December 13, 2010 — The sometimes tragic personal toll of impulse control disorders associated with use of the Parkinson's drug pramipexole is now being debated in US and Canadian courtrooms, and a health law expert says these lawsuits have important implications for prescribers.
The drug, marketed under the brand name Mirapex and also used to treat restless legs syndrome, has been shown to trigger compulsive gambling, shopping, eating, and heightened sexuality.
In August, the first pramipexole gambling addiction trial ended in an $8.3 million judgment for the plaintiff against drug-maker Boehringer Ingelheim.
Many lawsuits, including a class action in Canada, are now ongoing, alleging the manufacturer failed to provide patients with appropriate warning of the potential risks. The company declined to comment on how many cases are currently being debated.
"As part of our company's communication policy, Boehringer Ingelheim does not comment on pending litigation," Susan Holz, public relations manager, told Medscape Medical News.
But although current litigation is aimed at the drug manufacturer and not against any physicians, William Mandell, a lawyer specializing in health law with the firm of Pierce and Mandell, PC, in Boston, warned this could change, and prescribers may be held accountable.
"All physicians who regularly prescribe medications for which there could be significant and detrimental side effects should realize that they could also be named as defendants in such adverse reaction suits," Mr. Mandell said.
A prescribing physician could be found liable to a patient if the physician fails to adequately assess the potential risks of a medication's adverse side effects for that individual. This means, in certain situations, physicians should screen patients to determine whether they may be subject to the risks of taking a particular medication.
$8.3 Million Judgment
The first pramipexole case was heard in the US District Court in Minneapolis, Minnesota. Retired police officer Gary Charbonneau reportedly started taking pramipexole for Parkinson's disease in 1997. His lawsuit claimed he had a gambling addiction beginning in 2002 that cost him $260,000.
Charbonneau's lawsuit alleged not only that pramipexole caused his gambling problem but also that Boehringer Ingelheim and Pfizer, which marketed the drug in the United States, knew about its potential to cause compulsive behavior and did not issue any warnings or take steps to investigate the scope of the problem.
Other lawsuits claim the companies received reports linking the drug to compulsive behavior during clinical trials conducted in the 1990s and received additional reports of patients developing gambling addictions but failed to act. The suits charge that it wasn't until 2005 — 8 years after the drug's introduction — that information about compulsive behavior was finally added to the pramipexole label.
The companies argued they were not liable for Charbonneau's addiction because the US Food and Drug Administration (FDA) had not asked for any label changes despite reports that pramipexole was causing compulsive behavior. The companies also claimed that Charbonneau's gambling problems had preceded his use of the drug and continued after he stopped taking it.
The jury hearing the case was not convinced by these arguments. Charbonneau was awarded all of his gambling losses and punitive damages. Many legal experts say there is a good chance similar lawsuits will be successful. Boehringer Ingelheim and Pfizer are planning to appeal the decision. The FDA has declined to comment on the case.
Mr. Mandell was not involved in this lawsuit, but he says the judgment is "a wake-up call" for physicians who prescribe medications that may have significant risks.
Campaign Targeted Physicians
"Although Mirapex was initially hailed as having great promise for patients with Parkinson's disease and those suffering from restless legs syndrome, it turned out that the manufacturers had engaged in a major promotional campaign targeted at physicians and did not fully disclose all risks," he said. "$7.8 million of the jury verdict against the drug manufacturers was for punitive damages related to the finding that they had misrepresented the facts associated with the risks of taking Mirapex as it could cause patients to engage in compulsive behaviors such as gambling."
The companies, Mr. Mandell noted, had gradually changed the labeling information for the drug by listing compulsive behaviors such as pathological gambling under the adverse reactions and precautions sections of the label but stated that those compulsive behaviors "are generally reversible upon dose reduction or treatment discontinuation" and did not list compulsive behaviors in the warnings section of the label.
Asked by Medscape Medical News to comment, Anthony Lang, MD, director of the Movement Disorder Center at Toronto Western Hospital in Ontario, Canada, said the problem is a class effect with dopamine agonists and is not specific to pramipexole. "Many patients have suffered considerably from the presence of impulse control disorders," he noted.
Pramipexole is a nonergoline dopamine agonist. It is also sometimes used off label as a treatment for cluster headache and to counteract problems with sexual dysfunction experienced by some antidepressant users. It is currently being investigated for the treatment of clinical depression and fibromyalgia.
Dr. Lang agreed that physicians have a very important obligation to patients informing them of the potential occurrence of impulse control disorders and monitoring regularly. He pointed out, however, that he has seen patients who at first deny the problems.
"Initiating dopamine agonists has become a very time-consuming process because of the need to inform the patients carefully of the potential problems," he said. "We usually also insist on informing their spouses."
DOMINION Study
The DOMINION study included 3090 patients with Parkinson's disease treated at movement disorder centers in the United States and Canada. Each was assessed using the Massachusetts Gambling Screen for current problem or pathological gambling, the Minnesota Impulsive Disorders Interview for compulsive sexual behavior and buying, and the Diagnostic and Statistical Manual of Mental Disorders research criteria for binge eating.
The findings highlight the need for patients with Parkinson's to be screened for a range of impulse control symptoms as part of routine clinical care, said lead study author Daniel Weintraub, MD, from the University of Pennsylvania, Philadelphia.
Results from phase 2 of the DOMINION study were presented at the American Academy of Neurology 62nd Annual Meeting in April this year.
Here, the researchers found that impulse control disorder patients are much more functionally impaired, are more depressed and anxious, and have more obsessive-compulsive symptoms. They also score higher on scales of novelty seeking and impulsiveness compared with Parkinson's patients who had not developed such disorders.
"What's intriguing about this group of patients is that they're all exposed to the same dopamine agonist, but for some reason, some people develop specific behaviors, and not other behaviors, and the question is why that's the case," said presenter Valerie Voon, MD, from the University of Cambridge, England.
"It may be that some of these associated factors might reflect underlying mechanisms or individual susceptibilities, and we clearly need more prospective studies to identify risk factors for developing these behaviors," she concluded.
New Generic Doses of Pramipexole
Despite these concerns, new generic doses of pramipexole will soon be entering the US market. In October, the FDA approved Mylan Inc's application for new doses, including 0.125, 0.25, 0.5, 1, and 1.5 mg. Mylan already had approval for a 0.75-mg dose.
Mylan said pramipexole had US sales of about $536 million during the 12-month period ending June 30.
"Regardless of whether a medication's label warnings are adequate," Mr. Mandell told Medscape Medical News, "doctors must always exercise their best medical judgment in determining whether a medication is suitable for a patient."
Dr. Lang added, "The ongoing use of this treatment requires regular monitoring and questioning about all of the potential impulse control problems. We do this routinely."
Allison Gandey is a journalist for Medscape. She can be contacted at agandey@webmd.net.
http://www.medscape.com/viewarticle/734153
The drug, marketed under the brand name Mirapex and also used to treat restless legs syndrome, has been shown to trigger compulsive gambling, shopping, eating, and heightened sexuality.
In August, the first pramipexole gambling addiction trial ended in an $8.3 million judgment for the plaintiff against drug-maker Boehringer Ingelheim.
Many lawsuits, including a class action in Canada, are now ongoing, alleging the manufacturer failed to provide patients with appropriate warning of the potential risks. The company declined to comment on how many cases are currently being debated.
"As part of our company's communication policy, Boehringer Ingelheim does not comment on pending litigation," Susan Holz, public relations manager, told Medscape Medical News.
But although current litigation is aimed at the drug manufacturer and not against any physicians, William Mandell, a lawyer specializing in health law with the firm of Pierce and Mandell, PC, in Boston, warned this could change, and prescribers may be held accountable.
"All physicians who regularly prescribe medications for which there could be significant and detrimental side effects should realize that they could also be named as defendants in such adverse reaction suits," Mr. Mandell said.
A prescribing physician could be found liable to a patient if the physician fails to adequately assess the potential risks of a medication's adverse side effects for that individual. This means, in certain situations, physicians should screen patients to determine whether they may be subject to the risks of taking a particular medication.
$8.3 Million Judgment
The first pramipexole case was heard in the US District Court in Minneapolis, Minnesota. Retired police officer Gary Charbonneau reportedly started taking pramipexole for Parkinson's disease in 1997. His lawsuit claimed he had a gambling addiction beginning in 2002 that cost him $260,000.
Charbonneau's lawsuit alleged not only that pramipexole caused his gambling problem but also that Boehringer Ingelheim and Pfizer, which marketed the drug in the United States, knew about its potential to cause compulsive behavior and did not issue any warnings or take steps to investigate the scope of the problem.
Other lawsuits claim the companies received reports linking the drug to compulsive behavior during clinical trials conducted in the 1990s and received additional reports of patients developing gambling addictions but failed to act. The suits charge that it wasn't until 2005 — 8 years after the drug's introduction — that information about compulsive behavior was finally added to the pramipexole label.
The companies argued they were not liable for Charbonneau's addiction because the US Food and Drug Administration (FDA) had not asked for any label changes despite reports that pramipexole was causing compulsive behavior. The companies also claimed that Charbonneau's gambling problems had preceded his use of the drug and continued after he stopped taking it.
The jury hearing the case was not convinced by these arguments. Charbonneau was awarded all of his gambling losses and punitive damages. Many legal experts say there is a good chance similar lawsuits will be successful. Boehringer Ingelheim and Pfizer are planning to appeal the decision. The FDA has declined to comment on the case.
Mr. Mandell was not involved in this lawsuit, but he says the judgment is "a wake-up call" for physicians who prescribe medications that may have significant risks.
Campaign Targeted Physicians
"Although Mirapex was initially hailed as having great promise for patients with Parkinson's disease and those suffering from restless legs syndrome, it turned out that the manufacturers had engaged in a major promotional campaign targeted at physicians and did not fully disclose all risks," he said. "$7.8 million of the jury verdict against the drug manufacturers was for punitive damages related to the finding that they had misrepresented the facts associated with the risks of taking Mirapex as it could cause patients to engage in compulsive behaviors such as gambling."
The companies, Mr. Mandell noted, had gradually changed the labeling information for the drug by listing compulsive behaviors such as pathological gambling under the adverse reactions and precautions sections of the label but stated that those compulsive behaviors "are generally reversible upon dose reduction or treatment discontinuation" and did not list compulsive behaviors in the warnings section of the label.
Asked by Medscape Medical News to comment, Anthony Lang, MD, director of the Movement Disorder Center at Toronto Western Hospital in Ontario, Canada, said the problem is a class effect with dopamine agonists and is not specific to pramipexole. "Many patients have suffered considerably from the presence of impulse control disorders," he noted.
Pramipexole is a nonergoline dopamine agonist. It is also sometimes used off label as a treatment for cluster headache and to counteract problems with sexual dysfunction experienced by some antidepressant users. It is currently being investigated for the treatment of clinical depression and fibromyalgia.
Dr. Lang agreed that physicians have a very important obligation to patients informing them of the potential occurrence of impulse control disorders and monitoring regularly. He pointed out, however, that he has seen patients who at first deny the problems.
"Initiating dopamine agonists has become a very time-consuming process because of the need to inform the patients carefully of the potential problems," he said. "We usually also insist on informing their spouses."
DOMINION Study
Boehringer Ingelheim is currently funding the DOMINION study to explore the link between dopamine agonists and impulse control disorders. Phase 1 of the large cross-sectional trial was published in May in the Archives of Neurology (2010;67:589-595).
As expected, impulse control disorders were more common in those treated with a dopamine agonist, occurring in 17.1% vs 6.9% among those not taking a dopamine agonist (odds ratio, 2.72; 95% confidence interval, 2.08 – 3.54; P < .001). The frequency was reportedly similar between those taking pramipexole vs ropinirole (17.7% vs 15.5%; odds ratio, 1.22; 95% confidence interval, 0.94 – 1.57; P = .14).The DOMINION study included 3090 patients with Parkinson's disease treated at movement disorder centers in the United States and Canada. Each was assessed using the Massachusetts Gambling Screen for current problem or pathological gambling, the Minnesota Impulsive Disorders Interview for compulsive sexual behavior and buying, and the Diagnostic and Statistical Manual of Mental Disorders research criteria for binge eating.
The findings highlight the need for patients with Parkinson's to be screened for a range of impulse control symptoms as part of routine clinical care, said lead study author Daniel Weintraub, MD, from the University of Pennsylvania, Philadelphia.
Results from phase 2 of the DOMINION study were presented at the American Academy of Neurology 62nd Annual Meeting in April this year.
Here, the researchers found that impulse control disorder patients are much more functionally impaired, are more depressed and anxious, and have more obsessive-compulsive symptoms. They also score higher on scales of novelty seeking and impulsiveness compared with Parkinson's patients who had not developed such disorders.
"What's intriguing about this group of patients is that they're all exposed to the same dopamine agonist, but for some reason, some people develop specific behaviors, and not other behaviors, and the question is why that's the case," said presenter Valerie Voon, MD, from the University of Cambridge, England.
"It may be that some of these associated factors might reflect underlying mechanisms or individual susceptibilities, and we clearly need more prospective studies to identify risk factors for developing these behaviors," she concluded.
New Generic Doses of Pramipexole
Despite these concerns, new generic doses of pramipexole will soon be entering the US market. In October, the FDA approved Mylan Inc's application for new doses, including 0.125, 0.25, 0.5, 1, and 1.5 mg. Mylan already had approval for a 0.75-mg dose.
Mylan said pramipexole had US sales of about $536 million during the 12-month period ending June 30.
"Regardless of whether a medication's label warnings are adequate," Mr. Mandell told Medscape Medical News, "doctors must always exercise their best medical judgment in determining whether a medication is suitable for a patient."
Dr. Lang added, "The ongoing use of this treatment requires regular monitoring and questioning about all of the potential impulse control problems. We do this routinely."
Allison Gandey is a journalist for Medscape. She can be contacted at agandey@webmd.net.
http://www.medscape.com/viewarticle/734153
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