Document: spc-doc_PL 36687-0015 change

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• spc-doc_PL 40378-0104

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Pramipexole 0.18 mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Pramipexole 0.18 mg tablets

Each tablet contains 0.25 mg pramipexole dihydrochloride monohydrate equivalent to 0.18 mg pramipexole.

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.

3    PHARMACEUTICAL FORM

Tablet

Pramipexole 0.18 mg tablets

The tablets are white to off white, round, flat, bevel edged, uncoated tablets, debossed with “P2” on both sides of break line on one side and plain on other side. The tablets can be divided into equal halves.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Pramipexole is indicated for treatment of the 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).

4.2 Posology and method of administration

Parkinson’s disease

The tablets should be taken orally, swallowed with water, and can be taken either with or without food. The daily dose is administered in equally divided doses 3 times a day.

Initial treatment

Doses should be increased gradually from a starting-dose of 0.264mg of base (0.375mg 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 Pramipexole
Week	Dose	Total Daily Dose	Dose	Total Daily Dose
	(mg of base)	(mg of base)	(mg of salt)	(mg of salt)
1	3 x 0.088	0.264	3 x 0.125	0.375
2	3 x 0.18	0.54	3 x 0.25	0.75
3	3 x 0.35	1.1	3 x 0.5	1.50

If a further dose increase is necessary the daily dose should be increased by 0.54mg base (0.75mg salt) at weekly intervals up to a maximum dose of 3.3mg of base (4.5mg of salt) per day.

However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5mg (of salt) per day (see section 4.8).

Maintenance treatment

The individual dose of pramipexole should be in the range of 0.264mg of base (0.375mg of salt) to a maximum of 3.3mg of base (4.5mg of salt) per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.1mg of base (1.5mg of salt). Further dose adjustments should be done based on the clinical response and the occurrence of undesirable effects. In clinical trials approximately 5% of patients were treated at doses below 1.1mg of base (1.5mg of salt). In advanced Parkinson’s disease, pramipexole doses higher than 1.1mg of base (1.5mg 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 Pramipexole, depending on reactions in individual patients.

Treatment discontinuation

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 0.54mg of base (0.75mg of salt) per day until the daily dose has been reduced to 0.54mg of base (0.75mg of salt). Thereafter the dose should be reduced by 0.264mg of base (0.375mg of salt) per day (see section 4.4).

Patients with renal impairment

The elimination of pramipexole is dependent on renal function. The following dosage schedule is suggested for initiation of therapy:

Patients with a creatinine clearance above 50ml/min require no reduction in daily dose or dosing frequency.

In patients with a creatinine clearance between 20 and 50ml/min, the initial daily dose of Pramipexole should be administered in two divided doses, starting at 0.088mg of base (0.125mg of salt) twice a day (0.176mg of

base/0.25mg of salt daily). A maximum daily dose of 1.57mg pramipexole base (2.25mg of salt) should not be exceeded.

In patients with a creatinine clearance less than 20ml/min, the daily dose of Pramipexole should be administered in a single dose, starting at 0.088mg of base (0.125mg of salt) daily. A maximum daily dose of 1.1mg pramipexole base (1.5mg of salt) should not be exceeded.

If renal function declines during maintenance therapy the Pramipexole 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 daily dose should be reduced by 30%. The daily dose can be administered in two divided doses if creatinine clearance is between 20 and 50ml/min, and as a single daily dose if creatinine clearance is less than 20ml/min.

Patients with 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 Pramipexole pharmacokinetics has not been investigated.

Dosing in children and adolescents

Pramipexole is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

When prescribing Pramipexole in a patient with Parkinson’s disease with renal impairment a reduced dose is suggested in line with section 4.2.

Hallucinations

Hallucinations are known as a side-effect 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 Pramipexole. If they occur, the dose of levodopa should be decreased.

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 Pramipexole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of 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 section 4.5, 4.7 and section 4.8).

Impulse control disorders and compulsive behaviours

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural 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 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 section 4.5).

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 neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy (see section 4.2.).

4.5 Interaction with other medicinal products and other forms of interaction

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, 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.

Combination with levodopa

When Pramipexole 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 Pramipexole.

Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see section 4.4, 4.7 and 4.8).

Antipsychotic medicinal products

Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.4), e.g. if antagonistic effects can be expected.

4.6 Fertility, pregnancy and lactation

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 section 5.3). Pramipexole 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, Pramipexole should not be used during breastfeeding. However, if its use is unavoidable, breast-feeding should be discontinued.

4.7 Effects on ability to drive and use machines

Pramipexole has a major influence on the ability to drive and use machines. Hallucinations or somnolence can occur.

Patients being treated with Pramipexole 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 sections 4.4, 4.5 and 4.8).

Undesirable effects

Expected adverse events

The following adverse reactions are expected under the use of Pramipexole: abnormal dreams, amnesia, behavioural symptoms of impulse control disorders and compulsion such as binge eating, compulsive shopping, hypersexuality and pathological gambling; confusion, constipation, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hyperkinesia, hyperphagia, hypotension, inappropriate antidiuretic hormone secretion, 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 these tables 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 salt per day (see section 4.2). 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
Endocrine disorders
Uncommon	inappropriate antidiuretic hormone secretion1
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

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.

4.9 Overdose

There is no clinical experience with massive overdose. The expected adverse events 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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: dopamine agonists, ATC code: N04BC05

Mechanism of action

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.

Pharmacodynamic effects

In 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 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.

5.2 Pharmacokinetic properties

Absorption

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.

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 500ml/min and the renal clearance is approximately 400ml/min. The elimination halflife (t'A) varies from 8 hours in the young to 12 hours in the elderly.

5.3 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 2mg/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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Mannitol Maize starch

Silica, colloidal anhydrous Pregelatinized maize starch Povidone K-30 Magnesium stearate

6.2    Incompatibilities

Not applicable

6.3    Shelf life

5 years

6.4    Special precautions for storage

Store in the original package in order to protect from light.

6.5    Nature and contents of container

OPA-Al-PVC/Al blisters containing 20, 30, 60 or 100 tablets.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

TORRENT PHARMA (UK) Ltd Unit 4, Charlwood Court County Oak Way

Crawley RHII 7XA United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 36687/0015

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/05/2010

10    DATE OF REVISION OF THE TEXT

09/04/2014