BOEHRINGER INGELHEIM
Nonergot dopamine agonist approved for the treatment of primary restless legs syndrome
Pramipexole was approved on November 7, 2006, for the treatment of moderate-to-severe primary restless legs syndrome (RLS).
This agent has high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors.
Efficacy. The efficacy of pramipexole for the treatment of RLS was evaluated in 4 trials that enrolled approximately 1,000 patients
with moderate-to-severe primary RLS. Pramipexole 0.125 mg, 0.25 mg, 0.5 mg, or 0.75 mg or placebo was administered once daily
2 to 3 hours before bedtime. Outcome measures used to measure treatment effect were the International RLS Rating (IRLS) Scale
(0, absence of symptoms; 40, most severe symptoms) and a Clinical Global Impression-Improvement (CGI-I) assessment. Pramipexole-treated
patients in Study 1 were titrated from a starting dose of 0.125 mg to 1 of 3 doses of pramipexole (0.25, 0.5, and 0.75 mg)
during the first 3 weeks of the study. After 12 weeks, patients treated with pramipexole had significantly improved scores
for both outcome measures compared with patients who received placebo. Overall, the IRLS score for pramipexole-treated patients
demonstrated a change from baseline of –13.6 versus –9.4 for patients who received placebo. The CGI-I assessment demonstrated
that 72.0% of pramipexole-treated patients overall were responders versus 51.2% of placebo patients. Study 2 examined the
sustained efficacy of pramipexole after a treatment period of 6 months. Patients who had responded to pramipexole treatment
in a 6-month open-label treatment phase were randomized to receive either continued pramipexole treatment or placebo for 12
weeks. After 12 weeks, 85% of placebo-treated patients had experienced treatment failure versus 21% of pramipexole-treated
patients. Studies 3 and 4 demonstrated results similar to those seen in Study 1, with changes in IRLS scores after 6 weeks
of treatment and 3 weeks of treatment, respectively, ranging from –12 to –15 among pramipexole-treated patients versus –6
among placebo-treated patients; 63% to 76% of pramipexole-treated patients were classified as responders versus 32% to 43%
of placebo patients. Safety. Patients treated with pramipexole have reported falling asleep during activities of daily living, including during the operation
of motor vehicles, as late as 1 year after treatment initiation. Although some of these patients reported somnolence during
pramipexole treatment, some patients perceived no excessive drowsiness before falling asleep during daily activities. Patients
should be asked about any factors that could increase the risk of somnolence, such as the presence of sleep disorders and
the use of sedatives or concomitant medications that could increase pramipexole plasma levels. Dopamine agonists have also
been linked with orthostatic hypotension, especially during dose escalation. Pramipexole may cause or exacerbate dyskinesia.
Cases of pathological gambling, hypersexuality, and compulsive eating have been reported in patients treated with dopamine
agonists. Some patients treated with pramipexole have experienced rebound (shifting of symptoms from evening to early morning)
or augmentation (earlier onset of symptoms, increase of symptoms, and spread of symptoms to additional extremities). The most
commonly reported adverse events with pramipexole treatment include nausea, somnolence, fatigue, headache, and insomnia.
Dosing. The recommended starting dosage of pramipexole is 0.125 mg once daily 2 to 3 hours before bedtime. If patients do not experience
symptom relief, the dose may be increased to 0.25 mg after 4 to 7 days, and then to 0.5 mg after another 4 to 7 days if necessary.
The time between titration steps should be increased to 14 days in patients with moderate-to-severe renal impairment (creatinine
clearance 20 to 60 mL/min).
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