Our December 11, 2023 article on Drugs for Depression included a single sentence on the safety of bupropion use during pregnancy: "The safety of bupropion during pregnancy has not been established; data from a bupropion pregnancy registry suggested a possible increase in cardiac malformations." A reader asked us to provide more information.

On July 12, 2021, the FDA added a warning to the Fact Sheet for the Johnson & Johnson (Janssen) adenovirus-based COVID-19 vaccine about an increased risk of Guillain-Barré syndrome (GBS) following administration of the product.

On April 13, 2021, the FDA and CDC advised suspending use of the Johnson & Johnson adenovirus-based COVID-19 vaccine while the agencies investigate 6 cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia that occurred following administration of the vaccine. In an April 14 emergency meeting, the Advisory Committee on Immunization Practices (ACIP) recommended continuing the suspension until more data become available. About 7 million people in the US have received the Johnson & Johnson vaccine.

The once-monthly, subcutaneously injected calcitonin gene-related peptide (CGRP) receptor antagonist erenumab-aooe (Aimovig) was approved by the FDA in 2018 for preventive treatment of migraine in adults. Now the FDA has added a new warning to its labeling about a risk of new-onset hypertension and worsening of preexisting hypertension associated with use of the drug. CGRP is a potent microvascular vasodilator; blocking or deleting it has produced hypertensive effects in animals.

The FDA now requires boxed warnings in the package inserts of benzodiazepines describing the potential for these drugs to be abused and misused and to cause addiction and physical dependence. Benzodiazepine labels have contained a boxed warning about a risk of serious drug interactions with opioids since 2016.

The FDA has required a new warning in the labels of prescription and over-the-counter products containing nonsteroidal anti-inflammatory drugs (NSAIDs) advising against their use during pregnancy beginning at 20 weeks’ gestation because of a risk of renal dysfunction in the fetus that could lead to low amniotic fluid levels (oligohydramnios) and neonatal renal impairment. NSAID labels previously warned against use of the drugs beginning at 30 weeks' gestation because of a risk for premature closure of the ductus arteriosus and persistent neonatal pulmonary hypertension

Healthcare providers are often asked if drugs can be used past their expiration date. Because of legal restrictions and liability concerns, manufacturers do not sanction such use and usually do not comment on the safety or effectiveness of their products beyond the date on the label. Since our last article on this subject, more data have become available.

Over-the-counter products containing melatonin are widely used as sleep aids in children and adults.

The FDA has required new warnings in the labels of gabapentin (Neurontin, and others) and pregabalin (Lyrica, Lyrica CR, and generics) about the risk of life-threatening or fatal respiratory depression in patients with respiratory risk factors. Respiratory risk factors include chronic obstructive pulmonary disease (COPD) and concurrent use of opioids or other CNS depressants. Elderly patients are also at increased risk.

The FDA is requiring stronger warnings in the labeling of the leukotriene receptor antagonist montelukast (Singulair, and generics) about the risk of suicidal behavior and other serious neuropsychiatric events associated with its use.

We reviewed brolucizumab (Beovu – Novartis) for treatment of neovascular (wet) age-related macular degeneration in our February 10 issue. On February 23, the American Society of Retina Specialists reported that 14 patients who received the drug have developed retinal vasculitis, a potentially vision-threatening complication.

The FDA has required updates to the labeling of the Janus kinase (JAK) inhibitor tofacitinib (Xeljanz, Xeljanz XR) based on interim results of a postmarketing safety trial that showed an increased risk of pulmonary thromboembolism and death with a dosage of 10 mg twice daily.1 Tofacitinib is approved for treatment of rheumatoid arthritis (RA),2 psoriatic arthritis, and ulcerative colitis.

In the postmarketing trial, RA patients ≥50 years old taking methotrexate who had at least one cardiovascular risk factor were randomized to receive add-on treatment with tofacitinib 5 mg twice daily (the FDA-approved dosage for RA and psoriatic arthritis), tofacitinib 10 mg twice daily (an approved dosage for ulcerative colitis), or a tumor necrosis factor (TNF) inhibitor. At the time of the interim analysis in January 2019 (~3900 patient-years of data in each group), pulmonary thromboembolism had occurred in 19 patients taking tofacitinib 10 mg twice daily and in 3 patients taking a TNF inhibitor; 45 patients taking tofacitinib 10 mg twice daily and 25 taking a TNF inhibitor had died. Interim data from the 5-mg twice daily group have not been made available by the FDA. After the interim analysis, patients taking the higher dose of tofacitinib were transitioned into the 5 mg twice daily group; the trial is ongoing.3

Serious, sometimes fatal thromboembolic adverse events have also occurred with use of baricitinib (Olumiant),4 another JAK inhibitor that is FDA-approved for treatment of RA. Whether an increased risk of thromboembolism is a class effect of JAK inhibitors remains to be determined; RA itself has been associated with an increased thromboembolic risk.5

The tofacitinib package insert now contains a boxed warning describing the increased risk of thrombosis and mortality with a dosage of 10 mg twice daily and emphasizes that this dosage or Xeljanz XR 22 mg once daily is not recommended for treatment of RA or psoriatic arthritis. For treatment of ulcerative colitis, tofacitinib is now only indicated in patients who have had an inadequate response or intolerance to TNF inhibitors; for these patients, the 10-mg twice daily dosage is still recommended as induction therapy for 8 weeks (can be continued for up to 16 weeks) and for maintenance treatment when there is loss of response to a dosage of 5 mg twice daily.

1. FDA drug safety communication: FDA approves boxed warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). July 26, 2019. Available at: www.fda.gov. Accessed August 15, 2019.
2. Tofacitinib for rheumatoid arthritis. Med Lett Drugs Ther 2013; 55:1.
3. FDA drug safety communication: Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. February 25, 2019. Available at: https://www.fda.gov. Accessed August 15, 2019.
4. Baricitinib (Olumiant) for rheumatoid arthritis. Med Lett Drugs Ther 2018; 60:120.
5. IC Scott et al. Thromboembolism with Janus kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk? Drug Saf 2018; 41:645.

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A reader has questioned why the label for the COX-2 selective NSAID celecoxib (Celebrex, and generics), which contains a sulfonamide moiety, states that it is contraindicated for use in patients with an allergy to sulfonamides, while the labels of some other sulfonamide drugs recommend either caution or no precautions at all. The concept of cross-reactivity among sulfonamide drugs, particularly between antibacterial and nonantibacterial sulfonamides, has been controversial for many years.

The FDA has approved changes to the labeling of erenumab-aooe (Aimovig)1, a once-monthly, subcutaneously injected calcitonin gene-related peptide (CGRP) blocker approved in 2018 for prevention of migraine. The new label contains a warning about hypersensitivity reactions, including rash, angioedema, and anaphylaxis, that have been reported with post-marketing use of the drug.

According to the label, most of these reactions were not serious and occurred within hours after receiving the drug, but some occurred more than one week after administration. Because these reactions are voluntarily reported, it is not possible to determine the actual incidence or establish causality. Hypersensitivity reactions, including rash, urticaria, and dyspnea, were reported during pre-approval clinical trials of fremanezumab-vfrm (Ajovy) and galcanezumab-gnlm (Emgality), the other FDA-approved CGRP blockers.2 Because of the long half-lives of these drugs, hypersensitivity reactions may be prolonged.

1. Erenumab (Aimovig) for migraine prevention. Med Lett Drugs Ther 2018; 60:101.
2. Fremanezumab (Ajovy) and galcanezumab (Emgality) for migraine prevention. Med Lett Drugs Ther 2018; 60:177.


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The FDA has required changes in the labeling of all systemic fluoroquinolone antibiotics to strengthen warnings about the risk of severe hypoglycemia and mental health effects associated with their use.1

An FDA review identified 67 cases of hypoglycemic coma associated with fluoroquinolone use, 22 of which resulted in death or disability. Most cases occurred in patients with risk factors such as diabetes (especially those taking a sulfonylurea), older age, or renal insufficiency.1 In observational studies in older adults and patients with diabetes, fluoroquinolones have been associated with increased risks of hypo- and hyperglycemia.2,3 Patients taking a fluoroquinolone (especially those with risk factors) should be counseled about the symptoms of hypoglycemia and monitored for blood glucose disturbances. The drug should be stopped if dysglycemia occurs.

The labels of all systemic fluoroquinolones will now include warnings about delirium, agitation, nervousness, and disturbances in attention, memory, and orientation. These effects can occur after a single fluoroquinolone dose; the drug should be stopped if such effects occur. Systemic fluoroquinolones can also cause persistent or permanent peripheral neuropathy,4 and their use has been associated with an increased risk of pseudotumor cerebri syndrome.5

Other serious adverse effects associated with use of systemic fluoroquinolones include tendinitis and tendon rupture, exacerbation of myasthenia gravis, Clostridium difficile infection, and (except for delafloxacin [Baxdela]) QT-interval prolongation and torsades de pointes. The FDA recommends avoiding use of fluoroquinolones in patients with uncomplicated urinary tract infection, acute sinusitis, or acute exacerbation of chronic bronchitis, except when no alternative treatment option is available.6

Additional Content Available Online: Comparison Table: Some Systemic Fluoroquinolones

1. FDA. July 10, 2018. Available at: www.fda.gov. Accessed August 2, 2018.
2. LY Park-Wyllie et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med 2006; 354:1352.
3. HW Chou et al. Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan. Clin Infect Dis 2013; 57:971.
4. In brief: Fluoroquinolones and peripheral neuropathy. Med Lett Drugs Ther 2013; 55:89.
5. M Sodhi et al. Oral fluoroquinolones and risk of secondary pseudotumor cerebri syndrome: nested case-control study. Neurology 2017; 89:792.
6. Alternatives to fluoroquinolones. Med Lett Drugs Ther 2016; 58:75.

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The FDA has warned that the antiepileptic and mood-stabilizing drug lamotrigine (Lamictal, and generics) can rarely cause hemophagocytic lymphohistiocytosis (HLH), a serious and potentially fatal immune-related reaction.1

HLH, which can be familial, occurs most often in infants, but can occur at any age. Often induced by Epstein-Barr Virus infection (HIV infection and non-Hodgkin's lymphoma are other common triggers), HLH is characterized by an unremitting activation of CD8+ T cells and macrophages.2 If untreated, it causes organ damage, particularly in the liver, bone marrow, and CNS; organ failure and death occur within months after onset.3 Clinical features can include fever and rash, splenomegaly, hepatitis, cytopenias, elevated triglyceride levels or low fibrinogen levels, hyperferritinemia, hemophagocytosis, decreased or absent natural killer cell activity, and elevated blood CD25 levels.4

The optimal treatment for drug-induced HLH is unclear. Treatment of HLH generally involves use of corticosteroids and blood products, sometimes augmented by aggressive immunosuppression with the cytotoxic drug etoposide (Toposar, and generics). The anti-CD52 antibody alemtuzumab (Lemtrada) can be added in refractory HLH cases,5 and allogeneic hematopoietic cell transplantation has been used in genetic cases.

Since lamotrigine first became available in 1994, five confirmed and three suspected cases of HLH associated with its use have been reported. All of these cases occurred within 24 days of starting treatment and required hospitalization. One death was reported; in the other cases, improvement occurred after discontinuation of lamotrigine and treatment of HLH. Because initial signs and symptoms of HLH are nonspecific, the condition can be confused with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), another potentially fatal, multiorgan, immune-related adverse reaction associated with lamotrigine use.1,6

Patients being treated successfully with lamotrigine should continue taking it. Clinicians should monitor patients taking lamotrigine for signs and symptoms of HLH, especially during the first few weeks after starting the drug.

1. FDA Drug Safety Communication: FDA warns of serious immune system reaction with seizure and mental health medicine lamotrigine (Lamictal). Available at: www.fda.gov. Accessed June 7, 2018.
2. M Ramos-Casals et al. Adult haemophagocytic syndrome. Lancet 2014; 383:1503.
3. SA Parikh et al. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc 2014; 89:484.
4. JI Henter et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124.
5. RA Marsh et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer 2013; 60:101.
6. SH Kardaun et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol 2013; 169:1071.

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For many years, the goal of drug therapy for most patients with type 2 diabetes has been to achieve and maintain an A1C of <7%. Achieving that goal can prevent microvascular complications (diabetic retinopathy, nephropathy, neuropathy), but whether it prevents macrovascular complications (myocardial infarction [MI], stroke) has been less clear. The FDA now requires that cardiovascular safety studies be performed for all new drugs for type 2 diabetes.1 Recent findings that some of the newer second-line drugs for type 2 diabetes have cardiovascular benefits have led to new interest in the cardiovascular efficacy and safety of all antidiabetic drugs.

The FDA has approved an effervescent tablet formulation of acetylcysteine (Cetylev – Arbor) to prevent or lessen hepatic injury after acetaminophen overdose. Acetylcysteine has been available for years in an IV solution (Acetadote, and generics) and an oral solution for the same indication; use of the oral solution has been limited by its unpleasant odor and taste.

Per capita spending on prescription drugs in the US is higher than in other industrialized nations, including Canada.

The FDA has warned that eluxadoline (Viberzi – Allergan), a mu-opioid receptor agonist and delta-opioid receptor antagonist approved in 2015 for treatment of irritable bowel syndrome with diarrhea (IBS-D),1 should not be used in patients without a gallbladder because of an increased risk of serious pancreatitis.2

As of February 2017, the FDA had received reports of 118 cases of serious, nonfatal pancreatitis and 2 deaths associated with use of eluxadoline. Both deaths occurred in patients without a gallbladder who developed severe abdominal pain and vomiting shortly after taking the first dose. At least 48 of the cases occurred after only 1 or 2 doses of eluxadoline. Of the 68 patients whose gallbladder status was reported, 56 did not have a gallbladder. Most of the patients without a gallbladder (44/56) were taking the reduced dosage of eluxadoline recommended for such patients (75 mg once/day).

Patients considered at risk for pancreatitis were excluded from the two trials that led to approval of eluxadoline. One case of pancreatitis and 8 cases of abdominal pain with hepatic enzyme elevation associated with sphincter of Oddi spasm occurred with use of eluxadoline in the trials, all in patients without a gallbladder.3

According to the current label, eluxadoline is contraindicated in patients who abuse alcohol (including those who consume >3 servings of alcohol per day) and in those with known or suspected biliary duct, pancreatic duct, or GI tract obstruction, sphincter of Oddi disease or dysfunction, or severe hepatic impairment (Child-Pugh C). It is also contraindicated in those with a history of pancreatitis, structural pancreatic disease, or chronic or severe constipation.

Some alternatives to eluxadoline, which is only modestly more effective than placebo in relieving IBS-D symptoms, are the antidiarrheal loperamide (Imodium, and generics), the non-absorbed antibiotic rifaximin (Xifaxan), and the 5-HT₃ receptor antagonist alosetron (Lotronex, and generics). Taken as needed, loperamide can reduce postprandial urgency and stool frequency, but it does not improve global symptoms of IBS-D. Like eluxadoline, rifaximin has only been modestly effective in relieving symptoms. Because of concerns about severe constipation and ischemic colitis, alosetron should be used only in women with severe, chronic IBS-D that is unresponsive to other drugs.4

1. Eluxadoline (Viberzi) for irritable bowel syndrome with diarrhea. Med Lett Drugs Ther 2016; 58:4.
2. FDA Drug Safety Communication: FDA warns about increased risk of serious pancreatitis with irritable bowel drug Viberzi (eluxadoline) in patients without a gallbladder. Available at: www.fda.gov. Accessed April 13, 2017.
3. AJ Lembo et al. Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med 2016; 374:242.
4. Drugs for irritable bowel syndrome. Med Lett Drugs Ther 2016; 58:121.

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The antiplatelet drug clopidogrel (Plavix, and others) reduces major cardiovascular events, but can cause bleeding. Proton pump inhibitors (PPIs) are often used with clopidogrel to prevent gastrointestinal bleeding, however, some evidence suggests that PPIs may interfere with the activation of clopidogrel and diminish its antiplatelet effect. FDA-approved labeling recommends avoiding concurrent use of the PPIs omeprazole and esomeprazole with clopidogrel.

The results of a recently published study suggest that taking the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa) with either simvastatin (Zocor, and others) or lovastatin (Altoprev, and others) increases the risk of major hemorrhage.

Therapeutics (AZCERT) has recently added the proton pump inhibitors (PPIs) omeprazole (Prilosec, and others), esomeprazole (Nexium, and others), lansoprazole (Prevacid, and others), and pantoprazole (Protonix, and generics) to its lists of Drugs with Conditional Risk of Torsades de Pointes (TdP) and Drugs to Avoid in Patients with Congenital Long QT Syndrome.1

PPIs do not directly cause prolongation of the QT interval, but they can cause hypomagnesemia, which is often accompanied by hypocalcemia and hypokalemia and can result in cardiac repolarization disturbances such as QT interval prolongation.2 Reports have described cases of QT interval prolongation and TdP associated with severe PPI-induced hypomagnesemia.3,4 TdP has also been reported in patients taking a PPI concomitantly with drugs that directly prolong the QT interval.5,6 The newer PPIs dexlansoprazole (Dexilant) and rabeprazole (Aciphex, and generics) have not been linked to QT interval prolongation or TdP to date, but they have been associated with hypomagnesemia.

Serum magnesium levels should be monitored periodically in patients taking a PPI for an extended period of time (>2 weeks). If possible, extended PPI therapy should be avoided in patients who require treatment with drugs that carry a known risk of TdP7 and in those with long QT syndrome. If extended PPI therapy must be used with a drug that prolongs the QT interval, close monitoring of magnesium levels and the QT interval is recommended.

1. AZCERT. New drugs added to CredibleMeds drugs lists. November 2, 2016. Available at: www.crediblemeds.org. Accessed November 22, 2016.
2. In brief: PPIs and hypomagnesemia. Med Lett Drugs Ther 2011; 53:25.
3. EJ Hoorn et al. A case series of proton pump inhibitor-induced hypomagnesemia. Am J Kidney Dis 2010; 56:112.
4. BA Hansen and Ø Bruserud. Hypomagnesemia as a potentially life-threatening adverse effect of omeprazole. Oxf Med Case Reports 2016; 2016:147.
5. H Asajima et al. Lansoprazole precipitated QT prolongation and torsade de pointes associated with disopyramide. Eur J Clin Pharmacol 2012; 68:331.
6. JN Bibawy et al. Pantoprazole (proton pump inhibitor) contributing to torsades de pointes storm. Circ Arrhythm Electrophysiol 2013; 6:e17.
7. RL Woosley and KA Romero. QT drugs list. Available at: www.crediblemeds. org. Accessed November 22, 2016.

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Lipid-lowering drugs should be taken indefinitely; when they are stopped, plasma lipoproteins return to pretreatment levels. HMG-CoA reductase inhibitors (statins) remain the drugs of choice for treatment of most patients who require lipid-lowering therapy.

At the same time that the FDA announced it was strengthening existing warnings about the risk of acute kidney injury in patients with type 2 diabetes treated with the sodium-glucose co-transporter 2 (SGLT2) inhibitors canagliflozin (Invokana, and others) and dapagliflozin (Farxiga, and others), a study was published showing that the third SGLT2 inhibitor, empagliflozin (Jardiance, and others), slowed the progression of renal dysfunction in patients with type 2 diabetes.

A reader commenting on our Treatment of Lyme Disease article (Med Lett Drugs Ther 2016; 58:57) objected to a footnote in the table advising against use of doxycycline in children <8 years old. This warning has been included in the labeling of all tetracyclines since 1970 when it was recognized, after decades of use, that these drugs caused permanent staining and enamel hypoplasia of developing teeth. The CDC recently stated that short courses of doxycycline, which was first marketed in the US in 1967 and has less affnity for calcium than other tetracyclines, have not been shown to cause tooth staining.1 That statement was prompted by the discovery that children <10 years old have a disproportionately high fatality rate from rickettsial diseases, particularly Rocky Mountain spotted fever, for which doxycycline is the drug of choice and chloramphenicol is the only proven alternative.

The main evidence supporting the CDC's statement was a retrospective cohort study consisting of a record review and dental examination of 271 children living on a Native American reservation. No staining was detected in any of the 58 children who had been treated with doxycycline before the age of 8 years or in any of the 213 children who had not been exposed to the drug. Enamel hypoplasia was present in 4% of children in both cohorts.2

Lyme disease, unlike Rocky Mountain spotted fever, is seldom fatal and can be treated with antibiotics other than doxycycline. A single dose of doxycycline is recommended for prophylaxis after a tick bite. Given the CDC's statement about its safety, it would seem reasonable to use doxycycline for prophylaxis in all age groups. When longer treatment courses (10, 14, or 28 days) are recommended for the various clinical manifestations of Lyme disease in children <8 years old, alternative antibiotics generally could be used instead.

1. HM Biggs et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group Rickettsioses, Ehrlichioses, and Anaplasmosis – United States. MMWR Recomm Rep 2016; 65:1.
2. SR Todd et al. No visible dental staining in children treated with doxycycline for suspected Rocky Mountain spotted fever. J Pediatr 2015; 166:1246.

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The FDA has required labeling changes that replace serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) as the parameter used to determine the appropriateness of treatment with the biguanide metformin (Glucophage, and others) in patients with renal impairment. These changes will allow more patients with mild to moderate renal impairment to receive metformin, which is generally the first drug prescribed for treatment of type 2 diabetes.

Metformin was previously contraindicated in women with a SCr level ≥1.4 mg/dL and in men with a SCr level ≥1.5 mg/dL, but use of SCr as a surrogate indicator tends to underestimate renal function in certain populations (e.g., younger patients, men, black patients, patients with greater muscle mass). The calculation of eGFR takes into account age, race, and sex, as well as SCr level, providing a more accurate assessment of kidney function. A literature review summarized in an FDA Drug Safety Communication concluded that, based on eGFR, metformin is safe to use in patients with mild renal impairment and in some patients with moderate renal impairment.1

The eGFR should be calculated before patients begin treatment with metformin and at least annually thereafter. Metformin is now contraindicated in patients with an eGFR <30 mL/min/1.73 m², and starting treatment with the drug in patients with an eGFR between 30 and 45 mL/min/1.73 m² is not recommended. If the eGFR falls below 45 mL/min/1.73 m² in a patient already taking metformin, the benefits and risks of continuing treatment should be assessed. Metformin should be not be administered for 48 hours after an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m² or a history of liver disease, alcoholism, or heart failure, or in those receiving intra-arterial contrast, and the eGFR should be re-evaluated before treatment is restarted.

1. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. Available at: www.fda.gov. Accessed April 14, 2016.

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View the updated Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein table

Three coordinated double-blind, placebo-controlled clinical trials have evaluated the efficacy of one year of testosterone replacement therapy in improving sexual function, physical function, and vitality in a total of 790 men ≥65 years old with moderately low serum testosterone concentrations and symptoms suggesting hypoandrogenism. Sexual function improved modestly, and there appeared to be marginal benefits in some areas of physical function and vitality as well. The trials were not designed to evaluate the safety of testosterone replacement therapy.

Healthcare providers are often asked if drugs can be used past their expiration date. Because of legal restrictions and liability concerns, manufacturers do not sanction such use and usually do not even comment on the safety or effectiveness of their products beyond the date on the label. Since our last publication on this subject, more data have become available.

The FDA recently announced labeling changes for the combination antiviral products Viekira Pak (ombitasvir/paritaprevir/ritonavir with dasabuvir)1 and Technivie (ombitasvir/paritaprevir/ritonavir)2 warning of a risk of serious, potentially fatal liver injury.3 Viekira Pak, approved in December 2014 for treatment of hepatitis C virus (HCV) genotype 1 infection, including patients with compensated cirrhosis, and Technivie, approved in July 2015 for treatment of HCV genotype 4 infection without cirrhosis, have been identified as "possible" or "probable" causes in 26 postmarketing cases of hepatic decompensation, including 10 cases (mostly in patients with preexisting advanced cirrhosis) that resulted in death or liver transplant. Hepatic injury generally occurred within 1-4 weeks of treatment initiation.

All therapies for chronic HCV infection have been associated with cases of hepatic decompensation in patients with advanced fibrosis or cirrhosis, but cause and effect are difficult to determine. Viekira Pak and Technivie are now contraindicated in patients with moderate to severe (Child-Pugh B/C) hepatic impairment. Ledipasvir/sofosbuvir (Harvoni), another recently approved treatment for HCV genotype 1 infection,4 is still indicated for treatment of patients with any degree of compensated hepatic impairment (Child-Pugh A/B/C). The efficacy and safety of all three combinations in patients with decompensated cirrhosis have not been established.

1. A 4-drug combination (Viekira Pak) for hepatitis C. Med Lett Drugs Ther 2015; 57:15.
2. In brief: Technivie for HCV genotype 4 infection. Med Lett Drugs Ther 2015; in press.
3. FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. Available at: www.fda.gov. Accessed October 29, 2015.
4. A combination of ledipasvir and sofosbuvir (Harvoni) for hepatitis C. Med Lett Drugs Ther 2014; 56:111.

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The recent report of a reduction in cardiovascular mortality in patients with type 2 diabetes treated with the SGLT2 inhibitor empagliflozin (Jardiance) was published soon after the FDA issued new warnings about an increased risk of fractures with canagliflozin (Invokana).

The FDA has warned that use of an SGLT2 (sodium-glucose co-transporter 2) inhibitor for treatment of type 2 diabetes may lead to ketoacidosis.1 Three SGLT2 inhibitors, canagliflozin (Invokana, Invokamet), dapagliflozin (Farxiga, Xigduo XR), and empagliflozin (Jardiance, Glyxambi), are approved for treatment of type 2 diabetes in the US. Between March 2013 and June 2014, 20 cases of ketoacidosis requiring emergency room visits or hospitalization were reported in patients who had recently started taking an SGLT2 inhibitor; the median time to onset of symptoms after initiation of therapy was 2 weeks (range 1-175 days). SGLT2 inhibitors decrease renal glucose reabsorption and increase urinary glucose excretion, resulting in a reduction in blood glucose levels. The mechanism by which these drugs could cause ketoacidosis has not been established.

Diabetic ketoacidosis (DKA) occurs primarily in patients with type 1 diabetes; it is characterized by elevated blood glucose levels (usually ≥250 mg/dL), a high anion gap, glucosuria, and ketonuria.2 Unlike typical cases of DKA, most ketoacidosis cases associated with SGLT2 inhibitors have occurred in patients with type 2 diabetes, and in some patients glucose levels were <200 mg/dL. Only half of the 20 cases were associated with a recognizable DKA-precipitating factor, such as infection, reduced caloric intake, or reduced insulin dose. Other factors that may contribute to the development of high anion gap metabolic acidosis, such as hypovolemia, hypoxemia, reduced oral intake, acute renal impairment, and a history of alcohol use, were identified in some patients.1

1. FDA drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Available at: www.fda.gov. Accessed June 11, 2015.
2. AE Kitabchi et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335.

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The FDA recently announced changes in the labeling of the hepatitis C drugs Sovaldi (sofosbuvir) and Harvoni (sofosbuvir/ledipasvir) to warn about a risk of serious and potentially fatal bradycardia when either drug is taken with the antiarrhythmic drug amiodarone (Cordarone, and others).1 Symptomatic bradycardia was reported following initiation of treatment with Harvoni or with Sovaldi plus simeprevir (Olysio) or the investigational antiviral drug daclatasvir in 9 patients already taking amiodarone; it occurred within 24 hours of starting hepatitis C therapy in 6 patients and within 2-12 days in 3 others. One patient died of cardiac arrest and 3 required pacemaker implantation. In 3 patients who continued taking amiodarone, rechallenge with Harvoni or Sovaldi resulted in recurrence of symptomatic bradycardia. In another patient, rechallenge 8 weeks after stopping amiodarone did not result in bradycardia.

The mechanism of this effect is unknown. Factors possibly contributing to the cardiac events include concomitant beta blocker therapy (in 7 patients) and preexisting cardiac and hepatic disease. Hepatic impairment increases the risk of cardiac conduction abnormalities and could increase adverse effects of amiodarone, which is metabolized by the liver.2 Use of sofosbuvir without amiodarone has not been associated with significant bradycardia.

The new labels warn that sofosbuvir and amiodarone should not be taken concurrently. If concomitant use is necessary, cardiac monitoring in an inpatient setting is recommended for the first 48 hours. Daily monitoring of heart rate, either at home or in an outpatient setting, should continue for at least the first 2 weeks of treatment. Amiodarone has a very long half-life, and its effects may persist for weeks to months after discontinuation.

1. FDA. FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir Harvoni or Sovaldi in combination with another direct acting antiviral drug. Available at http://www.fda.gov. Accessed April 2, 2015.
2. U Klotz. Antiarrhythmics: elimination and dosage considerations in hepatic impairment. Clin Pharmacokinet 2007; 46:985.

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The Drug Enforcement Administration (DEA) has reclassified all hydrocodone combination products as schedule II controlled substances; they were previously classified as schedule III. Hydrocodone alone (Zohydro ER) is already a schedule II controlled substance.

In 2012, the FDA required manufacturers of HMG-CoA reductase inhibitors (statins) to add a warning to their labels about reports of increased blood glucose and glycosylated hemoglobin (HbA1c) levels. Since then, several new studies have been published.

The FDA has authorized two manufacturers (Teva, Mylan) to market generic formulations of celecoxib (Celebrex – Pfizer), the only COX-2 selective inhibitor remaining on the US market. Celecoxib is less likely than nonselective NSAIDs to cause gastric ulcers or other GI toxicity,1 and unlike traditional NSAIDs, it does not have an antiplatelet effect.

Celecoxib is much less COX-2 selective than rofecoxib (Vioxx), which was removed from the US market because of an increased risk of cardiovascular events. One analysis of randomized clinical trials that included a total of about 26,000 patients taking celecoxib found no evidence of an increased risk of cardiovascular thrombotic events compared to nonselective NSAIDs or placebo.2 A review of controlled observational studies found an increased cardiovascular risk with celecoxib (RR 1.17) that was similar to the risk with ibuprofen (RR 1.18) and slightly higher than the risk with naproxen (RR 1.09).3 All NSAIDs can cause renal toxicity, especially in the elderly.4

1. PL McCormack. Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Drugs 2011; 71:2457.
2. WB White et al. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Am J Cardiol 2007; 99:91.
3. P McGettigan and D Henry. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med 2011; 8:e1001098.
4. RL Barkin et al. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging 2010; 27:775.

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The FDA has removed prescribing and dispensing restrictions placed on rosiglitazone (Avandia, and others) in 2010 because of concerns about its cardiovascular safety.1 The removal of restrictions was based on the results of an independent reevaluation of the RECORD trial, which found no significant difference between rosiglitazone and metformin/sulfonylurea in the risk of cardiovascular (or unknown cause) death, myocardial infarction, or stroke.2

1. FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. Available at www.fda.gov. Accessed January 27, 2014.

2. KW Mahaffey et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J 2013; 166:240.

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The FDA recently issued a Drug Safety Communication saying that it had asked the manufacturer of ponatinib (Iclusig – Ariad) to suspend marketing and sales of the drug because of the risk of life-threatening blood clots and severe narrowing of blood vessels.1 Ponatinib is a tyrosine kinase inhibitor that was granted accelerated approval by the FDA in December 2012 for treatment of chronic-, accelerated, or blast-phase chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to (or the patients were intolerant to) prior tyrosine kinase inhibitor therapy. It is the first tyrosine kinase inhibitor that is effective against the T315I mutation, which is present in up to 20% of patients with treatment-resistant CML.2

The labeling of Iclusig includes a warning about the risk of arterial thrombosis, but recent clinical trial results showed an unexpectedly high incidence of serious adverse vascular events, some fatal, which occurred in 24% of patients in one clinical trial with a median duration of 1.3 years and 48% in another with a median duration of 2.7 years. These adverse events occurred in some patients as early as 2 weeks after starting ponatinib. Neither trial included a control group. Blindness has occurred in some patients and in one of the trials, 8% of those treated with the drug developed heart failure.

Suspension of marketing and sales does not necessarily mean that Iclusig will be withdrawn permanently; it is the only option available for some treatment-resistant patients.3 The drug could be returned to the market, possibly with new labeling narrowing the selection of patients, lowering the dosage, or recommending use of aspirin concomitantly to decrease the risk of thrombosis.4

1. FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales. Available at www.fda.gov. Accessed November 18, 2013.

2. Ponatinib (Iclusig) for CML and Ph+ ALL. Med Lett Drugs Ther 2013; 55:71.

3. JH Doroshow. Overcoming resistance to targeted anticancer drugs. N Engl J Med 2013; 369:1852.

4. Ariad expects narrower label, not withdrawal, for Iclusig following halted study. "The Pink Sheet" 2013; 75:16.

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The FDA recently announced changes in the labeling of ezogabine (Potiga – GSK/Valeant) to warn about the risks of retinal abnormalities, possible vision loss, and bluish skin discoloration, all of which could be permanent.1

Ezogabine was approved in 2011 for adjunctive treatment of partial-onset seizures in adults.2 The FDA first warned about these risks in April 2013.3 At that time, skin discoloration had developed in 38 of an estimated 605 patients (6.3%) who had taken the drug (most for ≥2 years) in various studies. Retinal pigment abnormalities were found in 11 of 36 patients who had eye examinations; some of these patients had impaired visual acuity, but baseline visual acuity assessments were not available.

The new label recommends limiting the use of ezogabine to patients who have not responded adequately to several alternative antiepileptic drugs. Patients taking the drug should have a baseline eye exam and follow-up exams every 6 months.

1. FDA Drug Safety Communication: FDA approves label changes for anti-seizure drug Potiga (ezogabine) describing risk of retinal abnormalities, potential vision loss, and skin discoloration. Available at www.fda.gov. Accessed November 18, 2013.

2. Ezogabine (Potiga) for epilepsy. Med Lett Drugs Ther 2012; 54:65.

3. FDA Drug Safety Communication: Anti-seizure drug Potiga (ezogabine) linked to retinal abnormalities and blue skin discoloration. Available at www.fda.gov. Accessed November 18, 2013.

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In 2011, the FDA asked the manufacturers of the selective serotonin reuptake inhibitor (SSRI) citalopram (Celexa, and generics) to lower the maximum daily dosage of the drug because of a dose-related increase in the QT interval. Since then, some of our readers have asked whether escitalopram (Lexapro, and generics), the active enantiomer of citalopram, could have the same effect.

Two FDA advisory committees recently concluded that use of a nasal spray formulation of the peptide hormone salmon calcitonin for treatment of postmenopausal osteoporosis is associated with an increased risk of cancer. Salmon calcitonin is available as 2 nasal sprays (Miacalcin, Fortical) and an injectable formulation (Miacalcin Injection) for use in osteoporosis.1

The new cancer concern arose from the results of an unpublished meta-analysis that included 18 studies of Miacalcin Nasal Spray in which the risk of any cancer was 1.54 times greater (95% CI: 1.06, 2.23) in patients who used the drug compared to controls.2

An earlier 5-year trial in >1200 postmenopausal women with osteoporosis also found that use of calcitonin was associated with a small, but statistically significant, increase in the risk of any malignancy (OR 1.62, 95% CI: 1.00, 2.61).2 New vertebral fractures occurred in 51 of 287 women (18%) receiving a 200 IU dose of calcitonin nasal spray once daily and in 70 of 270 women (26%) receiving placebo, a statistically significant difference.3

The advisory committees, meeting jointly, weighed the risk against the benefits of the drug and concluded that women should no longer use salmon calcitonin nasal spray for treatment of postmenopausal osteoporosis. The FDA now has to decide whether to approve their recommendations.

1. Drugs for postmenopausal osteoporosis. Treat Guidel Med Lett 2011; 9:67.

2. Novartis. FDA Joint Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee meeting on the benefit/risk of salmon calcitonin for the treatment of postmenopausal osteoporosis. Briefing book. Available at www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM341781.pdf. Accessed April 4, 2013.

3. CH Chesnut 3rd et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med 2000; 109:267.

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The FDA has asked Impax Laboratories/Teva Pharmaceuticals to stop production and distribution of Budeprion XL 300 mg, a generic extended-release formulation of the antidepressant bupropion (Wellbutrin XL), because it has found that Budeprion XL 300 mg releases bupropion more rapidly than Wellbutrin XL 300 mg, the original brand name product. Patients switched from the brand name to the generic formulation have complained for years that the generic was less effective and caused more side effects than the original formulation. In 2007, ConsumerLab.com, an independent laboratory, conducted dissolution testing of Budeprion XL, which uses a matrix for slow release, and Wellbutrin XL, which uses a membrane. According to the test results, the Budeprion XL matrix released more bupropion in the first 4 hours than the Wellbutrin XL membrane did.1 The FDA decided to conduct its own studies of Budeprion XL 300 mg and arrived at a similar conclusion. The original approval of the generic formulation was based on pharmacokinetic tests conducted on 150-mg tablets of the Impax/Teva formulation, with results extrapolated to the 300-mg tablet.

Bupropion is often used as an alternative to a selective serotonin reuptake inhibitor (SSRI) or another antidepressant because it does not cause sexual dysfunction, sedation, or weight gain.2 It is also used as an aid in smoking cessation.3 It is contraindicated in patients at increased risk of seizures (including patients with a history of an eating disorder). Other 300-mg formulations of generic extended-release bupropion have not been associated with post-marketing complaints and continue to be available.

1. Wellbutrin versus generic bupropion. Med Lett Drugs Ther 2008; 50:54.

2. Drugs for depression and bipolar disorder. Treat Guidel Med Lett 2010; 8:35.

3. Drugs for tobacco dependence. Treat Guidel Med Lett 2008; 6:61.

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The FDA has asked the manufacturers of the selective serotonin reuptake inhibitor (SSRI) antidepressant citalopram (Celexa, and others) to revise the labeling of the drug to include new warnings about the risk of QT interval prolongation.

Breaking drug tablets in half is a common practice. Since our last article on this subject, some new data have become available.

Recently published results of a large, carefully conducted retrospective study indicated that use of the antibiotic azithromycin (Zithromax, and others) may increase the risk of cardiovascular death, especially in patients with a high baseline risk of cardiovascular disease.1 One possible mechanism is prolongation of the QT interval, which is known to occur rarely with azithromycin and more frequently with the other macrolide antibiotics erythromycin (Erythrocin, and others) and clarithromycin (Biaxin, and others).

Among the patients who received 347,795 prescriptions for azithromycin, there were 29 cardiovascular deaths, a significantly higher rate than the 42 that occurred among the patients who received 1,348,672 prescriptions for amoxicillin (which does not prolong the QT interval) or the 41 that occurred among the 1,391,180 patients who took no antibiotics. Among patients with the highest baseline risk of cardiovascular disease, treatment with azithromycin, compared to amoxicillin, would have resulted in 245 additional cardiovascular deaths per million courses of the antibiotic.

As with any retrospective study, there could have been some undetected differences between the patients who received one drug or the other, but use of an appropriate non-macrolide alternative2 instead of azithromycin might be reasonable in patients with cardiovascular disease or in those who are taking other drugs that can prolong the QT interval (www.azcert.org).

1. WA Ray et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366:1881.

2. Drugs for bacterial infections. Treat Guidel Med Lett 2010; 8:43.

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A randomized, placebo-controlled trial evaluating the addition of the direct renin inhibitor aliskiren (Tekturna – Novartis) to an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in 8606 patients with type 2 diabetes and renal impairment (ALTITUDE) was terminated prematurely by the manufacturer because the combined incidence of cardiovascular and renal events was higher in patients who received aliskiren than in those who received placebo.1

Combining two different types of drugs that block the renin angiotensin system in patients at high-risk for cardiovascular and renal events has been studied previously. Use of both the ACE inhibitor ramipril (Altace, and others) and the ARB telmisartan (Micardis) in hypertensive patients with diabetes or vascular disease (ONTARGET) did not improve cardiovascular or renal outcomes compared to use of either drug alone, and patients treated with both drugs had more hypotensive symptoms, syncope and renal dysfunction.2

Aliskiren is available alone (Tekturna) and in fixed-dose combinations with hydrochlorothiazide (Tekturna HCT), the calcium channel blocker amlodipine (Tekamlo), both hydrochorothiazide and amlodipine (Amturnide) and the ARB valsartan (Valturna) for treatment of hypertension.3 None of these products has been shown to improve clinical outcomes. Novartis is advising prescribers not to use aliskiren-containing products with an ACE inhibitor or an ARB in patients with diabetes.

1. Novartis.Novartis announces termination of ALTITUDE study with Rasilez/Tekturna in high-risk patients with diabetes and renal impairment. Available at www.novartis.com/newsroom/rasileztekturna-information-center/index.shtml. Accessed January 17, 2012.

2. S Yusuf et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547.

3. Aliskiren/valsartan (Valturna) for hypertension. Med Lett Drugs Ther 2009; 51:94.

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The labeling of dabigatran etexilate (Pradaxa – Boehringer Ingelheim), an oral direct thrombin inhibitor, has recently been updated to include new dosing and monitoring recommendations and a warning on the risk of bleeding. Dabigatran etexilate was approved in the US in 2010 for the prevention of thromboembolic stroke in patients with non-valvular atrial fibrillation. It has been shown to be more effective than warfarin (Coumadin, and others) for this indication.

Dronedarone (Multaq – Sanofi), an analog of amiodarone, was approved by the FDA in 2009 for oral treatment of paroxysmal or persistent (non-permanent) atrial fibrillation or atrial flutter. Amiodarone (Cordarone, and others) is more effective for this indication, but its use is often limited by its adverse effects, including thyroid and pulmonary toxicity.

The FDA has announced that Eli Lilly has voluntarily withdrawn drotrecogin alfa (activated) (Xigris) after a recently completed trial (PROWESS-SHOCK) in patients with severe sepsis and septic shock failed to show an increase in survival in those treated with the drug.1 Drotrecogin alfa is a recombinant form of human activated protein C. Native activated protein C inhibits coagulation, increases fibrinolysis and has anti-inflammatory properties. FDA approval of Xigris (for patients with severe sepsis at high risk of death) was based on a single study (PROWESS).2 Post-marketing studies found a higher rate of bleeding than that reported in PROWESS.3,4

1. FDA Drug Safety Communication: voluntary market withdrawal of Xigris [drotrecogin alfa (activated)] due to failure to show a survival benefit. Available at http://www.fda.gov/Drugs/DrugSafety/ucm277114. htm. Accessed December 1, 2011.

2. Activated protein C (Xigris) for severe sepsis. Med Lett Drugs Ther 2002; 44:17.

3. E Abraham et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005; 353:1332.

4. KM Rowan et al. Drotrecogin alfa (activated): real-life use and outcomes for the UK. Crit Care 2008; 12:R58.

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Supplemental calcium is recommended for prevention of postmenopausal osteoporosis in women with an inadequate dietary intake of calcium. The safety of calcium supplements has recently been questioned; patients may ask if they should continue to take them. The source of this concern was the publication of 2 meta-analyses in the British Medical Journal.

Varenicline (Chantix), which has been associated with neuropsychiatric symptoms such as agitation, depressed mood, changes in behavior and suicidal ideation, appears to be the most effective drug available for treatment of tobacco dependence.1 Recently, the FDA warned that varenicline may also increase the risk of cardiovascular adverse events in patients with cardiovascular disease.2 This warning was based on the results of a 12-week randomized trial in 714 smokers with stable cardiovascular disease. The drug was effective in helping patients stop smoking; long-term quit rates (at 52 weeks) were 19% with varenicline and 7% with placebo.3 The results also included the following cardiovascular adverse events:

The authors of the study interpreted these results as providing reassurance that varenicline appears to be safe for use in smokers with stable cardiovascular disease. The FDA interpreted them as an association with a small increased risk of cardiovascular events if varenicline is used in patients with stable cardiovascular disease, and required the manufacturer to add this information to the labeling of the drug.

After the FDA's decision, a meta-analysis of 14 clinical trials in a total of 8216 patients with or without heart disease found that serious cardiovascular events occurred in 52 (1.06%) of 4908 patients treated with varenicline and in 27 (0.82%) of 3308 taking placebo. This difference was statistically significant.4

Until more data become available, the benefit of varenicline in helping patients stop smoking would appear to outweigh the risks of the drug.

1. Drugs for tobacco dependence. Treat Guidel Med Lett 2008; 6:61.

2. FDA Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease. Available at www.fda.gov/Drugs/DrugSafety/ucm259161.htm. Accessed August 15, 2011.

3. NA Rigotti et al. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation 2010; 121:221.

4. S Singh et al. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ 2011 July 4 (epub).

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The FDA and the manufacturer (Sanofi-Aventis) have warned healthcare professionals that use of dronedarone (Multaq), an analog of amiodarone (Cordarone, and others) approved in 2009 for treatment of atrial fibrillation,1,2 has been associated with "several" cases of severe liver injury and hepatic failure, including two that required liver transplants. Both transplants were in women about 70 years old; one had taken the drug for 4.5 months and the other for 6 months. According to the FDA, 147,000 patients have taken dronedarone.3 A new warning in the package insert recommends monitoring hepatic enzymes, especially during the first 6 months of treatment.

1. Dronedarone (Multaq) for atrial fibrillation. Med Lett Drugs Ther 2009; 51:78.

2. Treatment of atrial fibrillation. Treat Guidel Med Lett 2010; 8:65.

3. FDA drug safety podcast for healthcare professionals: severe liver injury associated with the use of dronedarone (marketed as Multaq). Available at www.fda.gov. Accessed February 24, 2011.

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The FDA recently warned that accidental ingestion of the antitussive benzonatate (Tessalon Perles, and others) by children less than 10 years old can be fatal.1 This widely prescribed oral agent, which has been available in the US since 1958, can also cause severe morbidity and death in older children and adults, and not only in overdosage.

Benzonatate is a polyglycol derivative structurally related to procaine and tetracaine. It acts peripherally on stretch receptors in the lower respiratory tract to suppress the cough reflex. If the patient chews or sucks the liquid-filled capsules or "softgels", the drug can cause laryngospasm, bronchospasm and circulatory collapse. Adverse effects that can occur after swallowing an intact capsule include a feeling of numbness in the chest, mental confusion, a sensation of burning in the eyes, and visual hallucinations.

Taken in overdose, benzonatate can rapidly cause seizures, cardiac arrhythmias and death. Serious adverse outcomes reported to the National Poison Center between 2000 and 2006 occurred in 116 patients (41 in children <6 years old), with 4 deaths.2 The 5 children known to the FDA who died from benzonatate ingestion were ≤2 years old and some apparently took only one or two capsules. In one well-documented case report, a 17-year-old girl who intentionally took 10 or more 200-mg capsules developed seizures, cardiac arrest from which she was resuscitated, and then blindness, which persisted.3 When a cough suppressant is truly necessary, dextromethorphan or even codeine might be a safer choice.

1. FDA. FDA Drug Safety Communication: Death resulting from overdose after accidental ingestion of Tessalon (benzonatate) by children under 10 years of age. Available at www.fda.gov/Drugs/DrugSafety/ucm236651.htm. Accessed January 27, 2011.

2. ML Winter et al. Benzonatate ingestion reported to the National Poison Center Database System (NPDS). J Med Toxicol 2010; 6:398.

3. V Cohen et al. Cardiac arrest with residual blindness after overdose of Tessalon (benzonatate) Perles. J Emerg Med 2009 Nov 4 (epub).

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The results of a postmarketing study of its cardiovascular safety have led to the removal of the weightloss drug sibutramine (Meridia) from the market in the US and Canada. It has also been withdrawn in Europe and Australia, but remains on the market in many other countries. The study that led the FDA to ask Abbott Laboratories to withdraw the drug randomized 10,744 overweight patients with cardiovascular disease, diabetes or both to sibutramine or placebo for a mean duration of 3.4 years. The primary endpoint (non-fatal myocardial infarction, nonfatal stroke, cardiovascular death or resuscitation after cardiac arrest) occurred in 561 of 4906 patients (11.4%) taking sibutramine and in 490 of 4898 (10%) taking placebo (p = 0.02). Death from any cause occurred in 8.5% of the patients who took sibutramine and in 8.2% of those on placebo; this difference was not statistically significant.1

1. WP James et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010; 363:905.

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At a US Senate hearing prompted by the withdrawal of Vioxx, an FDA officer cited 5 drugs as potentially dangerous. It may be useful to revisit Medical Letter reviews of these drugs.

Breaking drug tablets in half is a common practice. In some cases, a lower drug dose may be as effective as a higher one, with fewer adverse effects. Sometimes tablets are split to achieve an intermediate dose between marketed strengths. When 2 tablet sizes cost the same, as they often do, splitting the larger size saves money. Is this a reasonable practice?

Questions have been raised in the US press recently about the safety of Canadian drugs. The process of drug approval in Canada is similar to that in the US (D Paul, Int J Med Marketing 2001; 1:224). More than 90% of drugs available in Canada have also been approved by the FDA. Most of these drugs come from the same manufacturers as drugs in the US. Health Canada takes longer on average to release drugs than the FDA does; more than half the drugs discontinued for safety reasons by the FDA between 1992 and 2001 had not been approved for use in Canada (NS Rawson and KI Kaitin, Ann Pharmacother 2003; 37:1403). Websites claiming to sell Canadian drugs, however, may be selling counterfeit drugs from unregulated sources.

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