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QuarterWatch™ (2012—Quarter 1) Signals for DULoxetine, Pioglitazone, Aliskiren, and Rivaroxaban

QuarterWatch™ is an ISMP surveillance program that monitors serious, disabling, and fatal adverse drug events (ADEs) reported to the US Food and Drug Administration (FDA) by drug manufacturers and by health professionals and the public through its MedWatch reporting program. The goal of QuarterWatch™ is to improve patient safety through the identification of signals that may represent important drug safety issues. The term signal means evidence judged to be substantial enough to warrant publication but which usually requires further investigation to determine its frequency of occurrence and establish a causal relationship to the suspect drug. The latest QuarterWatch™ examines January to March 2012 report totals, trends, and ADE signals.   

Reporting totals and trends

During the last 4 years, the number of domestic, serious ADE reports received by FDA has increased by 90%. This sustained and substantial growth in reports remained unabated in the first quarter of 2012, with the FDA receiving 57,393 reports meeting our criteria, an increase of 23.8% from the previous quarter and 30.1% from the same quarter last year. As in previous quarters, the increase is due to more reports from manufacturers; the volume of direct reports from consumers and healthcare practitioners is largely unchanged since 2008. 

Reports for medications not widely used before 2008 or newly approved since then accounted for 23% of the report growth. The drugs with the largest number of reports in the first quarter of 2012 for these newer drugs were dabigatran (PRADAXA) (927) and fingolimod (GILENYA) (509). QuarterWatch™ has previously examined signals for both drugs. Increasing reports for drugs seen in all 4 years accounted for 40% of the growth, with adalimumab (HUMIRA), erlotinib (TARCEVA), and imatinib (GLEEVEC) leading the way. Growth in the remaining reports (37%) was due to special circumstances or heightened surveillance methods for certain drugs.

ADE signal upon withdrawal of DULoxetine

In the first quarter of 2012, FDA received 48 reports of drug withdrawal symptoms identifying DULoxetine (CYMBALTA) as the suspect drug, which outnumbered reports of withdrawal symptoms for all other monitored drugs. The reports described a wide spectrum of side effects that began when patients stopped the drug, including anger, suicidal thoughts, hallucinations, paresthesia, tremor, and nausea. Several cases involved hospitalization. During clinical trials for depression, withdrawal symptoms had been reported in 44% to 50% of patients who abruptly discontinued DULoxetine after 9 weeks or less. Symptoms were severe in about 10% of those with withdrawal symptoms, and in 54% of this group, the symptoms had not yet resolved when monitoring halted after 1 or 2 weeks.  

Before DULoxetine was approved in 2004, withdrawal effects were well documented when antidepressants were discontinued,1 although early reviews tended to be dismissive, categorizing the symptoms as “uncomfortable” but “self-limited and generally resolved within 1-2 weeks.”2 The FDA safety review of DULoxetine was similarly toned down: “It appears that symptoms are relatively mild and reliably predictable for a significant minority of patients. Tapering DULoxetine at discontinuation appears to be advisable for optimal patient comfort, but not tapering does not appear to pose any serious risk.”3 Given the severity and persistence of symptoms in some patients, these early assessments understated withdrawal risks.

There are also inadequate warnings about withdrawal symptoms and limited information about how to prevent or manage these adverse effects in official labeling. The patient Medication Guide notes that the drug should not be stopped without talking to a healthcare provider because it “suddenly can cause other symptoms.” However, the guide gives no hint of the persistence or severity of the symptoms, how slowly to taper the dose, what to do if depression or other symptoms recur, or if there is a way to tell whether the symptoms are due to withdrawal or the previous illness returning. Some information about symptoms associated with discontinuing the drug is provided in the prescribing information, but little guidance is offered for a tapering regimen: “A gradual dose reduction rather than abrupt discontinuation is recommended whenever possible.” When physicians call Lilly with questions, the company provides them with a 4-page summary that reiterates the prescribing information and results of studies on withdrawal symptoms. The company also provides physicians with a 1-page summary on discontinuation taper schedules that notes there have been few trials in which the dose was tapered, and then only over 2 weeks.

Three different publications about discontinuing antidepressants agreed that a much longer taper is needed. One suggested a starting point of about a 10% dose reduction per week.4 Another suggested at least 6 weeks.5 The third resource recommends tailoring the taper regimen to the individual patient, dose, and symptom severity.6 It notes that DULoxetine tapering could take from a few weeks to as long as a year for the most severe symptoms.6 The fact that 11% of the population takes an antidepressant, with 60% taking them for 2 years or more,7 elevates the issue of withdrawal effects of antidepressants onto a short list of major drug safety concerns. While the QuarterWatch™ report focused on DULoxetine, several other antidepressants are associated with withdrawal symptoms.   

ADE signal with pioglitazone

The possibility of a cancer risk for scores of approved drugs was first established in pre-approval studies in rats and mice that were fed high doses of drugs over a 2-year lifetime. But seldom is the human risk either confirmed or ruled out. Pioglitazone (ACTOS) has proven to be an exception. Early adverse drug event reports and an interim report from a 10-year study showed an increased risk of bladder cancer after 2 or more years of exposure, and now 1,025 cases of bladder cancer have been reported to FDA since January 2011, including 235 new cases in the first quarter of 2012.

During toxicology testing, rats developed calcium nodules in the urinary bladder and bladder cancer, but this was not seen with mice, making the cancer risk to humans difficult to assess. The FDA required the manufacturer, Takeda, to disclose the risk in the prescribing information, which said, “Drug induced tumors were not observed in any organ except for the urinary bladder.” Safety concerns continued, and in 2003, the company commissioned a 10-year study to examine bladder cancer risk. By 2010, pioglitazone was the most frequently prescribed brand name drug for Type 2 diabetes. Sales plummeted the next year after release of a 5-year interim report that showed an increased risk of bladder cancer in those taking  pioglitazone for 2 years or more,8 and other reports supported these findings. France suspended sales of the drug, and Germany recommended a halt on prescriptions for new patients. But the drug remained on the market in Europe and the US, with new warnings about an increased risk of developing bladder cancer. Enhanced awareness of this adverse effect resulted in an upward spike in reports submitted to FDA in the past 5 calendar quarters.  

The manufacturer acknowledged that some evidence of increased risk has emerged. But it said no final conclusion should be drawn until the completion of its long-term studies. It is not so much that the evidence is weak, but rather that cancer risks are likely to occur over several years and are notably hard to document.

ADE signal with aliskiren

In the first quarter of 2012, 100 cases of angioedema were reported with aliskiren (TEKTURNA), a newer direct renin inhibitor antihypertensive drug, and a combination product containing aliskiren and hydrochlorothiazide (TEKTURNA HCT). The cases included 1 patient death, 2 classified as life threatening, and 15 requiring hospitalization. This drug accounted for 237 reports overall, more than any other blood pressure medication but fewer than 43 other regularly monitored drugs. Given that a clinical trial showed that two drugs active in the renin-angiotensin pathway might be harmful in some patient groups, questions have been raised about the future of aliskiren. 

In clinical trials, the drug’s short-term efficacy was roughly comparable to other drugs used to lower blood pressure, but it had not yet been tested in trials long enough to assess its hoped-for clinical benefits—reducing the risk of heart attack and stroke. Novartis, the manufacturer, thought there might be additional benefits from combining two drugs active in the renin-angiotensin pathway (such as ACE inhibitors and angiotensin II receptor blockers [ARBs]). It launched a clinical trial in diabetes patients with impaired renal function. In December 2011, Novartis terminated the trial, detecting no advantage in efficacy and a higher incidence of adverse events.9 Similar results were seen in another trial in recent heart attack patients. In July 2012, VALTURNA, a combination product containing aliskiren and valsartan was withdrawn from the market in the US and Europe. The withdrawal left an unanswered question regarding whether it was safe to combine aliskiren with any other ACE inhibitor or ARB, particularly given that physicians often use multiple drugs to treat hypertension and may prescribe each separately. The European Medicines Agency concluded that the combination of aliskiren and any ACE inhibitor or ARB is not recommended, while the FDA has made no public comments on the matter.

Meanwhile, adverse event reports in the first quarter of 2012 provided new information about an additional risk—angioedema. Novartis said it is actively investigating this and is planning to conduct an epidemiological study. While the current angioedema warnings for physicians and patients are explicit and clear, we are concerned about the severity and still unclear incidence of angioedema. Also, with two problematic clinical trials involving combinations of two products active in the renin-angiotensin pathway, we agree with the European Medicines Agency that combination therapy with aliskiren and either an ACE inhibitor or ARB should not be recommended. With its low-keyed withdrawal of Valturna and silence on the combination therapy question, we also believe FDA has not kept physicians and patients informed about risks and safe use of aliskiren.

ADE signal with rivaroxaban

In the first quarter of 2012, we identified 356 adverse event reports in which rivaroxaban (XARELTO), one of the newest anticoagulants on the market, was the primary suspect drug. Rivaroxaban is rapidly replacing warfarin and enoxaparin to reduce the risk of pulmonary and venous thromboembolism after hip and knee surgery. When we examined the reports, we found that the primary event was not hemorrhage, as with other anticoagulants. Instead, the largest category of events (158 cases, 44.4% of the total) was serious thrombus, most often pulmonary embolism—the very event rivaroxaban is intended to prevent. As might be expected, there were also numerous reports of hemorrhage (121 cases, 34% of the total).

Janssen Pharmaceuticals attributes the large and rising volume of reports to a successful launch of the drug, which the company said had captured 22.5% of the market share for anticoagulation after hip and knee replacement surgery by the first quarter of 2012. While the volume of reports may be related in part to a successful product launch, the predominance of thromboembolic event reports suggests suboptimal anticoagulation and should be further investigated.

The full QuarterWatch™ report with references can be viewed here.


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