Mirapex ER

Pramipexole.

Each extended-release tablet contains 0.375 mg, 0.75 mg or 1.5 mg pramipexole dihydrochloride monohydrate respectively equivalent to 0.26 mg, 0.52 mg or 1.05 mg pramipexole.
Please note: Pramipexole doses as published in the literature refer to the salt form.
Therefore, doses will be expressed in terms of pramipexole salt.
Excipients/Inactive Ingredients: Hypromellose 2208, Maize starch, Carbomer 941, Colloidal anhydrous silica, Magnesium stearate.

Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonist. ATC code: N04BC05.
Pharmacology: Pharmacodynamics: Mechanism of action: Pramipexole is a dopamine agonist and 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 effects: In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where MIRAPEX extended-release tablets were titrated faster (every 3 days) than recommended 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 efficacy and safety in Parkinson's disease: In 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 MIRAPEX extended-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 MIRAPEX extended-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. MIRAPEX extended-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 MIRAPEX extended-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 MIRAPEX tablets to MIRAPEX extended-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 MIRAPEX 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.
Only one patient switched to MIRAPEX extended-release tablets experienced a drug-related adverse event leading to withdrawal.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with MIRAPEX in all subsets of the paediatric population in Parkinson's Disease (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Absorption: Pramipexole is completely absorbed following oral administration. The absolute bioavailability is greater than 90%.
In a Phase I trial, where pramipexole immediate release and extended-release tablets were assessed in fasted state, the minimum and peak plasma concentration (C_min, C_max) and exposure (AUC) of the same daily dose of MIRAPEX extended-release tablets given once daily and MIRAPEX tablets given three times a day were equivalent.
The once daily administration of MIRAPEX extended-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 MIRAPEX extended-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 (C_max) 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 C_max is not considered clinically relevant. In the Phase III studies that established safety and efficacy of MIRAPEX extended-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 C_max. A decreased body weight by 30 kg results in an increase in C_max 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 MIRAPEX extended-release tablets was detected.
Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels.
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. 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 (t ½) varies from 8 hours in the young to 12 hours in the elderly.
Toxicology: Preclinical safety data: Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving the CNS and female reproductive system, and 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.
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 selection of animal species and the limited parameters investigated, the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats. The relevance for humans is unknown.
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 salt) 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.

MIRAPEX is indicated in adults for the treatment of signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or "on off" fluctuations).

Posology: MIRAPEX extended-release tablets are a once-a-day oral formulation of pramipexole.
Initial treatment: Doses should be increased gradually from a starting dose of 0.375 mg 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. (See Table 1.)

Click on icon to see table/diagram/image

If a further dose increase is necessary the daily dose should be increased by 0.75 mg at weekly intervals up to a maximum dose of 4.5 mg per day. However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg per day (see Adverse Reactions).
Patients already taking MIRAPEX tablets may be switched to MIRAPEX extended-release tablets overnight, at the same daily dose. After switching to MIRAPEX extended-release tablets, the dose may be adjusted depending on the patient's therapeutic response (see Pharmacology: Pharmacodynamics under Actions).
Maintenance treatment: The individual dose of pramipexole should be in the range of 0.375 mg to a maximum of 4.5 mg per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.5 mg. 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 1.5 mg. In advanced Parkinson's disease, pramipexole doses higher than 1.5 mg 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 MIRAPEX, depending on reactions in individual patients (see Interactions).
Missed dose: When the intake of a dose is missed, MIRAPEX extended-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 discontinuation: Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome or a dopamine agonist withdrawal syndrome. Pramipexole should be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter the dose should be reduced by 0.375 mg per day (see Precautions). Dopamine agonist withdrawal syndrome could still appear while tapering and a temporary increase of the dose could be necessary before resuming tapering (see Precautions).
Renal impairment: The 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 0.375 mg MIRAPEX extended-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 0.375 mg at weekly intervals up to a maximum dose of 2.25 mg per day.
The treatment of patients with a creatinine clearance below 30 ml/min with MIRAPEX extended-release tablets is not recommended as no data are available for this patient population. The use of MIRAPEX tablets should be considered.
If renal function declines during maintenance therapy, the recommendations previously given should be followed.
Hepatic impairment: Dose 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 MIRAPEX pharmacokinetics has not been investigated.
Paediatric population: The safety and efficacy of MIRAPEX in children below 18 years has not been established. There is no relevant use of MIRAPEX extended-release tablets in the paediatric population for the indication of Parkinson's disease.
Method of administration: The 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.

There 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. There 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.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

When prescribing MIRAPEX in a patient with Parkinson's disease with renal impairment a reduced dose is suggested in line with Dosage & Administration.
Hallucinations: Hallucinations are known side effects of treatment with dopamine agonists and levodopa. Patients should be informed that (mostly visual) hallucinations can occur.
Dyskinesia: In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesia can occur during the initial titration of MIRAPEX. If they occur, the dose of levodopa should be decreased.
Dystonia: Axial dystonia including antecollis, camptocormia and pleurothotonus (Pisa Syndrome) has occasionally been reported in patients with Parkinson's disease following initiation or incremental dose increase of pramipexole. Although dystonia may be a symptom of Parkinson's disease, the symptoms in these patients have improved after reduction or withdrawal of pramipexole. If dystonia occurs, the dopaminergic medication regimen should be reviewed and an adjustment in the dose of pramipexole considered.
Sudden onset of sleep and somnolence: Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with MIRAPEX. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of the dose or termination of therapy may be considered. Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see Effects on ability to drive and use machines as follows, Adverse Reactions, and Interactions).
Impulse control disorders: Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioral symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including MIRAPEX. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Mania and delirium: Patients should be regularly monitored for the development of mania and delirium. Patients and carers should be made aware that mania and delirium can occur in patients treated with pramipexole. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Patients with psychotic disorders: Patients with psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see Interactions).
Ophthalmologic monitoring: Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease: In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.
Neuroleptic malignant syndrome: Symptoms suggestive of a neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy (see Dosage & Administration).
Dopamine agonist withdrawal syndrome (DAWS): DAWS has been reported with dopamine agonists, including pramipexole (see Adverse Reactions). To discontinue treatment in patients with Parkinson's disease, pramipexole should be tapered off (see Dosage & Administration). Limited data suggests that patients with impulse control disorders and those receiving high daily dose and/or high cumulative doses of dopamine agonists may be at higher risk for developing DAWS. Withdrawal symptoms may include apathy, anxiety, depression, fatigue, sweating and pain and do not respond to levodopa. Prior to tapering off and discontinuing pramipexole, patients should be informed about potential withdrawal symptoms. Patients should be closely monitored during tapering and discontinuation. In case of severe and/or persistent withdrawal symptoms, temporary readministration of pramipexole at the lowest effective dose may be considered.
Remnants in stool: Some patients have reported the occurrence of remnants in faeces which may resemble intact MIRAPEX extended-release tablets. If patients report such an observation, the physician should reassess patient's response to therapy.
Effects on ability to drive and use machines: MIRAPEX can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with MIRAPEX and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also Sudden onset of sleep and somnolence as previously mentioned, Adverse Reactions, and Interactions).

Pregnancy: The 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 Pharmacology: Toxicology: Preclinical safety data under Actions). MIRAPEX should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.
Breast-feeding: As 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, MIRAPEX should not be used during breast-feeding. However, if its use is unavoidable, breast-feeding should be discontinued.
Fertility: No 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.

Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,778 Parkinson's disease patients on pramipexole and 1,297 patients on placebo, adverse drug reactions were frequently reported for both groups. 67% of patients on pramipexole and 54% of patients on placebo reported at least one adverse drug reaction.
The majority of adverse drug reactions usually start early in therapy and most tend to disappear even as therapy is continued.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
The most commonly (≥ 5%) reported adverse drug reactions in patients with Parkinson's disease more frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of somnolence is increased at doses higher than 1.5 mg pramipexole salt per day (see Dosage & Administration). A more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too fast. (See Table 2.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Somnolence: Pramipexole is commonly associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes (see also Precautions).
Libido disorders: Pramipexole may uncommonly be associated with libido disorders (increased or decreased).
Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including MIRAPEX (see Precautions).
In a cross-sectional, retrospective screening and case-control study including 3,090 Parkinson's disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms of an impulse control disorder during the past six months. Manifestations observed include pathological gambling, compulsive shopping, binge eating, and compulsive sexual behavior (hypersexuality). Possible independent risk factors for impulse control disorders included dopaminergic treatments and higher doses of dopaminergic treatment, younger age (≤ 65 years), not being married and self-reported family history of gambling behaviors.
Dopamine agonist withdrawal syndrome: Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including pramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain (see Precautions).
Cardiac failure: In 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 reactions: Reporting suspected adverse reaction after authorization 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 reaction.

Plasma protein binding: Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by biotransformation, the potential for an interaction is limited, although an interaction with anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and levodopa.
Inhibitors/competitors of active renal elimination pathway: Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact with pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose should be considered when these medicinal products are administered concomitantly with MIRAPEX.
Combination with levodopa: When MIRAPEX is given in combination with levodopa, it is recommended that the dose of levodopa is reduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasing the dose of MIRAPEX.
Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see Precautions and Adverse Reactions).
Antipsychotic medicinal products: Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see Precautions), e.g. if antagonistic effects can be expected.

Special precautions for disposal: No special requirements.
Incompatibilities: Not applicable.

Store in the original package in order to protect from moisture.
Store below 30°C.

Antiparkinsonian Drugs

N04BC05 - pramipexole ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.

P₁S₁S₃