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Pharmacotherapeutic group: Dopamine agonist. ATC code: N04BC05.
Pharmacology: Mode of Action: Pramipexole, the active ingredient of SIFROL, is a dopamine agonist and binds with high selectivity and specificity to the dopamine D2 subfamily receptors and has a preferential affinity to D3 receptors; it has full intrinsic activity.
SIFROL alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and turnover. Pramipexole protects dopamine neurons from degeneration in response to ischemia or methamphetamine neurotoxicity.
The precise mechanism of action of Sifrol as a treatment for Restless Legs Syndrome is not known. Although the pathophysiology of Restless Legs Syndrome is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of Restless Legs Syndrome.
In vitro studies demonstrate that pramipexole protects neurons from levodopa neurotoxicity.
Pharmacodynamics: In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where SIFROL extended-release tablets were titrated faster than recommended (every 3 days) up to 4.5 mg per day, an increase in blood pressure and heart rate was observed. Such effect was not observed in patient studies.
Clinical Trials: Parkinson's disease: Efficacy of SIFROL in the controlled clinical trials was maintained for the duration of the trials, approximately six months. In open continuation trials lasting for more than three years, there were no signs of decreasing efficacy.
The efficacy and tolerability of an overnight switch from SIFROL tablets to SIFROL extended-release tablets at the same daily dose was evaluated in a double-blind clinical study in patients with early Parkinson's disease.
Efficacy was maintained in 87 of 103 patients switched to SIFROL extended-release tablets. Out of these 87 patients, 82.8% did not change their dose, 13.8% increased and 3.4% decreased their dose.
In half of the 16 patients who did not meet the criterion for maintained efficacy on UPDRS Part II + III score, the change from baseline was considered not clinically relevant.
One patient switched to SIFROL extended-release tablets experienced a drug-related adverse event leading to withdrawal.
Restless Legs Syndrome: The efficacy of SIFROL was evaluated in four placebo controlled trials in approximately 1000 patients with moderate to very severe Restless Legs Syndrome. Efficacy was demonstrated in controlled trials in patients treated for up to 12 weeks and sustained efficacy was shown over a period of 9 months. The efficacy of SIFROL was maintained during open continuation trials lasting for up to 1 year. In a placebo controlled clinical trial over 26 weeks, the efficacy of pramipexole was confirmed in patients with moderate to severe RLS.
Pharmacokinetics: Absorption: Pramipexole is rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90%.
Tablets: The maximum plasma concentrations occur between 1 and 3 hours. The rate of absorption is reduced by food intake but not the overall extent of absorption.
Extended-release tablets: The maximum plasma concentrations occur at about 6 hours. Generally, food does not affect the bioavailability of pramipexole. A slight increase of about 20% in peak concentration and a delay of about 2 hours in time to reach peak concentration after a high-fat meal are not considered clinically relevant.
Pramipexole shows linear kinetics and a relatively small inter-patient variation of plasma levels irrespective of the pharmaceutical form.
Distribution: In humans, the protein binding of pramipexole is very low (<20%) and the volume of distribution is large (400 L). High brain tissue concentrations were observed in the rat (approx. 8-fold compared to plasma).
Biotransformation: Pramipexole is metabolised in man only to a small extent.
Elimination: Renal excretion of unchanged pramipexole is the major route of elimination and accounts for about 80% of dose. Approximately 90% of a 14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total clearance of pramipexole is approx. 500 ml/min and the renal clearance is approx. 400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
Toxicology: Repeat-dose toxicity: Repeated-dose toxicity studies showed that pramipexole exerted functional effects, mainly involving the CNS and, in the rat, the female reproductive system, probably resulting from an exaggerated pharmacodynamic effect of pramipexole.
Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to a hypotensive effect was discerned in the monkey.
Reproductive and developmental toxicity: The potential effects of pramipexole on reproductive function have been investigated in rats and rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at maternally toxic doses. Due to the hypoprolactinaemic effect of the compound and the special role of prolactin in reproductive function in the female rat, the effects of pramipexole on pregnancy and female fertility were not fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats. The relevance for humans is unknown.
Genotoxicity and carcinogenicity: Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of the salt form) and higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study, or in any other species investigated.
