Parker Waichman LLP Injury Alerts
IN THE WORLD OF PRESCRIPTION DRUGS, EQUATING NEW WITH GOOD OR SAFE CAN BE HAZARDOUS TO YOUR HEALTHApr 1, 2005 Last month we focused on an array of prescription drugs (many in late-stage testing and some already on the market) which have shown promise in treating a wide range of conditions from insomnia to cancer. This month, however, we will discuss a number of prescription drugs which many experts regard as “failures” as a result of: (1) disappointing late-stage test results; (2) serious warning label updates; (3) potentially serious side effects which were unanticipated; or (4) unexpected recalls.
Anyone who assumes that new prescription drugs must be good (or at least better than) older drugs (with demonstrated safety records) is making a serious (and possibly fatal) error. As the COX-2 painkiller debacle has demonstrated, Bextra, Vioxx, and Celebrex turned out to be nothing more than expensive “super aspirins” which were no more effective and far less safe than existing pain medications. In addition, many drugs which have caused widespread injuries or deaths have been unceremoniously pulled from the market not long after their release. Some of the more recent “failures” in the longevity department are:
• Tysabri – 4 months
• Lotronex – 9 months
• Duract – 11 months
• Posicor – 12 months
• Redux – 17 months
• Raplon – 19 months
• Raxar – 23 months
• Baycol – 27 months
• Rezulin – 38 months
• Baycol – 50 months
One in five new drugs has serious side effects that do not show up until well after FDA approval. This often results from two serious flaws in the current “fast track” or “accelerated” approval process, namely, the lack of longitudinal (long-term) testing and the use of test groups which are far too small to represent an accurate sampling of the true range of patients who are likely to take the drugs being tested. Significantly, in a high percentage of situations, problems develop either; (1) after patients have taken a drug for greater periods of time than the test groups, or (2) in segments of the population which were never included in the test groups at all or, at least not in a sufficient representative sample size.
This is precisely why Public Citizen strongly suggests that consumers follow its “Seven Year Rule” by not taking any potentially dangerous prescription drug until it has been safely marketed for 7 years. Clearly, none of the 10 drugs listed above even survived for 5 years. In fact, 7 of them failed before being on the market 2 years.
An analysis of 548 drugs approved from 1975 through 1999 revealed that 56 (slightly more than 10 percent) were later given a serious side-effect warning or taken off the market entirely. In 2004, Merck’s voluntary withdrawal of Vioxx represented the largest prescription drug recall in history. That recall, however, was, by no means, the whole story with respect to problematic drugs that were either close to approval or already o the market.
While we would hope that manufacturers do not intend for their drugs to create such widespread problems for patients, their rush to gain FDA approval results (time and time again) with insufficient (or non-existent) long-term testing and the use of inadequate test groups, which (by accident or design) exclude patients with many of the conditions the drugs are intended to treat, produce distorted results with insufficient data required to infer what some of the effects of the drug will be when it is prescribed to a large group of people with varying conditions or levels of illness. In addition, companies may fail to conduct adequate longitudinal studies to determine the long-term effects of the drug and it may be years after the drug’s approval before patients start to exhibit serious and potentially fatal reactions.
The removal of a drug from the market is based on the level of risks associated with the drug, the availability of alternative treatments, and the nature of the illness that the drug is intended to treat. Robert Temple, director of the office of medical policy in the FDA’s drug center says the FDA tolerates “gross toxicities for cancer and AIDS drugs that [they] wouldn’t tolerate for an antihistamine.”
While pulling a drug from the market can prevent further instances of adverse reactions, it can also be a traumatic experience for those people who have benefited from the drug without suffering the negative side effects which caused the drug to fail.
The following information is intended to demonstrate the significant number of prescription drugs which may be in the process of “failing” at any given time. Many drugs fail during “late-stage” or final stage testing while others fail shortly after receiving accelerated approval.
Crestor – Although aggressively advertised for months by its manufacturer, AstraZeneca, Crestor is widely regarded by most impartial pharmaceutical experts as an extremely problematic drug with potentially dangerous side effects.
Crestor is a cholesterol-lowering drug in the “statin” family. Statins have been associated with a serious condition called rhabdomyolysis which results in muscle breakdown and the release of muscle cell contents into the bloodstream. Recently, a U.S. study found that Asian patients may be at a greater risk of developing rhabdomyolysis or other adverse effects. In response to this new information, the Canadian Product Monograph for Crestor was recently updated for the 40mg tablets to warn patients with the following conditions that they may be at a higher risk for developing rhabdomyolysis:
• Personal or family history of hereditary muscular disorders
• Previous history of muscle toxicity with another statin
• Liver disease
• Asian patients
In addition to the new warnings about serious health risks associated with Crestor, the FDA has recently warned AstraZeneca about false and misleading advertising for the cholesterol drug. Advertisements for Crestor claim that Crestor is better at lowering “bad” cholesterol than all other statins, including Pfizer’s top-selling Lipitor. According to the FDA, the advertisement in question is misleading because it “cherry picks” results from a study comparing Crestor and Lipitor to make it appear as if Crestor is the more effective choice for patients.
Public Citizen, a health advocacy consumer group, has alleged that Crestor has actually been linked to rhabdomyolysis at a rate of 6.2 times that of all other approved statin drugs combined. An analysis of adverse-event information showed that there were 13.1 reports of muscle damage per million prescriptions of Crestor and only 2.1 reports per million reports total for all other statins. This data was gathered from drug makers, doctors, and patients. AstraZeneca claims that the accusation is based on “unscientific information and incomplete analysis.”
The FDA has said that the risk of muscle problems associated with Crestor is no greater than any other statin. Yet Public Citizen warns patients that the data gathered from these “adverse events reports” can be misleading as the reports are voluntary and therefore may not contain all of the information necessary to draw educated conclusions. At this time, the FDA is making statements about the muscle and kidney safety of Crestor based on a comprehensive review of all available information. In any event, the overall safety of Crestor is legitimately in doubt and thus makes it unwise to undertake a regimen of the drug before further long-term data is compiled and analyzed.
Paxil CR and Avandment
In March of this year, the FDA seized entire batches of Paxil CR and Avandment tablets, manufactured by GlaxoSmithKline, after ongoing concerns about manufacturing quality proved to be true. Paxil CR is the extended-release version of the anxiety and depression drug, and Avandment is used to treat Type II diabetes. The quality control failure resulted in incorrect dosages of the active ingredients in the pills.
The FDA found that Paxil CR tablets could contain no active ingredient at all or a full dose of the active ingredient without the controlled-release effect. The FDA also found that Avandment tablets did not have an accurate dose of rosiglitazone (the active ingredient) in each tablet.
The FDA ordered the seizure after several inspections of the Puerto Rico manufacturing plant, where these two drugs are made, indicated that there were several quality problems in the manufacturing process that could cause risks to patients. Although there have been no reports of injuries from these particular errors to date, such quality control failures have the potential for catastrophic consequences depending upon the drug involved and the extent of the error. Patents taking these drugs should speak to their doctor or health care professional about available alternatives while this manufacturing error is being corrected.
MS Drugs (Tysabri and Avonex)
Tysabri, once a promising drug for the treatment of multiple sclerosis manufactured by Biogen Idec, was voluntarily pulled from the market on March 1, 2005, only 4 months after it had gained “accelerated approval” from the FDA. Biogen’s abrupt withdrawal of the drug came after two (now three) reported cases (one resulting in death) of a rare neurological infection called progressive multifocal leukoencephalopathy (PML) were reported. Biogen Idec is also suspending dosing of Tysabri in clinical trials while an investigation is conducted.
Significantly, prior to its “fast-track” approval, the safety of Tysabri had been questioned by Dr. Lawrence Steinman, a prominent neurobiologist and professor at Stanford University, who is also a recognized expert on MS. The New England Journal of Medicine also questioned raised concerns in an editorial in early 2003. Nonetheless, the drug was approved while still in a Phase II trial (short-term and small test group) and long before a Phase III (long-term and larger test group) was completed. This is precisely the type of problem which makes the entire “fast-track” approval process highly questionable.
Another MS drug that has been in the news recently is Avonex. Also manufactured by Biogen Idec, Avonex is now being linked to cases of liver failure and severe liver injury. Liver complications are associated with all of the class of drugs known as beta interferon drugs, including Avonex. Biogen has said that the liver conditions in patients have been extremely rare. Still, a warning about potential liver toxicity has been added to Avonex’s label.
The FDA has issued a public health advisory to inform patients and medical professionals about recent label-changes for nevirapine, an HIV drug used in what is known as “triple combination therapy.” The new warning is aimed at women with CD4+ cell counts greater than 250 cells/mm3 and advises against beginning treatment unless benefits clearly outweigh the risk. This recommendation is based on an apparent observed risk of serious liver toxicity in patients with higher CD4 cell counts. Nepravine has also been known to cause life-threatening liver toxicity and skin rashes yet it remains an essential part of HIV treatment worldwide.
Xigris, manufactured by Eli Lilly, is used to treat adult patients with severe sepsis, a potentially life-threatening condition that occurs when an infection spreads throughout the bloodstream. Recently, however, the FDA issued a warning about Xigris saying that it might increase the risk of death in patients who have had recent surgery and have single organ dysfunction. This information was gathered from clinical trial data which showed that patients with the aforementioned condition who took Xigris had higher rates of death than the placebo group. The new warning will be placed on the product label.
Elidel and Protopic
The FDA has issued a warning about Elidel and Protopic, two creams that are used to treat eczema, saying that both should carry a stronger warning regarding potential cancer risks. Data from an animal study showed that the risk of cancer increased as the amount of the drug given increased. Since the creams are absorbed into the body they may have the potential to cause cancer lymphoma, cancer of the immune system, as well as a variety of other cancers and therefore the FDA is currently working on a “black box” warning for the creams, the strongest warning available for medicines. In addition, babies should never be treated with either cream. Elidel manufacturers Novartis AG argued that there is no need for a black box warning and said that there would be no label change for the time being. Fujisawa Healthcare Inc. makes Protopic.
Procrit and Aransep
Clinical trials for this anemia drug, manufactured by Johnson & Johnson, were halted in 2003 after patients developed an unexpected number of blood clots. Procrit is a version of erythropoietin, a natural hormone that stimulates the body to produce oxygen-carrying red blood cell. It is primarily used to treat anemia caused by cancer chemotherapy or kidney failure. The risk is primarily a concern if the drug is used more than is necessary to reverse anemia. The clotting problems arose when the drug started being used to treat milder cases of anemia as opposed to the most serious cases.
Aranesp, manufactured by Amgen, has also had a recent label revision to include information about the increased risk of mortality and thrombotic vascular events.
Etezimibe is a cholesterol lowering drug manufactured by Merck Frosst/Schering Pharmaceuticals. In February 2005, the manufacturers issued a warning about rhabdomyolysis and other muscle related illnesses, hepatitis, acute pancreatitis, and thrombocytopenia. In addition, Etezimibe may react negatively with warfarin (coumadin), an anticoagulant used to thin the blood in order to prevent blood clots from forming.
Reminyl and Natrecor
Reminyl is an Alzheimer’s disease drug manufactured by Johnson & Johnson. In January 2005, the manufacturer, along with the FDA and drug regulators in Europe and Canada, announced that people taking Reminyl had a much higher death rate than those in the placebo group according to two clinical trials. In the 2-year trials, 15 patients taking Reminyl died compared with 5 in the placebo group. Still, Johnson & Johnson argues that overall, the number of deaths in the trials was low for the elderly population in the trial.
Natrecor is another Johnson & Johnson drug which now has some safety questions surrounding its usage. The drug is used to treat acute heart failure, a deadly disease in which the heart rapidly loses its ability to pump enough blood. Now, however, some cardiologists are concerned that Natrecor may harm the kidneys, which fail frequently in heart failure patients. In analyzing some of the original data about Natrecor, it appeared that the reason for an increase in mortality among Natrecor patients was kidney injury. Cardiologists and doctors are still analyzing data to determine the magnitude of the risk.
Humira is a drug used to treat rheumatoid arthritis in patients who have not responded to other treatments. Humira manufacturers Abbot Laboratories Ltd., along with Health Canada, have announced that there have been serious hematologic events associated with Humira. This information will now be included in the Canadian Product Monograph but U.S. labeling has not been affected as of now.
Manufactured by Bristol-Meyers Squibb, Entecavir is a drug used to treat hepatitis B that is currently waiting for approval from the FDA. Now, however, the FDA said it was concerned about possible long-term safety issues with the drug after animal studies showed the drug might cause cancer in high doses.
Valproate, otherwise known as Depakote or Depakene, is an anticonvulsant drug used to treat seizures, migraines, and psychiatric disorders such as bipolar disorder. It was recently reported, however, that women taking valproate had a fourfold increase of having a child with a major malformation. Potential birth defects include spina bifida, a neural tube defect.
A current study analyzed data from 149 women who took only valproate while pregnant during the years 1997 to 2003. Of those 149 women, 16 had babies with major birth defects, three with spina bifida. Neurologists are now going to focus more on birth defects associated with the drug.
Mobic, a COX-2 inhibitor like Vioxx and Celebrex saw a surge in popularity when Vioxx was pulled from the market and Bextra and Celebrex came under increased scrutiny by the FDA. Unfortunately, preliminary data has suggested that Mobic too may cause an increased risk of heart attacks and strokes. At this time, however, the manufacturers insist that the current data does not show “excessive cardiovascular risk.”
The FDA and Cephalon, Inc., manufacturers of Gabitril, have issued a bolded warning about the drug indicating that it can cause seizures in patients without epilepsy. The FDA has received reports of seizures in more than 30 patients who were prescribed Gabitril for conditions other than epilepsy. The new warning is meant to discourage healthcare professionals from prescribing Gabitril for any symptoms other than epilepsy.
The FDA has issued a Public Health Advisory to notify all medical professionals that Adderall XR has been suspended in the Canadian market due to reports of sudden death in pediatric patients. Adderall XR is approved in the US for the treatment of ADHD in adults and pediatric patients as young as 6 years old. While the FDA has refused to pull the drug from the market here, it is difficult to ignore the fact that Canada and
ZyPREXA AND Zyrtec
ZyPREXA, manufactured by Eli Lilly, is a powerful drug used to treat depression, schizophrenia, and bipolar disorder. Recently, the FDA notified healthcare professionals of a number of serious dispensing or prescribing errors in which ZyPREXA and Zyrtec (an allergy medication marketed by Pfizer) have been mistakenly confused. This has lead to unnecessary adverse events including potential relapses in patients suffering from schizophrenia or bipolar disorder.
In February 2005, Alliant Pharmacists, the makers of Methylin, issued a voluntary recall of the ADHD drug stating that one lot may have contained up to three times the active ingredient. What began as a recall of only one lot turned into a massive nationwide recall including all 2.5mg, 5mg, and 10mg tablets because some may contain too much or too little active ingredient. Clearly, the use of such significant overdoses can have dire consequences for children taking the drug.
Experimental Medications to Avoid
• Phenserine is an Alzheimer’s disease drug manufactured by Axonyx that may never make it to market as it has not shown that it can slow the disease more a placebo.
• Dexanabinol, manufactured by Pharmos, was set to be approved for patients with traumatic brain injury but late stage trials failed to show evidence that the drug allowed people to return to a more normal life.
• Exanta, manufactured by AstraZeneca was poised to replace warfarin (coumadin) for the use of preventing blood clots but now an issue of liver toxicity has arisen that forced the manufacturer to pull the drug’s application from before the FDA.
• Genasense, manufactured by Genta and Aventis, was intended for use by cancer patients. The drug works by blocking a protein called Bcl-2 thereby making cancer cells more likely to kill themselves. But the FDA found that it did not benefit skin cancer patients enough to outweigh its potentially serious side effects.
• Aprepitant, developed by Merck, was intended for use as a treatment for nausea caused by chemotherapy as well as for depression but it failed to work in late stage trials.
• Neovastat, developed by the Canadian biotech company Aeterna Laboratories, was intended to treat cancers by starving tumors of their blood supply by knocking out several proteins. But clinical trials failed to prove that Neovastat extended survival as anticipated.
Existing Drugs Which Are Highly Suspect
In November 2004, FDA scientist Dr. David Graham (FDA Office of Drug Safety) testified at a Senate hearing concerning Vioxx. He also expressed serious concerns about 5 other drugs widely prescribed drugs that he regarded as potentially unsafe. These included:
• Bextra – Ordered off the market 4 months after Dr. Graham’s testimony and less than 2 months after it had received a very close vote of confidence from the FDA.
• Crestor – Discussed above.
• Meridia – Abbott Laboratories’ weight loss drug has been linked to high blood pressure.
• Accutane – The acne drug manufactured by Roche has rapidly gained a reputation as a potential suicide risk when used by adolescents. It has also been linked to serious birth defects when used by pregnant women. Dr. Graham called Accutane a “Twenty-year regulatory failure.”
• Serevent – Used to treat asthma and chronic obstructive pulmonary disease, this drug, manufactured by GlaxoSmithKline, has been found to increase the risk of death from serious asthma complications. Although the FDA has issued a “black box warning” for this drug, Dr. Graham testified that there have been reports of patients “found dead clutching their Serevent inhaler.” Hardly a ringing endorsement for a drug that is supposed to help you breath better.
Clearly, the mere fact that a new drug has been developed or even approved is by no means the end of the story. Many promising drugs fail in development because they turn out to be ineffective or simply too dangerous. FDA approval does not make the gamble any safer for the public. Some of the worst drugs in history have been hailed by the FDA as worthy of accelerated approval only to be pulled from the market after leaving dead and injured consumers around the world.
Unless long-term studies using large test groups become the rule rather than the exception, this trend will continue with the public being treated as little more than a vast supply of laboratory animals. Laws being passed to protect the pharmaceutical companies from being held accountable for the catastrophic injuries and deaths they cause will only make matters worse. However, you can help protect yourself by remembering the “Seven-Year-Rule” and avoiding any new drug until it has proven itself safe and effective over that time period.
As always, we here at Parker & Waichman hope that this information has been of help to our clients and subscribers. If you have questions regarding a potential case involving any prescription drug, do not hesitate to contact us at http://www.yourlawyer.com.