anti-epilepsy drug Mirapex can cause compulsive gambling, shopping, eating, and heightened sexuality

[Guest guest]

http://www.medscape.com/viewarticle/734153

Pramipexole Lawsuits a Wake-Up Call for Prescribers

Gandey

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," Holz, public relations

manager, told Medscape Medical News.

But although current litigation is aimed at the drug

manufacturer and not against any physicians, 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

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,

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

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

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."

[Guest guest]

http://www.medscape.com/viewarticle/734153

Pramipexole Lawsuits a Wake-Up Call for Prescribers

Gandey

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," Holz, public relations

manager, told Medscape Medical News.

But although current litigation is aimed at the drug

manufacturer and not against any physicians, 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

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,

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

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

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."

[Guest guest]

http://www.medscape.com/viewarticle/734153

Pramipexole Lawsuits a Wake-Up Call for Prescribers

Gandey

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," Holz, public relations

manager, told Medscape Medical News.

But although current litigation is aimed at the drug

manufacturer and not against any physicians, 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

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,

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

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

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."

[Guest guest]

http://www.medscape.com/viewarticle/734153

Pramipexole Lawsuits a Wake-Up Call for Prescribers

Gandey

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," Holz, public relations

manager, told Medscape Medical News.

But although current litigation is aimed at the drug

manufacturer and not against any physicians, 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

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,

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

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

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."