Despite several warnings by the Food and Drug Administration (FDA), the popular cholesterol drug Zocor (simvastatin) continues to be prescribed in potentially lethal combination with (Codorone) amiodarone, a drug used to treat irregular heartbeat.  According to the FDA, this drug combination increases the risk of a serious muscle condition called rhabdomyolysis, which can cause kidney failure and death if not properly diagnosed and treated.

Several patients have already reported these serious side effects and many people continue to be prescribed this drug combination without fully understanding the inherent risks.

The 2002 FDA warning

In 2002, the FDA first warned the public about the serious risk of rhabdomyolysis associated with taking simvastatin (Zocor) in combination with amiodarone.  Despite this initial warning, patients continued to receive this drug combination.

The 2008 FDA warning

In 2008, the FDA issued another warning about the risk of serious muscle diseases (myopathy) associated with Zocor.  The regulators explained that the new warning was necessary because more than 50 patients had developed rhabdomyolysis between 2002 and 2008.

According to the 2008 Zocor warning, the risk of developing rhabdomyolysis, myopathy, and kidney problems increases with higher doses of Zocor (simvastatin).

The 2010 FDA Zocor warning

Just last month, in March 2010, the FDA issued yet another warning over Zocor.  This time the drug agency warned about the risks of taking 80 mg doses of simvastatin in Zocor and other medications with the same active ingredient, including Vytorin and Simcor.

The FDA explains that the risk of rhabdomyolysis is greater when simvastatin is given in higher doses and in combination with amiodarone.  This risk is greater for simvastatin—Zocor—than it is for other statin drugs.

All patients who are taking Zocor should speak to their doctor about the risks of muscle disease, kidney failure, kidney disease and death associated with this drug.  Any patient who experiences any muscle or kidney related symptoms (discussed here) should consult with a doctor immediately.  If you have suffered serious injury as a result of taking Zocor, please contact our law offices today for a free and confidential evaluation of your case.

In 1992, the Food and Drug Administration (FDA) implemented the Prescription Drug User Fee Act (PDUFA). According to the Act, funding for the FDA’s drug approval process would come directly from the pharmaceutical industry. More specifically, the act mandated that drug manufacturers pay a substantial fee for each New Drug Application (NDA) they wanted reviewed. In recompense, the FDA was bound to review the application within a given amount of time. Congress has reviewed and re-passed the act on three separate occasions (1997, 2002, 2007) since its ratification. Yet despite congressional support, PDUFA is the subject of much controversy.

Many, including those within the Administration, feel that the FDA should maintain a healthy antagonism toward the pharmaceutical industry, and that industry funding for FDA research offsets the balance of power between the two sides. These concerns are not unfounded. The pharmaceutical industry has undoubtedly gained leverage over the FDA through PDUFA. But given the current economic climate, there are few other practical funding options. With that in mind, Congress should aim to allocate a larger portion of the New Drug Application fee to the postmarket drug safety system, thereby ensuring that if a drug with harmful side effects does manage to slip through the review process safety net, the FDA recall will be quick and efficient. 

The FDA is in dire need of funding. According to the 1991 final report compiled by the Advisory Committee on the FDA, “Grave resource limitations impose sometimes staggering burdens on the Agency.”[1] The Institute of medicine went so far as to say that the administration was “begging for resources to do its job.”[2] This should never be the case with a program whose primary function is protecting the health of the American people.

PDUFA has undoubtedly helped reduce the funding problem. According to a study conducted by the School of Public Health and Health Services at George Washington University, “In FY 2006, PDUFA funds accounted for 42.5 percent of FDA’s total human drug program budget of $521 million (and for more than half the funds dedicated specifically to drug review).”[3] Since its inception in 1992, the act has helped increase the size of the FDA’s application review staff; as a result, the median review time for standard new drugs has decreased from 27 months in 1993, to 10.5 months in 2004.[4]  Unfortunately, when reviewing long-term drug side effects, speed and quality are not synonymous. As previously mentioned, under PDUFA the FDA is provided deadlines for its response to each NDA. Studies have shown that those drugs approved within the days and weeks closest to PDUFA deadlines are more likely to undergo labeling revisions and FDA recall.[5] One concludes then that pressure created by deadlines affects review quality.

In 2004, pharmaceutical giant Merck pulled its leading arthritis medication, Vioxx, from market. Postmarket studies found that the drug, approved as safe and effective by the FDA in May of 1999, significantly increased the risk of heart related side effects. At the time of its withdrawal, the drug had been prescribed to more than 84 million people worldwide.[6] Though perhaps the most publicized, the Vioxx incident is far from the only such instance of a faulty drug reaching the market. Another pharmaceutical powerhouse, The Warner Lambert Company, fabricated tests results so as to push three of their drugs through the NDA process. Amongst the drugs passed was Dilantin, an antiepileptic known to increase suicide risk in users. Clearly, pharmaceutical industry pressure affects the efficacy and reliability of the drug review process.

And yet, some maintain that the pharmaceutical industry’s interests are in line with those of the FDA. If drug companies push to release unsafe drugs, PDUFA advocates say, those companies will inevitably face consequences when their respective drugs face FDA recall. Pharmaceutical industry advocacy groups such as the Pharmaceutical Research and Manufacturers of America (PhRMA) argue vehemently against the repeal of PDUFA. In a 2006 press release, PhRMA stated, “fewer than three percent of approved prescription drugs have been withdrawn from the market for safety reasons over the last twenty years.”[7]—citing this statistic as proof that the industry had not abused its aforementioned leverage.

Anyone with a healthy amount of skepticism will see the fragility of these statistics, however. Assuming the approval of only 18 New Molecular Entities (NME) per year (this, the number of NMEs approved in 2006, was the lowest in a decade[8]), there are 360 NMEs approved every 20 years. If three percent of these NMEs are recalled, that’s nearly eleven drugs with harmful side effects that have slipped through the FDA safety net. Now, if each of those eleven recalled drugs is prescribed to just half the number of people as Merck’s Vioxx, that’s over 400 million people, or more than the population of the entire United States, consuming a potentially harmful drug. Evidently, even a three percent failure rate is too high.

Unfortunately, the economy is not as strong as it once was. Financial strains have made it nearly impossible for the government to fund FDA research without outside help. And so the FDA needs to check pharmaceutical industry pressure with one of the few tools it has left at its disposal: The postmarket safety system. The postmarket safety system is the series of reevaluations a drug faces after reaching market. Effectively, it is the FDA’s ability to recall or relabel a drug that has already been approved. In the most recent resigning of PDUFA, the act included a clause mandating the allocation of PDUFA fees to post-market safety. This is the first time the act included such a clause, and the results have been excellent. The smoking cessation drugs Chantix and Zyban, for instance, were recently relabeled to warn users against potentially harmful mood altering side effects.[9] Similarly, the FDA advisory committee recently urged for prescription painkillers such as Vicodin and Percocet, which combine opiates with acetaminophen, to be banned.[10] These postmarket alterations show not only that drugs with harmful side effects do slip through the FDA’s safety net, but also that a strong postmarket safety system is necessary and effective.

With PDUFA IV, the most recently signed version of PDUFA, an allocation of approximately $29.3 million was set aside for the enhancement of the postmarket safety system.[11] The positive effects of this allocation are clear. With the act setting a base target revenue of $392.8 million, however, the small fraction allotted to postmarket regulations is not enough. To ensure that pharmaceutical industry pressure doesn’t flood the market with unsafe drugs, a larger allocation of funds should go towards monitoring drug recall and relabeling.

Written by Nick Bakshi

[2] Committee on the Assessment of the US Drug Safety System, Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: National Academy of Sciences, 2007. 

[3] Wood , Susan . “Reauthorizing the Prescription Drug User Fee Act: How are PDUFA, the FDA Budget, and Drug Safety Related?.” Rapid Public Health Policy Response Project (2007): Print.

[4] Wood , Susan . “Reauthorizing the Prescription Drug User Fee Act: How are PDUFA, the FDA Budget, and Drug Safety Related?.” Rapid Public Health Policy Response Project (2007): Print.

[5] Wood , Susan . “Reauthorizing the Prescription Drug User Fee Act: How are PDUFA, the FDA Budget, and Drug Safety Related?.” Rapid Public Health Policy Response Project (2007): Print.

[6] Knox, Richard. “Merck Pulls Arthritis Drug Vioxx from Market.” NPR Web.6 Jul 2009. <http://www.npr.org/templates/story/story.php?storyId=4054991>.

[7] Press release, “PhRMA Statement on the IOM Drug Safety Report.” Sept. 22, 2006.

[8] Owens, Joanna. “2006 Drug Approvals: Finding the Niche.” Nature Reviews Web.6 Jul 2009. <http://www.nature.com/nrd/journal/v6/n2/full/nrd2247.html>.

[9] “Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban.” U.S. Food and Drug Administration 07 Jan 2009 Web.6 Jul 2009. <http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm169988.htm>.

[10] “FDA Panel Urges Ban on Vicodin, Percocet.” AJC 30 June 2009 Web.6 Jul 2009. <http://www.ajc.com/health/content/shared-auto/healthnews/arth/628586.html>.

[11] Wood , Susan . “Reauthorizing the Prescription Drug User Fee Act: How are PDUFA, the FDA Budget, and Drug Safety Related?.” Rapid Public Health Policy Response Project (2007): Print.

Between 2003 and 2006, over 35,000 women were treated for female stress urinary incontinence with the implantation of an ObTape vaginal sling, manufactured and designed by Mentor Corporation. The sling was designed to support weakened pelvic muscles at the bladder and urethra to prevent involuntary leakage. Due to a defective design, slings were manufactured with a non-woven surgical mesh that blocked nutrients and oxygen from passing through, potentially causing serious complications that will surface months or even years after the procedure. A study, published in the “Journal of Urology” in October, 2006, reported that more than 13% of women who received the Mentor Sling for incontinence suffered vaginal extrusions.  There were also a number of cases involving chronic vaginal discharge and abscess. Following the release of this study, some medical institutions stopped using the device.

In a letter to healthcare practitioners issued in October, 2008, the FDA reported that in the last three years they have received over 1000 adverse reports from surgical mesh manufacturers on complications associated with mesh devices implanted transvaginally to treat Pelvic Organ Prolapse (POP) and Stress Urinary Incontinence (SUI). The most frequently reported complications include:

• Erosion through vaginal epithelium
• Infection
• Urinary problems
• Recurrence of prolapsed and/or incontinence
• Perforation of bowel, bladder or blood vessel during insertion
• Vaginal scarring
• Mesh erosion
• Severe pain and discomfort

Treatments for various complications include IV therapy, blood transfusions, drainage of abscesses and additional surgeries to remove the mesh. Specific characteristics of patients who may be more at risk for complications are still unknown but several factors may contribute to the erosion and extrusion of the sling which include the size and placement of the sling, bacterial infection, incompatibility, attachment of sling to mobile structures, and the material of the sling. Solid or excessively woven materials were associated with higher instances of complications than meshed slings, most likely because they are not porous enough to allow tissue and capillaries to grow though and be fully incorporated into the body.  

The FDA recommended physicians to be vigilant of potential adverse events and to inform patients about the serious effects of complications that may alter the patient’s quality of life. Symptoms of complications from sling surgery include:

• High fever
• Vaginal pain
• Pelvic pain
• Pain during intercourse
• Chronic infections
• Perineal cellulitis
• Severe pain in the back, hips and legs

Any individual who is experiencing symptoms of complications from sling surgery should contact a healthcare professional immediately.

Numerous patients who were switched from brand name antiepileptic drug Keppra to the generic form, Levetiracetam, have reported serious seizure events and other injuries as a result of the medication switch.

The makers of this drug have known since 2006 that the generic Levetiracetam is known to produce serious injury in patients.  However, the manufacturer (Mylan Pharmaceuticals) continues to sell this drug, knowing that many patients are automatically and unknowingly switched to a drug with the potential to cause serious and even fatal consequences.  All the while the drug maker reaps millions of dollars in profit at the expense of patients with epilepsy and other neurological medical conditions.

Reports of Levetiracetam Injuries

Many patients have reported serious injuries shortly after being switched from Keppra to Levetiracetam.  Some have reported seizure activity within a few hours of taking the new medication, while others experienced side effects of the switch within the first week or so of changing from Keppra to Levetiracetam.  For many of these patients, their seizures have been under control while taking Keppra, but they suffered an episode shortly after the medication change.

Furthermore patients who switched from Keppra to the generic form of the drug have reported the following:

• Increased frequency of seizures
• Seizures of longer duration
• Re-emergence of frequent seizure episodes after the condition was under control
• A marked increase in extreme drowsiness
• Changes in mood, behavior and emotions
• Migranes
• Lightheadedness

In some cases, patients were driving or moving when these Levetiracetam injuries occurred, resulting in car accidents or patients hitting their heads, compounding the damage caused by this drug side effect.

Keppra and Levetiracetam are antiepileptic drugs (AEDs) used to treat certain types of seizures and other neurological conditions.  Many of the side effects linked to Levetiracetam are not found to be associated with Keppra, suggesting that certain serious side effects are unique to the generic version of this drug.  However, Keppra has also been associated with serious side effects, including hallucinations and psychotic episodes.

Popular weight loss drugs, prescription Xenical and over-the-counter Alli, are being reviewed by the FDA for possible connections to severe liver damage.

September 15, 2009

-A. Tse

Last month the FDA announced that it was reviewing a number of adverse event reports of liver injury in patients taking orlistat, the active pharmaceutical ingredient in the prescription weight loss drug Xenical and the over-the-counter Alli. Xenical, marketed by Roche, was approved by the FDA in 1999 and Alli, marketed by GlaxoSmithKline was approved in 2007 as an over-the-counter weight loss aid for adults.  In 2008, Xenical generated sales of $30million and Alli generated sales of $131 million during its first full year on the market.

Orlistat is not an appetite suppressant and is intended for use together with a reduced –calorie diet. It works by inhibiting the activities of enzymes in the gastrointestinal tract by preventing those enzymes from converting dietary fat and triglycerides into absorbable free fatty acids and monoglycerides.  Undigested dietary fat are not absorbed and are released from the body through bowel movements, therefore the prevention of absorption of fats reduces calorie intake and produces weight loss. (more…)