canadian product monograph for saquinavir (Invirase®) concerning the risk for abnormal heart rhythms with saquinavir/ritonavir use.

For additional information, refer to the following websites:

U.S.: http://www.fda.gov/NewsEvents/Newsroom/...

Canada:

http://hc-sc.gc.ca/dhp-mps/alt_formats/...1

http://hc-sc.gc.ca/dhp-mps/alt_formats/...2

Fentanyl Transdermal System: Recall Due to Potential for Faster Release of Fentanyl - October 2010

Actavis Inc. has announced a voluntary recall to the wholesale and retail level of 18 lots of Fentanyl Transdermal System 25 mcg/hour patches. The recall was initiated after the manufacturer identified a single 25 mcg/hour patch from one lot that released fentanyl at a faster rate than the approved specification, which could potentially lead to an increased risk of respiratory depression and sedation.

Further information, including the lots affected, may be found at: http://www.fda.gov/Safety/MedWatch/SafetyInformation...

Carboplatin Dosing Using Estimated Glomerular Filtration Rates - October 2010

When calculating the carboplatin dose using the Calvert formula and an estimated glomerular filtration rate (GFR), the laboratory method used to measure serum creatinine may impact dosing. By the end of 2010, all clinical laboratories in the United States will use standardized Isotope Dilution Mass Spectrometry (IDMS) to measure serum creatinine. Compared to prior methods used, IDMS may underestimate serum creatinine values in patients with low creatinine values (eg, ≤0.7 mg/dL) and overestimate GFR in patients with normal renal function. This may result in higher calculated carboplatin doses and increased toxicities. If using IDMS, the Food and Drug Administration (FDA) recommends that clinicians consider capping estimated GFR at a maximum of 125 mL/minute to avoid potential toxicity. If used as part of an ongoing clinical trial, the decision regarding capping should be assessed by the principal investigator.

For further information, refer to http://www.fda.gov/AboutFDA/....

Saquinavir (Invirase®): U.S. Prescribing Information Updated to Include Risk of Abnormal Heart Rhythms - October 2010

The U.S. Food and Drug Administration (FDA) has notified healthcare providers of recent updates to the prescribing information for saquinavir (Invirase®). The labeling changes, including new contraindications, are related to the potential for prolonged QT or PR intervals with saquinavir administered with ritonavir. Prolonged QT interval (potentially leading to torsade de pointes) and prolonged PR interval (potentially leading to heart block) have been observed with the FDA-approved saquinavir/ritonavir combination. Patients with preexisting cardiac conduction abnormalities, cardiomyopathies, or ischemic heart disease may be at increased risk.

The recent labeling updates were prompted by an FDA review, initiated in February 2010, of a clinical study evaluating the effects of saquinavir/ritonavir on the QT interval. The randomized, crossover study used a placebo, an active control of moxifloxacin, the FDA-approved regimen of saquinavir 1000 mg/ritonavir 100 mg twice daily, and a supratherapeutic regimen of saquinavir 1500 mg/ritonavir 100 mg twice daily. The study demonstrated a dose-dependent effect of saquinavir/ritonavir on the QTc and PR intervals.

U.S. healthcare professionals are advised by the FDA to:

- Note the additional contraindications for saquinavir in patients with congenital or acquired QT prolongation, refractory hypokalemia or hypomagnesemia, or concomitant use of medications that both increase saquinavir plasma concentrations and prolong the QT interval. Saquinavir is also contraindicated in patients with complete AV block (without implanted ventricular pacemakers) or those at high risk of complete AV block.

- Prior to initiation of therapy, an electrocardiogram (ECG) should be performed. Patients with a QT interval >450 msec should not receive saquinavir/ritonavir. In patients with a QT interval <450 msec, a second ECG after 3-4 days of therapy is suggested. If QT interval is >480 msec or if QT prolongation exceeds pretreatment value by >20 msec, saquinavir/ritonavir should be discontinued.

A medication guide, also communicating the risk of abnormal heart rhythms, is available and required for patient distribution. Patients should be instructed to contact a healthcare provider immediately if they experience symptoms of an abnormal heart rate/rhythm.

Of note, in April 2010, a "Dear HealthCare Professional" letter was distributed to Canadian practitioners regarding updates made to the Canadian product monograph for saquinavir (Invirase®) concerning the risk for abnormal heart rhythms with saquinavir/ritonavir use.

For additional information, refer to the following websites:

U.S.: http://www.fda.gov/NewsEvents/Newsroom...

Canada: http://hc-sc.gc.ca/dhp-mps/alt_formats/pdf/medeff...

GnRH Agonists: Prescribing Information to Include Increased Risk of Diabetes and Cardiovascular Disease - October 2010

In October 2010, the U.S. Food and Drug Administration (FDA) announced that manufacturers of gonadotropin-releasing hormone (GnRH) agonists will be required to update their prescribing information to include the increased risk of diabetes and cardiovascular disease in men receiving these agents for prostate cancer treatment. In May 2010, the FDA issued a notice regarding initiation of a safety review of GnRH agonists (eg, goserelin, leuprolide) for the treatment of prostate cancer and a possible increased risk of diabetes and cardiovascular disease (ie, heart attack, sudden cardiac death, or stroke). The FDA evaluated preliminary data from one randomized, controlled clinical trial and several observational studies. A Science Advisory statement from the American Heart Association, the American Cancer Society, and the American Urological Association was also considered in the evaluation. Some of these studies demonstrated a small, but statistically significant increased risk of diabetes and/or cardiovascular disease in men receiving GnRH agonist therapy versus men receiving alternative therapy for prostate cancer. The decision to update current labeling was based on the Agency's review of these data.

The FDA believes that although the risk for diabetes and cardiovascular disease appears to be low, patients should be evaluated for these risks. Healthcare providers are also encouraged to:

• Follow prescribing recommendations for GnRH agonists
• Carefully weigh known benefits/risks of GnRH agonists when determining appropriate treatment for prostate cancer
• Monitor patients receiving GnRH-agonist therapy for diabetes (periodic blood glucose and/or glycosylated hemoglobin) and signs/symptoms of cardiovascular disease
• Manage cardiovascular risk factors (blood pressure, weight, cholesterol, blood sugar, smoking) according to current clinical practice

Although GnRH agonists may be used in women and children, there are no known comparable studies evaluating this same risk in either of these populations.

Further information may be found at http://www.fda.gov/NewsEvents/Newsroom...

Bisphosphonates for Osteoporosis: Risk of Atypical Fracture - October 2010

The U.S. Food and Drug Administration (FDA) has reviewed all available data concerning the association between the use of bisphosphonates for osteoporosis (ie, alendronate, ibandronate, risedronate, zoledronic acid) and the risk of atypical fractures of the thigh (subtrochanteric and diaphyseal femur fractures). Subtrochanteric femur fractures occur in the bone just below the hip joint; diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon, occurring as <1% of all femur fractures. It is unclear if bisphosphonates are the cause, but these unusual fractures have been predominantly reported in patients taking bisphosphonates. In some cases, patients may experience dull, aching thigh pain prior to the fracture occurring. In Canada, an ongoing review is being conducted by Health Canada to similarly evaluate this safety information.

Patients are encouraged to consult their healthcare providers for new hip or thigh pain. The FDA and Health Canada are recommending that patients continue these medications unless their healthcare providers discontinue the treatment. Healthcare providers should evaluate patients with new complaints of thigh or groin pain, and discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture. Reports of these adverse events should be made in the U.S. to the FDA, and in Canada, to Health Canada's Vigilance Program.

Based on their safety review, the FDA will require a medication guide to be given to patients when they pick up their bisphosphonate prescription. The FDA is continuing its evaluation of data concerning the safety and efficacy of long-term use (longer than 3-5 years) of bisphosphonates used for osteoporosis. Manufacturers are updating product labeling to reflect the risk of atypical fractures.

Further information may be found at:

US: http://www.fda.gov/Drugs/DrugSafety...

Canada: http://www.hc-sc.gc.ca/ahc-asc...

Zoledronic Acid (Aclasta®) Association with Renal Dysfunction - October 2010

Novartis Pharmaceuticals Canada Inc, in collaboration with Health Canada, has issued a "Dear Health Care Professional" letter to address renal safety concerns regarding Aclasta® (zoledronic acid). Renal dysfunction, including acute renal failure, has been associated with infusions of zoledronic acid even after a single administration. Risk factors for renal dysfunction include underlying renal impairment, advanced patient age, concomitant nephrotoxins, concurrent use of diuretics, or dehydration. As of April 2010, 265 reports of renal dysfunction (20 cases/100,000 patient-years of exposure) have been filed with Novartis.

Patient risk may be minimized by:

• Avoiding use in patients with severe renal impairment (creatinine clearance <30 mL/minute);
• Cautiously using other potential nephrotoxins;
• Calculating creatinine clearance with each treatment;
• Monitoring serum creatinine in patients with risk factors;
• Adequately hydrating patients prior to and following administration;
• Following maximum single dose recommendations and administration guidelines

Further information may be found at http://www.hc-sc.gc.ca/dhp-mps...

Manufacturing Defect In RediPen® Delivery System, Health Canada Notice - October 2010

Schering-Plough Canada Inc, in conjunction with Health Canada, has issued a "Dear Healthcare Professional" letter regarding a manufacturing defect affecting all strengths of peginterferon alfa-2b, a component of Pegetron® (ribavirin 200 mg capsules plus peginterferon alfa-2b powder for solution in RediPen® Single Dose Delivery System). The RediPen® stopper sealing flange at one end of the glass container may be defective and unable to sustain a vacuum, potentially compromising product sterility.

Healthcare providers should advise patients to visually inspect the RediPen® before use and avoid use of cartridges that appear defective. A defective cartridge may have little or no powder in the window, may not mix properly or may appear deformed. Some defective cartridges may, however, appear normal. Patients should also report signs of injection site infections or unexpected adverse reactions.

In order to ensure a continuous medication supply to patients currently receiving Pegetron®, healthcare providers should wait to start new patients on therapy. Schering-Plough Canada anticipates a resupply of the affected products in up to 5 weeks.

Further information may be found at http://www.hc-sc.gc.ca/dhp-mps...

Voluntary Withdrawal From U.S. and Canadian Markets - October 2010

Abbott Labs, in conjunction with the U.S. Food and Drug Administration (FDA) and Health Canada, has voluntarily withdrawn sibutramine (Meridia®) from both the U.S. and Canadian markets. This decision comes as a result of postmarketing data from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial, which indicated an increased risk of heart attack and stroke in sibutramine-treated patients with cardiovascular disease.

Healthcare providers are being advised to:

• No longer prescribe/dispense sibutramine
• Discuss alternative weight loss programs with patients
• Monitor/assess patients for signs/symptoms of cardiovascular events

Patients are advised to:

• Discontinue the use of and discard any remaining sibutramine
• Promptly contact their healthcare providers with the onset of adverse cardiovascular events (eg, angina, palpitations, abnormal heart rate, dizziness)

Further information may be found at:

U.S.: http://www.fda.gov/NewsEvents/Newsroom...

Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2010/2010_169-eng.php

Epoetin Alfa Recall - September 2010

The U.S. Food and Drug Administration (FDA) and Amgen are notifying health care providers to a recall involving certain lots of epoetin alfa (Epogen® and Procrit®). The recalled lots may contain extremely thin glass flakes (lamellae) due to the interaction of the formulation with glass vials over the shelf life of the product.

Currently, no adverse events due to lamellae have been reported. Potentially, embolic, thrombotic and other vascular events (eg, phlebitis), may occur following I.V. administration, and foreign body granuloma, local injection site reactions, and increased immunogenicity may occur following SubQ administration of an injectable product with particulate matter.

The affected product lot numbers are available at www.epogen.com and www.procrit.com.

For additional information, refer to the following websites:

Amgen press release: http://www.fda.gov/Safety/Recalls/ucm227202.htm

FDA Safety alert: http://www.fda.gov/Safety/MedWatch...

Voluntary Market Withdrawal of Octagam® Due to Thromboembolic Events - Updated September 2010

Octapharma USA, Inc, manufacturer of the Octagam® brand of intravenous immune globulin 5%, is initiating a voluntary market withdrawal of all currently remaining lots in the U.S. market. This precautionary action is being taken until the cause of previously reported thromboembolic events potentially associated with Octagam® has been determined. In August 2010, nine thromboembolic events potentially associated with the product lead to the withdrawal of 31 lots of Octagam® from the U.S. market. The company is currently advising customers to immediately quarantine the use of all lots, and to contact Octapharma's customer service department to arrange for immediate product return.

Additional information, including affected lot numbers, can be found at: http://www.fda.gov/BiologicsBloodVaccines...

Pioglitazone (Actos®): Ongoing Safety Review: Potential Increased Risk of Bladder Cancer - September 2010

The U.S. Food and Drug Administration (FDA) has notified healthcare professionals and patients that it is reviewing data from an ongoing, 10-year epidemiological study evaluating if pioglitazone (Actos®) is associated with an increased risk of bladder cancer. At this time, the FDA has not concluded that pioglitazone increases the risk of bladder cancer. The review is ongoing, and the Agency will update the public when it has additional information. Currently, the FDA recommends that healthcare professionals continue following the recommendations in the product label when prescribing Actos®. Patients should be instructed to continue taking the medication unless otherwise instructed by their healthcare professional. Any adverse events involving pioglitazone should be reported to the FDA MedWatch program (http://www.fda.gov/MedWatch/report.htm).

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

Valganciclovir: Potential for Overdose in Pediatric Patients - September 2010

The U.S. Food and Drug Administration (FDA) has issued an alert regarding a new recommended valganciclovir (Valcyte®) dosing strategy for prevention of CMV disease in pediatric patients (ages 4 months to 16 years) who have undergone a kidney or heart transplant. When calculating the pediatric dose of valganciclovir with the modified Schwartz formula, a maximum creatinine clearance of 150 mL/minute/1.73 m2 should be used in the equation even if the calculated creatinine clearance exceeds 150 ml/minute/1.73 m2. This change is being made to prevent potential overdosing in children with below normal serum creatinine, low body surface area, or low body weight. Previous dosing recommendations may have resulted in children receiving doses that approached or surpassed the recommended adult dose of 900 mg. If the calculated pediatric dose of valganciclovir exceeds 900 mg, a dose of 900 mg should be given to the patient. Supratherapeutic dosing can cause adverse effects such as abdominal pain, vomiting, diarrhea, tremor, or seizure. Any adverse events involving valganciclovir should be reported to the FDA MedWatch program (www.fda.gov/MedWatch/report.htm)

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

Gadolinium-Based Contrast Agents: Labeling Changes Due to the Risk of Nephrogenic Systemic Fibrosis - September 2010

The U.S. Food and Drug Administration (FDA) has announced a requirement for the manufacturer's of gadolinium-based contrast agents (GBCAs) to revise their labeling to include updated information regarding the risk of developing nephrogenic systemic fibrosis (NSF). Of the GBCAs marketed within the U.S. (gadobenate dimeglumine [Multihance®], gadodiamide [Omniscan®], gadofosveset [Ablavar™], gadopentetate dimeglumine [Magnevist®], gadoteridol [ProHance®], gadoversetamide [OptiMARK®], gadoxetate [Eovist®]), three products (Magnevist®, Omniscan®, OptiMARK®) are now considered to be contraindicated in patients with acute kidney injury or chronic, severe kidney disease (GRF <30 mL/minute/1.73 m2). All GBCA labeling will be updated to emphasize the need to screen patients to identify those with, or at risk for, acute kidney injury or chronically reduced kidney function.

Clinicians should also be aware that, although not specifically included in the U.S. FDA announcement, a GBCA product marketed in Canada (gadobutrol [Gadovist™]) also carries a risk for NSF in this patient population.

Further information may be found at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm225286.htm

Tigecycline: Increased Risk of Mortalit - September 2010

The U.S. Food and Drug Administration (FDA) has issued an alert informing healthcare providers of an increased risk of mortality associated with tigecycline (Tygacil®) compared with other antibiotics when used to treat serious infections. An analysis of pooled trial data (for both approved and unapproved uses) demonstrated an increased risk of mortality, observed predominantly in patients treated for hospital-acquired pneumonia (especially if ventilator-associated), which is not an approved use. Mortality risk was also observed in patients with complicated skin and skin structure infections, complicated intra-abdominal infections, and diabetic foot infections. While the differences in mortality did not reach statistical significance for each indication, the overall number of mortalities was greater in patients treated with tigecycline. The prescribing information for tigecycline has been updated to reflect the increased mortality risk. The FDA recommends considering the use of alternative antimicrobials when treating patients with serious infections. Any adverse event involving tigecycline should be reported to the FDA MedWatch program.

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

Droperidol: Canadian Labeling Updated Due to Risk of QT Prolongation and Arrhythmia - August 2010

Sandoz Canada Inc, in conjunction with Health Canada, has issued a "Dear Healthcare Professional" letter advising of updates to the droperidol Canadian product monograph. Revisions to the monograph include removal of certain indications, and the addition of new contraindications, new warnings, and new dosing. These changes are a result of the risk for QT-interval prolongation and severe arrhythmia (eg, torsade de pointes).

For further detail regarding these monograph changes, please refer to http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2010/droperidol_2_hpc-cps-eng.php.

Nimodipine: Serious Medication Errors from Inadvertent Intravenous Administration of Nimodipine Oral Capsules - Updated August 2010

The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of continued reports of medication errors involving erroneous I.V. administration of the contents of nimodipine oral capsules. Nimodipine is intended for oral administration only. Alternatively, nimodipine may also be administered via nasogastric (NG) tube for patients unable to swallow. The potential for a medication error exists when the contents of the oral capsule are withdrawn into a syringe for subsequent NG tube administration, and the syringe is inadvertently administered intravenously. Nimodipine should NOT be given I.V.; erroneous I.V. administration can result in severe hypotension, cardiac arrest, death, and other heart-related complications. Syringes intended for administration via NG tube should always be labeled "Not for I.V. Use," and the needle used to withdraw the contents of the oral capsule should be removed from the syringe. According to the Institute for Safe Medication Practices (ISMP), ways to help prevent this medication error include

- labeling the distal ends of all catheters to help identify which tube or catheter is being accessed,

- doses intended for gastric/nasogastric administration should be prepared in oral syringes, preferably amber in color, and

- as appropriate, remove I.V. lines as soon as possible to reduce confusion.

The FDA has identified 31 cases of medication errors associated with the use of nimodipine between 1989 and 2009. Of these cases, 25 involved erroneous intravenous nimodipine prescribing or administration, including 4 deaths. In 2006, similar reports also prompted the addition of a boxed warning to the prescribing information concerning this potential for error.

On August 12, 2010, ISMP further recommended that liquid nimodipine be prepared ONLY in the pharmacy, and be dispensed ONLY in an oral syringe labeled "WARNING: For Oral Use Only." ISMP recommends that affirmative warnings ("do this") may be better understood than negative warnings ("do not do that").

Further information may be found at:

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

http://www.ismp.org/Newsletters/acutecare...

http://www.ismp.org/Newsletters/acutecare...

Bevacizumab Associated with Hypersensitivity and Infusion Reactions - August 2010

In conjunction with Health Canada, Hoffman-La Roche is distributing a "Dear Healthcare Professional" letter advising of the increased incidence of hypersensitivity reactions and/or infusion-related reactions in patients receiving bevacizumab (Avastin®) in combination with chemotherapy compared to chemotherapy alone. The incidence of anaphylactic/anaphylactoid reactions was 5% in clinical trials, and these reactions were also reported in postmarketing experience. Evidence of positive reaction upon drug rechallenge and positive cutaneous tests suggests drug causality. Although premedication may be employed if clinically warranted, no general recommendation is given at this time. Patients should be appropriately monitored for signs/symptoms during and after infusion of bevacizumab, and infusions terminated should a reaction occur.

More information can be found at: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2010/avastin_5_hpc-cps-eng.php

Voluntary Market Withdrawal of Octagam® Due to Thromboembolic Events - August 2010

Octapharma USA, Inc, manufacturer of the Octagam® brand of intravenous immune globulin 5%, is notifying healthcare providers that the product is being voluntarily withdrawn due to reports of 9 thromboembolic events potentially associated with 7 lots of the product. Testing methods developed by the company have suggested increased thromboembolic risk with additional lots. As a precautionary measure, the company is withdrawing an additional 24 lots of the product and advising customers to quarantine these lots for return to the manufacturer.

Additional information, including affected lot numbers, can be found at: http://www.fda.gov/BiologicsBloodVaccines...

Levodopa, Carbidopa, and Entacapone (Stalevo®): FDA Evaluating Trial Suggesting a Possible Increased Cardiovascular Risk - August 2010

The U.S. Food and Drug Administration (FDA) is conducting an on-going review of data to assess whether patients with Parkinson's disease are at an increased risk of cardiovascular events (heart attack, stroke, and cardiovascular death) when treated with levodopa/carbidopa/entacapone (Stalevo®) as compared to levodopa/carbidopa (Sinemet®) treatment.

The double-blind, randomized, parallel group trial, Stalevo Reduction In Dyskinesia Evaluation ? Parkinson's Disease (STRIDE-PD), was designed to evaluate the time to onset of dyskinesia in patients receiving Stalevo® compared to patients receiving Sinemet®. Myocardial infarctions (n=7) and cardiovascular death (n=1) were reported in the Stalevo® group; however, the Sinemet® group did not have any adverse cardiovascular events.

To further evaluate this concern, the FDA conducted a meta-analysis of cardiovascular events (myocardial infarction, stroke, cardiovascular death) from 15 trials, including STRIDE-PD. An increased risk of cardiovascular events in the Stalevo® group (n=27) was observed compared to 10 cardiovascular events in the Sinemet® group (relative risk: 2.46; 95% CI: 1.19-5.09). However, when the STRIDE-PD trial was removed from meta-analysis, the cardiovascular events observed were not statistically significant (relative risk: 1.67; 95% CI: 0.77-3.61).

The cardiovascular status of patients taking Stalevo® should be evaluated regularly. Patients should not discontinue their Stalevo® unless recommended by a healthcare professional and patients should discuss any history of cardiovascular disease with their healthcare professional. The FDA continues to assess the results of the STRIDE-PD trial and develop a plan to further evaluate the risk of cardiovascular events potentially caused by Stalevo®.

Further information may be found at: http://www.fda.gov/Safety/MedWatch/Safety...

Midodrine Hydrochloride: FDA Proposal for Withdrawal - August 2010

The U.S. Food and Drug Administration (FDA) has issued a Proposal to Withdraw Marketing Approval/Notice of Opportunity for a Hearing letter to companies who manufacture midodrine hydrochloride. Midodrine was approved in 1996 via an accelerated process that required manufacturers to verify clinical benefit to patients through post-approval studies. Shire Development Inc (ProAmatine®) has been given 15 days to respond in writing to request a hearing, while generic manufacturers Apotex Corp, Impax Laboratories Inc, Mylan Pharmaceuticals, Sandoz Inc, and Upsher-Smith Laboratories have been given 30 days.

The proposal was issued due to a lack of post-approval studies demonstrating the efficacy of midodrine hydrochloride for the treatment of orthostatic hypotension. The FDA and manufacturers are developing an expanded-access program to allow current patients to continue therapy. Patients are urged to keep taking their medication and speak with their healthcare provider about alternative therapies available.

Further information may be found at:

http://www.regulations.gov/search/Regs/home.html#docketDetail?R=FDA-2007-N-0475

http://www.fda.gov/NewsEvents/Newsroom...

Epinephrine: Inadvertent Injection of Topical Epinephrine: Health Canada Issues Notice - August 2010

Erfa Canada Inc, in conjunction with Health Canada, has issued a "Dear Health Care Professional" letter describing package similarities between topical epinephrine chloride 1:1000 (Adrenalin®) and injectable epinephrine chloride vials that can result in an inadvertent injection of topical epinephrine. Serious cardiovascular events, including death, have been reported due to the unintended injection of topical epinephrine.

Current packaging of topical epinephrine vials includes a rubber stopper, similar to injectable vials, which allows for needle insertion and withdrawal of concentrated epinephrine into a parenteral syringe. Additionally, the rubber stopper is held in place by a metal pull tab which can break and prevent the user from pouring the topical epinephrine, thereby leading to the use of a parenteral syringe to withdraw the topical solution which increases the potential for inadvertent injection. Erfa Canada, Inc and ISMP Canada are working to resolve these packaging issues.

Until resolved, healthcare professionals should:

• Have pharmacy personnel prepackage epinephrine for topical use
• Label syringes and containers appropriately; discard any unlabeled syringes and containers
• Store medications for injection in original containers (not in open containers)
• Withdraw injectable medications into a labeled syringe just prior to use

Product-related adverse reactions or events should be reported to Erfa Canada Inc, Health Canada, or ISMP Canada (http://www.ismp-canada.org/cmirps.htm).

For additional information, refer to the following website: http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2010/adrenalin_hpc-cps-eng.php

Lamotrigine: Risk of Aseptic Meningitis - August 2010

The U.S. Food and Drug Administration (FDA) is warning healthcare professionals about the risk of aseptic meningitis associated with lamotrigine. Aseptic meningitis is an inflammation of the meninges that surround the brain and spinal cord caused by viruses and other nonbacterial infections, toxic agents, some vaccines, malignancy, and certain medications, including lamotrigine. Symptoms of aseptic meningitis include headache, fever, nuchal rigidity, nausea, vomiting, rash, and photophobia.

Between December 1994 and November 2009, the FDA has identified 40 cases of aseptic meningitis in patients taking lamotrigine out of an estimated 46 million lamotrigine prescriptions. Symptoms associated with aseptic meningitis typically occurred 1-42 days (mean: 16 days) after initiation and resolved upon discontinuation. In 15 of the 40 cases, symptoms of aseptic meningitis recurred upon reinitiation of lamotrigine with an onset of within 30 minutes to 24 hours (mean: 5 hours) and were more severe after re-exposure. Based on this information, the FDA has revised the Warnings and Precautions section of the prescribing information and the patient medication guide.

Patients should continue taking their lamotrigine and be advised to contact their healthcare professional if they experience any signs or symptoms associated with aseptic meningitis. Healthcare professionals should evaluate and continue to treat, as indicated, for other causes of meningitis. Consider discontinuation of lamotrigine if no other clear cause of meningitis is identified.

For more information, healthcare professionals may refer to the following: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrug...

Influenza Virus Vaccine: 2010-2011 Season Composition - August 2010

The 2010-11 seasonal influenza vaccine contains the same influenza A (H1N1) 2009 strain which was used in the 2009 pandemic H1N1 monovalent vaccine. In addition to the A/California/7/2009 (H1N1)-like antigen (the same strain as was used for 2009 H1N1 monovalent vaccine), the upcoming seasonal influenza vaccine also contains A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens. Vaccination of children <9 years of age is based on their vaccination history using both the seasonal and monovalent strains from previous seasons. Adults =65 years of age also have the option of receiving a high-dose vaccine containing hemagglutinin (HA) 180 mcg per dose in comparison to HA 45 mcg contained in a standard dose of vaccine.

For additional information, refer to the following CDC document: http://www.cdc.gov/mmwr/pdf/rr/rr59e0729.pdf

Influenza Virus Vaccines (2010-2011 Season): Afluria® Labeling Change Regarding Risk of Fever and Febrile Seizures - Updated August 2010

The Food and Drug Administration (FDA) has announced approval of the influenza vaccines for use during the 2010-11 influenza season in the United States. The available vaccines are: Afluria®; Agriflu®; Fluarix®; FluLaval®; FluMist®; Fluvirin®; Fluzone® and Fluzone® High-Dose. Of these, the prescribing information for Afluria® (manufactured by CSL Limited for use in the Northern Hemisphere) has been changed to include information regarding postmarketing reports of fever and febrile seizures, primarily occurring in children <5 years of age. These adverse events were observed with the use of CSL's 2010 influenza vaccine formulation used in the Southern Hemisphere.

Countries in the Southern Hemisphere (eg, Australia, New Zealand) are currently experiencing their 2010 influenza season. Available data suggest that the increased incidence of fever and febrile seizure observed has been associated only with CSL's 2010 influenza vaccine manufactured for use in the Southern Hemisphere. The data do not suggest that other vaccines approved for use in children in the Southern Hemisphere have been associated with an increased rate of fever and febrile seizure. Therefore, Afluria® is the only U.S. distributed vaccine that will carry this additional warning in the prescribing information.

The FDA and Centers for Disease Control (CDC) will continue to monitor adverse events associated with the vaccine administration via the Vaccine Adverse Event Reporting System (VAERS).

On August 5, 2010, the Advisory Committee on Immunization Practices (ACIP) evaluated the available data and provided the following recommendations for use of Afluria® vaccine in the United States. For the 2010-11 influenza season:

- Afluria® should not be used in children 6 months to 8 years of age (other age-appropriate vaccines should be used)

- If other age appropriate vaccines are not available, children 5-8 years of age who are also considered at risk for influenza complications may be given Afluria®. The benefits and risks of this vaccine should be discussed with parents or caregivers prior to administration.

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

CDC recommendations: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr59e0729a1.htm...

ACIP statement: http://www.cdc.gov/media/pressrel/2010/s100806.htm

Methylnaltrexone: Possible Increased Risk of GI Perforation: Health Canada Issues Notice - August 2010

Wyeth Canada, in conjunction with Health Canada, has issued a "Dear Health Care Professional" letter regarding a possible increased risk of GI perforation with the use of methylnaltrexone (Relistor®). Postmarketing experience suggests that patients with advanced illness and conditions associated with impaired structural integrity of the GI wall (eg, cancer, GI malignancy, GI ulcer, Ogilvie's syndrome, concomitant use of certain medications including bevacizumab, NSAIDs, and steroids) may be at greater risk of perforation.

Canadian practitioners are advised to:

• Weigh the potential benefits and risks of methylnaltrexone therapy
• Use caution in patients with known or suspected GI lesions
• Discontinue therapy with onset of severe, persistent, and/or worsening abdominal symptoms

Additional information may be found at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof...

Ibuprofen Lysine Injection (NeoProfen®): Recall Due to Risk of Particulate Matter - August 2010

The Food and Drug Administration (FDA), in conjunction with Lundbeck Inc, has notified healthcare professionals of a nationwide voluntary recall of two lots of NeoProfen® (ibuprofen lysine) injection. The recall was initiated after the product failed to meet quality requirements due to the presence of visible particulate matter. Particulate matter in an injectable product may result in adverse events such as anaphylactic reactions or blood vessel obstruction and the potential for subsequent pulmonary emboli.

The two lots affected by the recall are the only lots currently available to prescribers. Therefore, a temporary product shortage of NeoProfen® is expected. The lots affected by the recall are 1734991 (expiration date April, 2011) and 1922319 (expiration date March, 2012).

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

Influenza Virus Vaccines (2010-2011 Season): Afluria® Labeling Change Regarding Risk of Fever and Febrile Seizures - August 2010

The Food and Drug Administration (FDA) has announced approval of the influenza vaccines for use during the 2010-11 influenza season in the United States. The available vaccines are: Afluria®; Agriflu®; Fluarix®; FluLaval®; FluMist®; Fluvirin®; Fluzone® and Fluzone® High-Dose. Of these, the prescribing information for Afluria® (manufactured by CSL Limited for use in the Northern Hemisphere) has been changed to include information regarding postmarketing reports of fever and febrile seizures, primarily occurring in children <5 years of age. These adverse events were observed with the use of CSL's 2010 influenza vaccine formulation used in the Southern Hemisphere.

Countries in the Southern Hemisphere (eg, Australia, New Zealand) are currently experiencing their 2010 influenza season. Available data suggest that the increased incidence of fever and febrile seizure observed has been associated only with CSL's 2010 influenza vaccine manufactured for use in the Southern Hemisphere. The data do not suggest that other vaccines approved for use in children in the Southern Hemisphere have been associated with an increased rate of fever and febrile seizure. Therefore, Afluria® is the only U.S. distributed vaccine that will carry this additional warning in the prescribing information.

The FDA and Centers for Disease Control (CDC) will continue to monitor adverse events associated with the vaccine administration via the Vaccine Adverse Event Reporting System (VAERS). Of note, the CDC has published the updated 2010 Advisory Committee on Immunization Practices (ACIP) recommendations regarding the use influenza vaccines during the upcoming season.

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

CDC recommendations: http://www.cdc.gov/mmwr/preview...