Summary of Product Characteristics Updated 20-May-2016 | Consilient Health Ltd
Please note:Pramipexole doses as published in the literature refer to the salt form.Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in brackets).For the full list of excipients, see section 6.1.
PosologyOprymea prolonged-release tablets are a once-a-day oral formulation of pramipexole.
Initial treatmentDoses should be increased gradually from a starting dose of 0.26 mg of base (0.375 mg of salt) per day and then increased every 5 - 7 days. Providing patients do not experience intolerable undesirable effects, the dose should be titrated to achieve a maximal therapeutic effect.
|Ascending dose schedule of Oprymea prolonged-release tablets|
|Week||Daily dose (mg of base)||Daily dose (mg of salt)|
Maintenance treatmentThe individual dose of pramipexole should be in the range of 0.26 mg of base (0.375 mg of salt) to a maximum of 3.15 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.05 mg of base (1.5 mg of salt). Further dose adjustments should be done based on the clinical response and the occurrence of adverse reactions. In clinical trials approximately 5% of patients were treated at doses below 1.05 mg of base (1.5 mg of salt). In advanced Parkinson's disease, pramipexole doses higher than 1.05 mg of base (1.5 mg of salt) per day can be useful in patients where a reduction of the levodopa therapy is intended. It is recommended that the dose of levodopa is reduced during both the dose escalation and the maintenance treatment with Oprymea, depending on reactions in individual patients (see section 4.5).
Missed doseWhen the intake of a dose is missed, Oprymea prolonged-release tablets should be taken within 12 hours after the regularly scheduled time. After 12 hours, the missed dose should be left out and the next dose should be taken on the following day at the next regularly scheduled time.
Treatment discontinuationAbrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Pramipexole should be tapered off at a rate of 0.52 mg of base (0.75 mg of salt) per day until the daily dose has been reduced to 0.52 mg of base (0.75 mg of salt). Thereafter the dose should be reduced by 0.26 mg of base (0.375 mg of salt) per day (see section 4.4).
Patients with renal impairmentThe elimination of pramipexole is dependent on renal function. The following dose schedule is suggested:Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing frequency.In patients with a creatinine clearance between 30 and 50 ml/min, treatment should be started with 0.26 mg Oprymea prolonged-release tablets every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week. If a further dose increase is necessary, doses should be increased by 0.26 mg pramipexole base at weekly intervals up to a maximum dose of 1.57 mg pramipexole base (2.25 mg of salt) per day.The treatment of patients with a creatinine clearance below 30 ml/min with Oprymea prolonged-release tablets is not recommended as no data are available for this patient population. The use of Oprymea tablets should be considered.If renal function declines during maintenance therapy, the recommendations given above should be followed.
Patients with hepatic impairmentDose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed active substance is excreted through the kidneys. However, the potential influence of hepatic insufficiency on Oprymea pharmacokinetics has not been investigated.
Paediatric populationThe safety and efficacy of Oprymea in children below 18 years has not been established. There is no relevant use of Oprymea prolonged-release tablets in the paediatric population in Parkinson's Disease.
Method of administrationThe tablets should be swallowed whole with water, and must not be chewed, divided or crushed. The tablets may be taken either with or without food and should be taken each day at about the same time.
PregnancyThe effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3). Oprymea should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.
Breast-feedingAs pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected. The excretion of pramipexole into breast milk has not been studied in women. In rats, the concentration of active substance-related radioactivity was higher in breast milk than in plasma.In the absence of human data, Oprymea should not be used during breast-feeding. However, if its use is unavoidable, breast-feeding should be discontinued.
FertilityNo studies on the effect on human fertility have been conducted. In animal studies, pramipexole affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However, these studies did not indicate direct or indirect harmful effects with respect to male fertility.
|System Organ Class||Adverse Drug Reaction|
|Infections and infestations|
|Uncommon||inappropriate antidiuretic hormone secretion1|
|Common||abnormal dreams, behavioural symptoms of impulse control disorders and compulsions; confusion, hallucinations, insomnia|
|Uncommon||binge eating1, compulsive shopping, delusion, hyperphagia1, hypersexuality, libido disorder, paranoia, pathological gambling, restlessness, delirium|
|Nervous system disorders|
|Very common||dizziness, dyskinesia, somnolence|
|Uncommon||amnesia, hyperkinesia, sudden onset of sleep, syncope|
|Common||visual impairment including diplopia, vision blurred and visual acuity reduced|
|Respiratory, thoracic, and mediastinal disorders|
|Skin and subcutaneous tissue disorders|
|Uncommon||hypersensitivity, pruritus, rash|
|General disorders and administration site conditions|
|Common||fatigue, peripheral oedema|
|Common||weight decrease including decreased appetite|
Cardiac failureIn clinical studies and post-marketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole (observed risk ratio 1.86; 95% CI, 1.21-2.85).
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
SymptomsThere is no clinical experience with massive overdose. The expected adverse reactions would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension.
ManagementThere is no established antidote for overdose of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent may be indicated. Management of the overdose may require general supportive measures, along with gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram monitoring.
Mechanism of actionPramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic activity.Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and turnover.
Pharmacodynamic effectsIn human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where pramipexole prolonged-release tablets were titrated faster (every 3 days) than recommended up to 3.15 mg pramipexole base (4.5 mg of salt) per day, an increase in blood pressure and heart rate was observed. Such effect was not observed in patient studies.
Clinical efficacy and safety in Parkinson's diseaseIn patients pramipexole alleviates signs and symptoms of idiopathic Parkinson's disease. Placebo-controlled clinical trials included approximately 1,800 patients of Hoehn and Yahr stages I V treated with pramipexole. Out of these, approximately 1,000 were in more advanced stages, received concomitant levodopa therapy, and suffered from motor complications.In early and advanced Parkinson's disease, efficacy of pramipexole in controlled clinical trials was maintained for approximately six months. In open continuation trials lasting for more than three years there were no signs of decreasing efficacy.In a controlled double blind clinical trial of 2 year duration, initial treatment with pramipexole significantly delayed the onset of motor complications, and reduced their occurrence compared to initial treatment with levodopa. This delay in motor complications with pramipexole should be balanced against a greater improvement in motor function with levodopa (as measured by the mean change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally higher in the escalation phase with the pramipexole group. However, there was no significant difference during the maintenance phase. These points should be considered when initiating pramipexole treatment in patients with Parkinson's disease.The safety and efficacy of pramipexole prolonged-release tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of three randomised, controlled trials. Two trials were conducted in patients with early Parkinson's disease and one trial was conducted in patients with advanced Parkinson's disease.Superiority of pramipexole prolonged-release tablets over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS Parts II+III score) and the key secondary (CGI-I and PGI-I responder rates) efficacy endpoints in a double-blind placebo-controlled trial including a total of 539 patients with early Parkinson's disease. Maintenance of efficacy was shown in patients treated for 33 weeks. Pramipexole prolonged-release tablets were non-inferior to pramipexole immediate release tablets as assessed on the UPDRS Parts II+III score at week 33.In a double-blind placebo-controlled trial including a total of 517 patients with advanced Parkinson's disease who were on concomitant levodopa therapy superiority of pramipexole prolonged-release tablets over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS Parts II+III score) and the key secondary (off-time) efficacy endpoints.The efficacy and tolerability of an overnight switch from pramipexole tablets to pramipexole prolonged-release tablets at the same daily dose were evaluated in a double-blind clinical study in patients with early Parkinson's disease.Efficacy was maintained in 87 of 103 patients switched to pramipexole prolonged-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.Only one patient switched to pramipexole prolonged-release tablets experienced a drug-related adverse event leading to withdrawal.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with pramipexole in all subsets of the paediatric population in Parkinson's Disease (see section 4.2 for information on paediatric use).
AbsorptionPramipexole is completely absorbed following oral administration. The absolute bioavailability is greater than 90%.In a Phase I trial, where pramipexole immediate release and prolonged-release tablets were assessed in fasted state, the minimum and peak plasma concentration (Cmin, Cmax) and exposure (AUC) of the same daily dose of pramipexole prolonged-release tablets given once daily and pramipexole tablets given three times a day were equivalent.The once daily administration of pramipexole prolonged-release tablets causes less frequent fluctuations in the pramipexole plasma concentration over 24 hours compared to the three times daily administration of pramipexole immediate release tablets.The maximum plasma concentrations occur at about 6 hours after administration of pramipexole prolonged-release tablets once daily. Steady state of exposure is reached at the latest after 5 days of continuous dosing.Concomitant administration with food does generally not affect the bioavailability of pramipexole. Intake of a high fat meal induced an increase in peak concentration (Cmax) of about 24% after a single dose administration and about 20% after multiple dose administrations and a delay of about 2 hours in time to reach peak concentration in healthy volunteers. Total exposure (AUC) was not affected by concomitant food intake. The increase in Cmax is not considered clinically relevant. In the Phase III studies that established safety and efficacy of pramipexole prolonged-release tablets, patients were instructed to take study medication without regard to food intake.While body weight has no impact on the AUC, it was found to influence the volume of distribution and therefore the peak concentrations Cmax. A decreased body weight by 30 kg results in an increase in Cmax of 45%. However, in Phase III trials in Parkinson's disease patients no clinically meaningful influence of body weight on the therapeutic effect and tolerability of pramipexole prolonged-release tablets was detected.Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels.
DistributionIn 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).
BiotransformationPramipexole is metabolised in man only to a small extent.
EliminationRenal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of 14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
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