Pramipexole Hydrochloride 0.125 mg tablets are white to off-white, round, flat, bevelled edge tablets debossed with 'P' on one side of the tablet and no debossing on the other side of the tablet. Pramipexole Hydrochloride 0.25 mg tablets are white to off-white, oval, flat, bevelled edge tablets with a breakline on both sides of the tablet and debossed with 'P' on either side of the breakline on one side of the tablet and no debossing on the other side of the tablet. Pramipexole Hydrochloride 0.5 mg tablets are white to off-white, oval, flat, bevelled edge tablets with a breakline on both sides of the tablet and debossed with 'P' on either side of the breakline on one side of the tablet and no debossing on the other side of the tablet. Pramipexole Hydrochloride 1 mg tablets are white to off-white, round, flat, bevelled edge tablets with a breakline on both sides of the tablet and debossed with 'P' on either side of the breakline on one side of the tablet and no debossing on the other side of the tablet.

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Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05. Pramipexole 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. In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where Pramipexole Hydrochloride tablets prolonged-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.

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.

Pharmacokinetics

Pramipexole is rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3 hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels. 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). Pramipexole is metabolised in man only to a small extent. 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 (t1/2) varies from 8 hours in the young to 12 hours in the elderly.

Dosage and Administration

This product may not be interchangeable with similar products on the New Zealand market. The daily dose is administered in equally divided doses 3 times a day.

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.

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 Effects).

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 Pramipexole Hydrochloride tablets, depending on reactions in individual patients (see Interactions).

Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Therefore, 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 Warnings and Precautions).

The elimination of pramipexole is dependent on renal function. The following dose schedule is suggested for initiation of therapy: 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 20 and 50 ml/min, the initial daily dose of Pramipexole Hydrochloride tablets should be administered in two divided doses, starting at 0.125 mg twice a day (0.25 mg daily). A maximum daily dose of 2.25 mg should not be exceeded. In patients with a creatinine clearance less than 20 ml/min, the daily dose of Pramipexole Hydrochloride tablets should be administered in a single dose, starting at 0.125 mg daily. A maximum daily dose of 1.5 mg should not be exceeded. If renal function declines during maintenance therapy the Pramipexole Hydrochloride tablet daily dose should be reduced by the same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then the Pramipexole Hydrochloride tablets daily dose should be reduced by 30%. The daily dose can be administered in two divided doses if creatinine clearance is between 20 and 50 ml/min and as a single daily dose if creatinine clearance is less than 20 ml/min.

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 Pramipexole Hydrochloride tablets pharmacokinetics has not been investigated.

The safety and efficacy of Pramipexole Hydrochloride tablets in children below 18 years has not been established. There is no relevant use of Pramipexole Hydrochloride tablets in the paediatric population in Parkinson's Disease.

The tablets should be taken orally, swallowed with water, and can be taken either with or without food.

Contraindications

Warnings and Precautions

When prescribing Pramipexole Hydrochloride tablets in a patient with Parkinson's disease with renal impairment a reduced dose is suggested in line with the Dosage and Administration.

Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that (mostly visual) hallucinations can occur.

In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesia can occur during the initial titration of Pramipexole Hydrochloride tablets. If they occur, the dose of levodopa should be decreased.

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 Pramipexole Hydrochloride tablets. 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 Interactions, Adverse Effects and Effects on the Ability to Drive and Use Machines).

Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including Pramipexole Hydrochloride tablets. Furthermore, patients and caregivers should be aware of the fact that other behavioural symptoms of impulse control disorders and compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered discontinuation should be considered.

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 is recommended at regular intervals or if vision abnormalities occur.

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.

Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy (see Dosage and Administration).

Use in 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 Preclinical Safety Data). Pramipexole Hydrochloride tablets should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.

Use in Lactation

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, Pramipexole Hydrochloride tablets should not be used during breast-feeding. However, if its use is unavoidable, breast-feeding should be discontinued.

Effect on Fertility

Effects on Ability to Drive and Use Machines

Pramipexole Hydrochloride tablets can have a major influence on the ability to drive and use machines. Hallucinations or somnolence can occur. Patients being treated with Pramipexole Hydrochloride tablets 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 Warnings and Precautions, Interactions and Adverse Effects).

Adverse Effects

Expected adverse reactions

The following adverse reactions are expected under the use of Pramipexole Hydrochloride tablets: abnormal dreams, amnesia, behavioural symptoms of impulse control disorders and compulsions such as binge eating, compulsive shopping, hypersexuality and pathological gambling; confusion, constipation, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hyperkinesia, hyperphagia, hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus, rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual disturbance including vision blurred and visual acuity reduced, vomiting, weight decrease, weight increase. Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients on pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently reported for both groups. 63% of patients on pramipexole and 52% of patients on placebo reported at least one adverse drug reaction. Table 1 displays the frequency of adverse drug reactions from placebo-controlled clinical trials in Parkinson's disease. The adverse drug reactions reported in this table are those events that occurred in 0.1% or more of patients treated with pramipexole and were reported significantly more often in patients taking pramipexole than placebo, or where the event was considered clinically relevant. The majority of adverse drug reactions were mild to moderate, they usually start early in therapy and most tended to disappear even as therapy was 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).

Parkinson's disease, most common adverse reactions

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 per day (see Dosage and 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. Table 1: Parkinson's disease

System Organ Class	Adverse Drug Reaction
Infections and infestations
Uncommon	Pneumonia
Psychiatric disorders
Common	abnormal dreams, behavioural symptoms of impulse control disorders and compulsions, confusion, hallucinations, insomnia, restlessness
Uncommon	compulsive shopping, delusion, hypersexuality, libido disorder, paranoia, pathological gambling
Not known	binge eating, hyperphagia
Nervous system disorders
Very common	dizziness, dyskinesia, somnolence
Common	amnesia, headache
Uncommon	hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common	visual disturbance including vision blurred and visual acuity reduced
Vascular disorders
Very common	Hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon	Dyspnoea
Gastrointestinal disorders
Very common	Nausea
Common	constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon	hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common	fatigue, peripheral oedema
Investigations
Common	weight decrease
Uncommon	weight increase

Post-Marketing Experience

In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified (essentially in Parkinson's disease patients) during post- approval use of pramipexole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: abnormal dreams, amnesia, cardiac failure, accidents (including fall), blackouts, fatigue, hallucinations, headache, hiccups, hypotension (including postural hypotension), inappropriate antidiuretic hormone secretion, increased eating (including binge eating, compulsive eating, and hyperphagia), libido disorders, hypersexuality, compulsive shopping and other abnormal behaviour (reflecting symptoms of impulse control disorders and compulsions); restlessness, paranoia, syncope, visual disturbance including blurred vision and reduced visual acuity, vomiting, weight decrease including decreased appetite, weight increase, pneumonia, dyspnoea and hypersensitivity. Patients treated with pramipexole have rarely reported suddenly falling asleep (or sudden onset of sleep) while engaged in activities of daily living, including operation of motor vehicles which has sometimes resulted in accidents (see Warnings and Precautions). Some of them did not report a warning sign such as somnolence, which is a common occurrence in patients receiving pramipexole at doses above 1.5 mg/day, and which, according to the current knowledge of sleep physiology, always proceeds falling asleep. There was no clear relation to the duration of treatment. Some patients were taking other medication with potentially sedative properties. In most cases where information was available, there were no further episodes following reduction of dosage or termination of therapy. Patients treated with dopamine agonists for Parkinson's disease, including pramipexole, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation. 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 behaviour (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 behaviours. 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).

Interactions

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.

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, and mexiletine, may interact with pramipexole resulting in reduced clearance of either or both medicinal products. Reduction of the pramipexole dose should be considered when these medicinal products are administered concomitantly with Pramipexole Hydrochloride tablets.

When Pramipexole Hydrochloride tablets are 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 Pramipexole Hydrochloride tablets. Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see Warnings and Precautions, Effects on Ability to Drive and Use Machines and Adverse Effects).

Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see Warnings and Precautions), e.g. if antagonistic effects can be expected.

Overdosage

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.

Pharmaceutical Precautions

Medicine Classification

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Further Information

List of Excipients

Mannitol Maize starch Colloidal silica anhydrous Povidone K 30 Magnesium stearate

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. 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 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.

Name and Address

Dr Reddy's New Zealand Ltd Level 6, AMI House 63 Albert Street PO Box 911-267 AUCKLAND Tel: (09) 356 7000 Fax: (09) 356 7001

Ascending dose schedule of Pramipexole Hydrochloride tablets
Week	Dose	Total Daily Dose
1	3 x 0.125	0.375
2	3 x 0.25	0.75
3	3 x 0.5	1.50

New Zealand Datasheet

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