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QuarterWatch (3rd quarter 2008)

Safety concerns with generics, Chantix aggressive behavior, and more

From the May 7, 2009 issue

QuarterWatch, an ISMP program used to identify new drug risks and errors reported to the US Food and Drug Administration (FDA), evaluated computer excerpts of 24,872 serious, disabling, and fatal adverse drug events submitted during the third quarter of 2008. The reports involved 854 different drugs which led to 2,778 deaths, 1,162 cases of disability, and 20,932 other kinds of serious injuries. Of the 854 different drugs associated with death and disability, 53 drugs accounted for 100 or more reported cases. The leading drugs in this category appear in Table 1 (in the PDF version of the newsletter).

Compared to the first two quarters of 2008, little has changed in the number of reported adverse events, although patient deaths have declined, with 4,724 deaths in the first quarter, 3,820 deaths in the second quarter, and 2,778 deaths in the third quarter. Nevertheless, the total number of reported events was 30% higher, and reported deaths were 41% higher, than the same quarter in 2007.

Specific Drugs
Interferon Beta (AVONEX, REBIF, BETASERON). Used to treat multiple sclerosis, this drug available from three manufacturers accounted for 1,380 reported serious adverse drug events—more than any other prescription drug in the third quarter. Most events involved complaints about relapse or exacerbation of multiple sclerosis. These reports were difficult to interpret since both events would be expected to occur despite treatment, which slows rather than eliminates the disease. After contacting the manufacturer with the largest number of reports, we concluded that the frequency of reports did not signal a new patient safety risk. Most reports resulted primarily from consistent, monthly contact with patients by one manufacturer to uncover adverse events, which included relapses and exacerbation of symptoms. 

Digoxin. More than 1,000 deaths have now been reported, potentially linked to the recall of 800 million digoxin (branded generic DIGITEK) tablets manufactured by the Actavis Group in NJ. The strength of the tablets may have been greater than labeled, exposing patients to a potentially lethal overdose. Inexplicably, 1 year after announcement of this recall—no doubt one of the largest class 1 recalls recorded—no testing of the returned tablets has been performed to establish how many deaths resulted from a manufacturing defect, and how many occurred for other reasons. Furthermore, a new recall in March 2009 of digoxin tablets from another manufacturer—Caraco Pharmaceutical Laboratories—underscores weaknesses in the US system for ensuring quality in the manufacture of generic drugs.

Baclofen (LIORESAL INTRATHECAL). Despite use in a relatively small patient population, Lioresal ranked third among all prescription drugs for reported serious, disabling, and fatal injuries in the third quarter of 2008. Problems with an implantable pump used to administer the drug into cerebrospinal fluid to lessen involuntary muscle contractions from brain or nerve injuries, cerebral palsy, and multiple sclerosis, were associated with approximately 140 cases of serious injury including one death. Medtronic Neuromodulation, which provides both the implantable pump and the drug Lioresal, issued an urgent alert ( to doctors that the catheter tubes delivering the drug to the spine were not being properly attached to the pump. This led to interruption of the drug supply and severe withdrawal symptoms. This cluster of confirmed cases was among 872 reports of serious injury associated with baclofen.

Reaction Types
Psychiatric side effects. Varenicline (CHANTIX), a drug to help quit smoking, continued to account for more reports of serious psychiatric side effects than any other prescription drug. Despite a reduced number of adverse event reports for varenicline in the third quarter, this drug still ranked fourth among all prescription drugs for causing serious injury. Although the FDA and manufacturer have already warned consumers about the possible risk of suicidal behavior, the case reports also suggest a possible link to violence towards others. Table 2 provides the terms used in reports when describing this aggression and violence. Since the 2006 approval of varenicline, QuarterWatch has identified 30 cases that describe physical assaults, 148 cases that mention homicidal thoughts, and 331 cases of aggression. (One case could include multiple symptoms.)

Infection. We noted increasing reports of infection in connection with DIANEAL, a product used for peritoneal dialysis. After conferring with the manufacturer, Baxter Healthcare, we agreed that report volume was likely a result of increased vigilance by the company and extensive direct contact with patients rather than a signal of a new safety problem. There was no indication of a product problem or contamination of the solution that might account for frequently reported abdominal infections. However, the risk of infection is a major, recognized complication of peritoneal dialysis.

Strengths and Limitations
One of the primary strengths of the FDA adverse drug event reporting system is its sensitivity. With millions of patients and hundreds of thousands of health professionals as observers, and no restrictive rules for reporting, the system is capable of detecting adverse drug effects that may have been overlooked or underestimated in clinical testing prior to approval. While many of the reports stem from required reports by drug manufacturers, healthcare providers and patients may also identify an adverse effect overlooked by manufacturers or experts who may have preconceptions about the drug’s properties, or were bound by restrictive testing protocols.

Nevertheless, QuarterWatch results should be interpreted with caution because of the known limitations of these data. Because reporting is voluntary, only a small fraction of adverse drug events that occur are ever reported to FDA, or to drug manufacturers which then investigate and forward reports to the FDA. Also, while the sum of adverse event reports normally provides an overall adverse event profile for a drug, the individual reports themselves may not prove that the drug caused the event described. We have also identified several problems with the reports themselves (e.g., coding errors, inconsistent use of product names), which have subsequently been investigated, communicated to FDA, and corrected when possible.

Quality of generic products. Concerns continue regarding serious problems our nation seems to be facing to ensure generic drugs are manufactured with adequate quality controls. In the first quarter of 2008, there were urgent recalls of most of the nation’s supply of one form of generic heparin(1) and millions of fentanyl patches from several generic drug manufacturers.(2) In the second quarter, about 50% of the nation’s supply of generic digoxin was recalled because over-strength tablets may have been manufactured and distributed. An additional generic digoxin recall was announced in March 2009. In the third and fourth quarters of 2008, urgent recalls were announced for generic versions of morphine sulfate, propafenone, and isosorbide—all involved over- or under-strength tablets that could lead to significant health consequences.(3) In addition, two NJ plants of the Actavis Group were closed and all products manufactured there were recalled due to manufacturing concerns. In December 2008, KV Pharmaceuticals’ plants were closed to resolve quality control problems.4

The concern regarding the manufacture of generic drugs has received little public and official notice in part because FDA does not require disclosure of the size and impact of a product recall. To cite one example, neither Caraco Pharmaceutical Laboratories nor FDA would reveal how many digoxin tablets were involved in its March 31, 2009, recall notice.(5) Based on these findings, it seems apparent that FDA’s current system for inspecting plants, dealing with violations, and managing product recall notices requires systematic, independent review.

Warnings with varenicline. We continue to be concerned about the safety profile of varenicline which accounts for more psychiatric side effects reported to the FDA than any other prescription drug. In addition, no action has been taken to provide a prominent warning about the drug’s potential to cause motor vehicle accidents through its effects on mood, memory, vision, and motor control. Further, little follow-up has occurred in response to reports of aggression, physical assaults, and homicidal thoughts. While we might assume that these serious side effects have been disclosed to patients who consent to take varenicline, such violence affects patients’ families and the public at large, from whom consent to the possibility of violence has clearly not been obtained.

Analysis of device used to deliver Lioresal. The signal involving Lioresal brand of baclofen illustrated that serious patient injury can result from complex interactions between an implanted device and a drug. We believe this case warrants additional study to determine what went wrong: Was the connector hard to use? Were the instructions for implanting the device and its catheter error-prone? Was more practitioner training needed? What were the underlying device, drug, patient, and system factors that shaped this series of events? In any case, the result was tragic: in more than 100 confirmed cases, patients were harmed and a vulnerable patient population experienced abrupt discontinuation of a vital drug.

The full QuarterWatch report can be viewed at:

References: 1) US Food and Drug Administration (FDA). Questions and answers on heparin sodium injection (Baxter). Updated on June 16, 2008. 2) Moore TJ, Cohen MR, Furberg CD. QuarterWatch: 2008 quarter 2. January 15, 2009; page 15. 3) FDA. Ethex Corporation initiated nationwide voluntary recalls of specific lots of five generic products due to the potential for oversized tablets. Recall—Firm Press Release. November 7, 2008. recalls/ethex11_08.html 4) KV Pharmaceutical. KV Pharmaceuticals voluntarily suspends all shipments of its approved tablet form drugs. St. Louis, MO; December 23, 2008. 5) FDA. Caraco Pharmaceutical Laboratories, Ltd. announces a nationwide voluntary recall of all lots of digoxin tablets due to size variability. Recall—Firm Press Release. March 31, 2009.
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