April 15, 2007 (table of contents)Vol. 75 No. 8

Pramipexole (Mirapex) for Restless Legs Syndrome

courtney i. jarvis, pharm.d., Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts
jeremy golding, m.d., University of Massachusetts/Memorial Medical Center, Worcester, Massachusetts

Pramipexole (Mirapex) is a non-ergot selective dopamine receptor agonist that has been used since 1997 for the treatment of idiopathic Parkinson's disease. It is now labeled for the treatment of moderate to severe restless legs syndrome (RLS),1 which is defined as having symptoms at least two to three days per week for at least three months and having a baseline score higher than 15 on the 40-point International Restless Legs Syndrome Study Group Rating Scale.2

Name
Starting dosage
Dose form
Approximate monthly cost*

Pramipexole (Mirapex)
0.125 mg daily, two to three hours before bedtime
0.125-, 0.25-, 0.5-, 1.0-, and 1.5-mg tablets
$45 (for 0.25-mg tablets)


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*-Average wholesale cost, based on Red Book, Montvale, N.J.: Medical Economics Data, 2006.

Safety
Adverse effects occur less often with the lower doses of pramipexole used to treat RLS than with the higher doses used to treat Parkinson's disease. Approximately 6 percent of patients with Parkinson's disease who are treated with pramipexole have reported daytime drowsiness compared with 3 percent of those treated with placebo. Case reports have described episodes of falling asleep while engaged in normal activities, including driving. This sudden somnolence may occur up to one year after starting treatment and may not be preceded by warning signs.3 These events have only been reported by patients treated with pramipexole for Parkinson's disease, and not by patients treated for RLS. To minimize the risk of daytime somnolence, patients should be given the lowest effective dose.3

Hallucinations, pathologic gambling and other compulsive behaviors, and orthostatic hypotension are uncommon in patients taking higher doses of pramipexole for Parkinson's disease and are seen even less in patients taking lower doses for RLS. Pramipexole is U.S. Food and Drug Administration pregnancy category C.

Augmentation of RLS symptoms with long-term therapy occurs in approximately one fourth of patients taking pramipexole.1,4 Symptoms may begin earlier in the evening, become more severe, and spread to the arms and trunk. Rebound or recurrence of RLS symptoms in the early morning also may occur over time; one study reported an incidence of 13 percent.4 Initiating therapy earlier in the day is often effective at controlling these symptoms; however, increasing the dose may worsen augmentation, requiring alternative therapies (e.g., opioids) to attain control.

Tolerability
Nausea and sedation will occur in up to 30 percent of patients.1,4-6 Approximately 7 percent of patients with RLS receiving pramipexole discontinued treatment because of adverse effects compared with 5 percent of patients receiving placebo.1

Effectiveness
In the first three months of treatment, approximately 60 percent of patients receiving pramipexole instead of placebo will have at least a 50 percent reduction in symptoms; however, there is a profound placebo effect, and 42 percent of patients receiving placebo will also report this reduction. Approximately six patients need to be treated with pramipexole instead of placebo for one additional person to have a decrease in symptoms.6,7 On average, all studied doses (0.25, 0.5, and 0.75 mg) produce the same reduction of RLS symptoms, so patients should be started on the lowest dose (0.125 mg) and only titrated to higher doses as needed.4-6 Symptoms will recur when treatment is stopped. Pramipexole has not been directly compared with any other treatments for RLS.

Price
The approximate monthly cost of pramipexole 0.25 mg is $45; higher doses are more expensive.

Simplicity
The starting dosage of pramipexole is 0.125 mg taken once daily two to three hours before bedtime. If needed, the dosage may be doubled every four to seven days up to a maximal dosage of 0.5 mg daily. The duration between titration steps should be increased to 14 days in patients with a creatinine clearance of 20 to 60 mL per minute (0.33 to 1.00 mL per second).1 Pramipexole can be discontinued without tapering doses.

Bottom Line

Although many patients with RLS do not need pharmacologic therapy, pramipexole is one option for treating moderate to severe symptoms. As with other agents used to manage RLS, potentially serious adverse reactions are possible.

Address correspondence to Courtney I. Jarvis, Pharm.D., at courtney.jarvis@mcphs.edu. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. Mirapex (pramipexole dihydrochloride) [Product information]. Ridgefield, Conn.: Boehringer Ingleheim International GmbH, 2006. Accessed February 22, 2006, at: http://bidocs.boehringer-ingelheim.c...t&folderPath=/
Prescribing+Information/PIs/Mirapex/Mirapex.pdf.

2. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J, for the International Restless Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4:101-19.

3. Olanow CW, Schapira AH, Roth T. Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole and ropinirole. Neurology 2000;54:274; author reply 276-7.

4. Montplaisir J, Fantini ML, Desautels A, Michaud M, Petit D, Filipini D. Long-term treatment with pramipexole in restless legs syndrome. Eur J Neurol 2006;13:1306-11.

5. Silber MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome: an extended study. Sleep 2003;26:819-21.

6. Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 2006;67:1034-9.

7. Oertel WH, Stiasny-Kolster K, Bergtholdt B, Hallstrom Y, Albo J, Leissner L, et al., for the Pramipexole RLS Study Group. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study). Mov Disord 2007;22:213-9.



STEPS new drug reviews cover Safety, Tolerability, Effectiveness, Price, and Simplicity. Each independent review is provided by authors who have no financial association with the drug manufacturer.

The series coordinator for AFP is Allen F. Shaughnessy, Pharm.D., Tufts University Family Medicine Residency Program, Malden, Mass.


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Copyright © 2007 by the American Academy of Family Physicians

Do Pharmaceutical Companies Market Diseases as well as Drugs?

These days - if you watch TV - television drug commercials are so ubiquitous that it's hard to remember a time when they didn't exist. But direct-to-consumer advertising, as it is called, has only been around in the US for 10 years, and it's illegal in many other countries. Despite having been around for such a short time, some doctors and scientists believe that direct advertising has already changed the way drug companies do business in the US, allowing them to not only market drugs but also market diseases.

Take Restless Legs Syndrome, a disorder that few had heard of until recently, when ads began popping up to raise interest in the drugs that treat it. According to the ads, the disorder is characterized by unpleasant sensations in the legs accompanied by an uncontrollable urge to move them. Dig a little deeper and you'll find that the drugs that treat Restless Legs Syndrome are the same ones that treat Parkinson's disease - raising the question of whether pharmaceutical companies "created" Restless Legs Syndrome in order to sell more drugs.

It's a contentious issue.

Doctors disagree over whether pharmaceutical companies create diseases or simply bring attention to little-known disorders. And certainly the industry has done a tremendous amount to improve medicine.

But has it gone too far?

WIRED SCIENCE explores the business of disease and the truth about Restless Legs Syndrome - is it a legitimate disorder or something created to boost drug sales? Read also our web original feature Art tackles Big Pharma about what a few creative people are doing to raise awareness about direct-to-consumer advertising and its influence on American society.

their is many comments on this article link below
http://www.pbs.org/kcet/wiredscience...f_disease.html

I appreciate your point about the advertising of drugs. Drug marketing is sophisticated and relentless.

However, I don't think that the drug companies invented RLS. I had RLS before I knew what it was and had a clinical sleep study to confirm my neurologist's suspicions. Apparently about a third of people with MS will also develop RLS. By the way, I have it in an arm as well! It is a little understood disorder.

Drugs seem to be marketed differently here (Australia). There are many advertisements for common pain killers and the like in the popular press but few about drugs for more serious conditions. However, the drug companies do target doctors. They are offered inducements to prescribe particular products. This has been reported in the media and seems to happen quite a lot. I believe there are many advertisements in professional journals, however.

I was prescribe Permax (pergolide) for my RLS and within six months developed one of the negative side effects of such dopamine agonists. Later some of the other side effects also emerged. The first effect for me was significant drowsiness but the drug works silently in creating obsessive/compulsive behaviours in about 7% of those who take it. So not everyone is affected. It is related to the role of dopamine in brain biochemistry and may depend on individual make-up. I was prescribed the medication in 2000, before there was any public or much professional awareness of the side effects.

Incidentally. Permax has been removed from the market because it is connected with heart disease, not because of its connection with compulsivity.

Now there IS public and professional awareness of the possible side effects of dopamine agonists and people can monitor themselves for these. Professionals should also regularly check their patients as well. The drugs instigate behaviours which people may be reluctant to discuss so honest sensitivity is required.

i had this b4 knew what it was and never really considered it a disease or a problem. however, i was tired and a sleep study had me thrashing my legs 96 times in 8 hrs and the jerks were violent enough to wake me up each time. i was oblivious to this aspect but i did know the syndrome often prevented me from falling asleep. my self treatment was to beat the bed with both legs till they got tired. the dog did not like it.

I had RLS many years ago and they gave me Neurontin. After couple of years RLS seemed to go away. I was put on Morphine after that and RLS disappeared. Starting July 2008 I had to get off opiates (life threatening Respiratory disease) and that is when RLS, PN, TN and some other neurological disorders started.

My Neurologist gave me two or three different meds to try and only Mirapex worked. Before Mirapex I could not sleep unless I was "drugged". Now ... .5mg of Mirapex a day and I can sleep through the night. Is it bad for me? Who knows. I have been on as many as 25 prescriptions for Respiratory issues, Urological problems, Acid Reflux, VCD, CCHS, Chronic Pain, Carpal Tunnel (spine damage), what else?? Sorry, Mild Cognitive Impairment (MCI) ... oh yeah, RLS ... COPD ... high blood pressure ...

So my meds help me, but as you are wisely pointing out, side effects start adding up. I am down to only 17 prescriptions and I want to be off of them, but as my Pulmonologist told me, the side effects of not being able to breathe outweigh all other side effects. I am not so sure anymore.

Good article and very thought provoking -- Thanks again