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QuarterWatch™ (2016 Quarter 2 Data) Liver Failure with Hepatitis C Drugs, Drugs with Signals for Insomnia, and Harm from Antipsychotic Drugs

The latest issue of ISMP’s QuarterWatch™ provides a review of drug safety issues reflected in adverse drug events reported to the US Food and Drug Administration (FDA) during the second quarter (Q2) of 2016 and during the previous 12 months. Key topics included:

  • Emerging risks of new hepatitis C drugs for triggering reactivation of hepatitis B, liver injuries, and liver failure
  • Drugs with signals for insomnia, one of the most common side effects that can impair the quality of life and affect health

In this report, we also summarize our recently published study of the harm associated with antipsychotic drugs.

Adverse drug event report totals for Q2 2016

The FDA received 269,776 reports about adverse drug events in Q2 2016, a decline of 20.8% from the previous quarter, but an increase of 5.9% from the same quarter in 2015. The reports identified 1,386 different primary suspect drugs, but only 385 drugs were involved in 100 or more reports. Among the 2016 Q2 reports, 78,123 cases (29%) described drug-related injuries in the US that were serious, disabling, or fatal. 

The oral anticoagulant rivaroxaban (XARELTO) accounted for more reports in several categories than any other drug regularly monitored by QuarterWatch™. It accounted for the most US reports of serious injury (n = 6,262), the largest number of patient deaths (n = 614), and the most serious events reported in patients age 75 years and older (n = 669). The following factors account for the high rivaroxaban totals:

  • Because of the risk of hemorrhage, oral anticoagulants rank among the highest-risk outpatient drug treatments by several measures
  • As reported previously in QuarterWatch™, rivaroxaban has a 5- to 9-hour half-life, which may render it poorly suited to once-a-day administration
  • The totals for Q2 included some serious injuries and many non-serious injuries that were reported by the manufacturer on an annual rather than quarterly basis

 New safety issues for hepatitis C antivirals

Chronic hepatitis C infection is widespread, affecting 2-3 million people in the US and millions more worldwide. The infection, which can persist for decades without symptoms, can progress to cirrhosis of increasing severity and in some cases lead to liver cancer. The direct-acting antivirals, the first approved in late 2013, represent a major advance:

  • They often suppress the virus to undetectable levels more quickly than other antivirals (12 weeks instead of 26-48 weeks)
  • They are more effective, eliminating detectable virus in 89-100% of selected patients enrolled in clinical studies
  • They are better tolerated in some combination therapies, cutting dropout rates nearly in half

However, we examined two issues that have emerged with postmarketing surveillance.

Reactivation of hepatitis B. In October 2016, FDA identified the first new major safety problem linked to the nine new direct-acting antiviral drugs for hepatitis C. For patients who currently or previously had an infection with the hepatitis B virus, the direct-acting antivirals can cause reactivation of the virus and result in serious liver problems or death. The FDA report described 24 cases of hepatitis B reactivation, including 3 cases of acute liver failure leading to 2 deaths and 1 liver transplant. The reactivation of hepatitis B was not detected in clinical testing done prior to approval because such patients were excluded in the studies. This risk potentially can be managed by pretreatment virologic testing for hepatitis B, as the FDA now recommends.

Liver injury and failure. Searching beyond the FDA’s cited cases above to review the most recent 12 months of data up to Q2 2016 in the FDA adverse event reporting system (FAERS), we identified 524 reported cases of liver failure associated with the drugs, and another 1,058 reports of severe liver injury that had apparently not progressed to liver failure. The 524 reported cases of liver failure included all the approved direct-acting antivirals as either primary or secondary suspect drugs (Table 1), often in combination with each other or with ribavirin. Almost half of the cases reported encephalopathy, the hallmark symptom of liver failure.  Overall, 165 (31.5%) had died at the time of the report. While the complications of hepatitis C rather than the suspect drug might have contributed to some cases, 90% of the reports were submitted by healthcare professionals, who would be more likely to understand the natural progression of the disease.

Suspect drugs in liver failure
Table 1. Primary (PS) and secondary (SS) suspect drugs in liver failure cases (n=524)


Conclusion. Policies to approve new treatments quickly can exact a price in serious injuries and deaths that might have been avoided with a more complete safety profile and better understanding of the most vulnerable patients. Important questions remain unanswered about the long-term effects and appropriate patient population for these drugs. While direct-acting antivirals to treat hepatitis C are a major medical advance, further investigation should focus on achieving better understanding of what is occurring when the drugs appear to cause liver injury rather than improve liver function.

Drugs with signals for insomnia

Having trouble falling asleep, staying asleep, or awaking too early is a problem that affects nearly half the adult population, with chronic insomnia rates reported to be in the range of 10 to 42%. Insomnia is also one of the most frequently reported adverse drug events. In the most recent 12 months of data in FAERS, we identified 16,301 reported cases in the US indicating insomnia (excluding abnormal dreams, sleep apnea, or shift-work disorder) as an adverse drug event. Among these, we evaluated the suspect drugs that had at least twice as many reports of insomnia as would be expected if it had occurred by chance. The results showed credible signals indicating a link to insomnia for 87 different drugs. These cases excluded anxiety, sedative-hypnotic, and narcolepsy drugs, because an insomnia complaint could have indicated treatment failure rather than an adverse effect. In many instances, our suspect drugs had a plausible mechanism of action, or the drug had established warnings regarding insomnia. Some key findings follow.

Fluoroquinolone antibiotics. We saw signals for the three most widely prescribed drugs in this class, ciprofloxacin (CIPRO), levoFLOXacin (LEVAQUIN), and moxifloxacin (AVELOX). No other antibiotics were implicated, and the result was consistent with known neurological activity of the fluoroquinolones.

Antidepressants. Most antidepressants were associated with higher than expected reports of insomnia. This effect is consistent with clinical trial data, mechanism of action, and existing warnings. Given that sleep disturbances are also a symptom of depression, these adverse effects may limit effectiveness of these drugs in depression.

Drugs with stimulant effects. It was not surprising to find drugs with simulant effects implicated in insomnia. The list included many allergy and cold medications containing pseudoephedrine, obesity drugs with phentermine, drugs used to treat attention deficit hyperactivity disorder (ADHD), and synthetic thyroid hormone, the most frequently prescribed drug in the most recent quarter.

Antivirals. We identified signals for 11 antiviral drugs targeting a wide spectrum of viral disorders including influenza, hepatitis B and C, and human immunodeficiency virus (HIV). A link between these antivirals and insomnia has not been extensively studied.

Conclusion. While we saw clear signals for all 87 drugs identified in the full report, concern regarding safety varies based on the drug type and its use in certain patient populations. Concerns would be greater for long-term use of ADHD drugs and antidepressants, compared to a few days of treatment with oseltamivir (TAMIFLU). In other cases, such as drugs that treat hepatitis C for 12 weeks, the risk of insomnia might be regarded as a lesser side effect to be tolerated to achieve suppression or eradication of the virus. The data and complete list of suspect drugs appears in the full QuarterWatch™ report.

The harm of antipsychotics reappraised

With long-term use, 40-65% of patients taking antipsychotic drugs experience serious side effects, many of them irreversible. A comprehensive review of antipsychotic drugs by QuarterWatch™ team members, Thomas J. Moore & Curt D. Furberg (see full report), showed that treatment failure was the most common outcome, partly because the drugs were poorly tolerated due to adverse effects. The review focused on clinical trials for the six most widely used antipsychotic drugs—QUEtiapine (SEROQUEL), risperiDONE (RISPERDAL), ARIPiprazole (ABILIFY), OLANZapine (ZYPREXA), haloperidol (HALDOL), and ziprasidone (GEODON). These drugs are used not only to treat psychosis but also for treatment-resistant depression, some forms of bipolar disorder, and off-label in the elderly with dementia and in children with behavioral problems. In the January 2017 issue of Drug Safety, the QuarterWatch™ team members concluded that antipsychotic drugs may not provide enough benefit to justify their serious adverse effects. 

Treatment failure was a common outcome and occurred when patients stopped the drug because of intolerable adverse effects, or because the physician or patient refused continued treatment for other reasons. Treatment failure occurred in a majority of patients treated for psychosis with QUEtiapine, even though they were hospitalized for most of the 6-week study. Overall patient improvement in that study was rated as “minimal” or less by the treating physicians.

Results were worse when antipsychotic drugs were used in hopes of preventing relapse. In a 1-year clinical trial comparing haloperidol to risperiDONE, relapse or treatment failure occurred in 93% of the haloperidol patients and 69% of risperiDONE patients. In another study of the same two drugs, 10% of early schizophrenia patients who were treated for a year suffered irreversible damage to the motor system, and more than 40% were taking medications to treat parkinsonism adverse effects. When a course of long-term treatment with antipsychotics can lead to injury of 10% or more of patients in 1 years’ time, these data alone should make reducing these risks a major priority in drug safety for 2017.

The full QuarterWatch™ report, with references, can be found here.

What is QuarterWatch™?
QuarterWatch™ is the publication of an independent ISMP surveillance program that monitors adverse drug events reported to FDA by manufacturers, health professionals, and the public. The agency releases, for research and data analysis, excerpts of all domestic and foreign reports it receives into the FDA Adverse Event Reporting System (FAERS). The goal is to identify signals that may represent important drug safety issues which often require further investigation to determine their frequency and establish a causal relationship to the suspect drug.