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Quarterwatch™ Report (Quarters 2 and 3, 2013): Signals for Chantix, Xyrem, Gilenya, and Tecfidera

The new issue of ISMP’s Quarterwatch™ on adverse drug events (ADEs) reported to the US Food and Drug Administration (FDA) focuses on safety signals involving four drugs. The report examines cases of homicidal, self-injurious, and suicidal ideation for varenicline (CHANTIX); multiple adverse effects on the brain with sodium oxybate (XYREM); cardiac, ocular, infection, and pregnancy risks with fingolimod (GILENYA); and severe gastrointestinal (GI) toxicity and hypersensitivity associated with dimethyl fumarate (TECFIDERA).

Varenicline (Chantix): Thoughts of suicide/self-injury and homicide

In October 2014, FDA will move the smoking cessation drug varenicline back into the drug safety spotlight. The agency has scheduled a joint public meeting of two advisory committees to review the current Boxed Warning and Medication Guide. Thus far, FDA has revealed little about why it scheduled this special meeting. The inaugural issue of Quarterwatch™ in 2008 featured an unexpectedly large number of serious psychiatric and other ADEs for this drug. We thought it was troubling that an alternative to nicotine replacement products was the primary suspect in more reported cases of serious injury than toxic chemotherapeutic agents, potent opioids, or powerful immunosuppressant drugs. In response, the Federal Aviation Administration banned the use of Chantix by airline pilots, the Department of Transportation limited its use among truck drivers, and the Department of Defense prohibited its use by aircraft and missile crews. Also, more than 3,000 patients sued Pfizer, the manufacturer, related to the drug’s psychiatric adverse effects, and thousands were compensated. The FDA required the company to add a Boxed Warning to the package insert and to provide more information in the Medication Guide in 2009.  

In light of the October meeting, we reassessed selected varenicline ADE data collected since drug approval 7 years ago, using as endpoints thoughts of suicide, self-injury, or homicide. These new data show that varenicline continues to account for more cases of suicidal, self-injurious, or homicidal thoughts than any other therapeutic drug from 2007 through 2013 Q3 (Table 1) - more than 3 times as many as the second-ranked drug. Leading drugs self-injurousFor varenicline reports, thoughts of suicide and self-injury also correlated with attempted and completed suicides. Since 2007, varenicline was the primary suspect drug in 293 cases of completed suicide and 490 cases of attempted suicide. Varenicline stands out even more prominently in the subset of homicidal ideation, with a 5-fold margin over second-ranked QUEtiapine. If examining only the reports for 2011 to 2013, the margin by which varenicline cases outnumbered all others was reduced. That reduction was consistent with the 73% decline in dispensed outpatient prescriptions since its peak in 2008. Of note, based on IMS Health data for 2013 Q3, eight of nine other drugs in Table 1 had a much wider patient exposure, ranging from pregabalin (4.2 times higher than varenicline) to montelukast (14.4 times higher than varenicline). Only ISOtretinoin (CLARAVIS) had fewer prescriptions (47% of the total for varenicline).

Current FDA warnings about suicidal behavior are reasonably clear in the varenicline Boxed Warning. However, warnings about homicidal thoughts, hostility, aggression, psychosis, and violence need to be strengthened. In addition, the promotional language about smoking cessation benefits should be removed from the Boxed Warning, and the indications section should explicitly state that use is not recommended for sensitive occupations such as pilots, air traffic controllers, deployed military personnel, police, fire fighters, and emergency medical care professionals.

Sodium oxybate (Xyrem): High adverse event report rate

Sodium oxybate, also known as gamma hydroxybutyric acid (or GHB), is an extremely fast-acting sedative and central nervous system (CNS) depressant. It was once a widely available addictive drug of abuse and one of the first known date-rape drugs. The drug is available as sodium oxybate to treat daytime sleepiness and catalepsy manifestations of narcolepsy. It is classified as a Schedule III controlled substance. Illicit use is subject to Schedule I penalties. The drug is only available under a restricted distribution program from one central pharmacy, and prescribing doctors and patients must complete an education program. The drug acts so fast that patients are warned to take the evening dose in or near a bed, and it is metabolized so rapidly that patients are instructed to set an alarm to take a second dose 2.5 to 4 hours later.   

Jazz Pharmaceuticals, the manufacturer, published an optimistic safety overview of sodium oxybate in 2009 in a medical journal and gave a similar portrayal at a 2010 FDA meeting. However, in 2011, Jazz revealed that it had included only 21 of 103 reported patient deaths. The problem was traced to inadequate coordination of reporting procedures with the central pharmacy that distributed the prescriptions. Thus, this Quarterwatch™ issue provides the first published overview of a fully reported ADE profile.

We identified an unexpectedly high number of serious ADEs reported for the drug given its use by a small patient population of approximately 9,000 in 2013. Sodium oxybate accounted for more reported serious ADEs than other drugs taken by millions of patients. According to the reports, the drug was suspect as causing adverse effects on motor control (e.g., falls, bedwetting), the extrapyramidal motor system (e.g., dystonia, Parkinsonism, akathisia), memory and alertness (e.g., blackout, memory loss), and mood and behavior (e.g., depression, psychosis, hostility, suicidal behaviors). Serious reported ADEs involved 15% of the exposed population, measured in patient years. Close follow-up with patients and manifestations of the disease itself could account for the high total of reported events.    

There are also safety concerns associated with the off-label use of sodium oxybate, which was illegally promoted by Jazz’s predecessor company for use in insomnia and various psychiatric disorders, leading to civil and criminal penalties in 2005. In recent data, we found that off-label use was documented in at least 19% of the reported ADEs, including fibromyalgia, insomnia, and unspecified sleep disorders. Given the risks now seen in the current adverse event reports, questions remain whether the drug’s benefits justify its unusually high risks, and whether off-label use has been or could be controlled.

Fingolimod (Gilenya): Cardiac, ocular, infection, and pregnancy risks

Two years ago, Quarterwatch™ first reported early safety signals for fingolimod, the first oral immunosuppressant treatment for multiple sclerosis (MS), which received expedited FDA approval. Meanwhile, postmarket data continue to highlight four important safety risks.

First, because fingolimod has the capacity to disrupt normal heart rhythm, initiating treatment requires that the patient be observed for the first 6 hours in a medical setting. ADE reports for the most recent 12 months show that this cardiac risk is neither rare nor hypothetical. We identified 473 cases of heart rhythm disturbances, primarily bradycardia and heart block, including 13 deaths, 11 life-threatening cases, and 141 cases resulting in hospitalization. Next, a large group of cases (348) reported macular edema or less specific ocular adverse effects. (Vision disturbances are also an early symptom of MS.) Because of the known risk of macular edema, baseline and follow-up eye exams are recommended, and reminders should be sent to patients. A third concern was increased risk of infection due to fingolimod’s effect on lymphocytes. In the 12 months of data, we identified 172 cases of reported viral infections, mostly herpes simplex and zoster. Finally, pregnancy risks were a substantial concern based on animal studies linking the target fingolimod receptor to vascular malformations in rodents as well as human fetal abnormalities in clinical studies. In the 12 months of ADE data for this issue, we identified 3 additional cases in postmarket surveillance with an outcome of birth defect. While the drug is currently classified with a Pregnancy Category C risk profile, FDA and the manufacturer should now consider reclassifying fingolimod as Pregnancy Category X, clearly identifying it as a drug not suitable for women who may become pregnant.

The large number of serious injury reports (2,716) shows that fingolimod remains a high-risk drug with multiple toxicities. This underlies the critical importance of observation during administration of the first dose, follow-up eye exams, and prohibitions during pregnancy.

Dimethyl fumarate (Tecfidera): GI side effects and hypersensitivity

Approved in March 2013, the product launch for dimethyl fumarate—the third orally administered immunosuppressant for MS—was so successful that the manufacturer, Biogen Idec, reported that it was the leading oral disease-modifying MS therapy in the US after only 6 months. However, during this time, adverse event reports showed a marked signal for severe GI disorders and hypersensitivity.

Additional safety questions arise from animal studies. In premarket testing, dimethyl fumarate produced toxic effects in multiple animal species at both clinically relevant and higher exposures. The primary target organs were the kidneys, stomach, and testes. The postmarket ADE reports also include GI reactions (202) that were often severe and required hospitalization, and hypersensitivity reactions (125). More than half (55%) of the hypersensitivity cases also involved GI reactions.

Important questions about the safety of dimethyl fumarate remain unanswered, particularly related to possible damage to the kidneys and testes. In fact, the toxic effects on the kidney were so pervasive in animal studies that the toxicology reviewer recommended against FDA approval. However, human clinical studies did not provide evidence of adverse effects on the kidneys. But one FDA reviewer thought the slow kidney deterioration seen in a 1-year monkey study might not be evident. Adverse effects on the testes were also seen in three animal species. The severe hypersensitivity and GI adverse effects associated with dimethyl fumarate show the need to re-evaluate these risks, provide clear warnings for physicians, develop guidelines for optimal treatment, and conduct robust postmarketing analysis.

The full Quarterwatch™ report with references can be found here.

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