Composition:

Each tablet contains 0.25mg Pramipexole dihydrochloride monohydrate (equivalent to 0.18mg Pramipexole)

Each tablet contains 0.5mg Pramipexole dihydrochloride monohydrate (equivalent to 0.35mg Pramipexole)

Each tablet contains 1mg Pramipexole dihydrochloride monohydrate (equivalent to 0.7mg Pramipexole)

 

Pharmacodynamic Properties:

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.

Pharmacokenitic Properities: 

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.

Distribution: the protein binding of pramipexole is very low (< 20%) and the volume of distribution is large (400 l).

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 elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.

Indications:

Pramipexole indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson's disease.

It is indicated in adults for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome.

Contraindications:

      Hypersensitivity to the active substance or to any of the excipients.

Warnings and precautions:

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.

Dystonia:

Axial dystonia including (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 Pramipexole.

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 Pramipexole. 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 cares 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.

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.

Dopamine agonist withdrawal syndrome:

To discontinue treatment in patients with Parkinson's disease, pramipexole should be tapered off.

Side effects:

Very common: somnolence, dizziness, dyskinesia, nausea.

Common: Insomnia, hallucinations, abnormal dreams, confusion, behavioral symptoms of impulse control disorders and compulsions, headache, visual impairment, including diplopia, vision blurred, visual acuity reduced, hypotension, constipation, vomiting, fatigue, peripheral oedema, weight decrease including decreased appetite.

Uncommon: pneumonia, inappropriate antidiuretic hormone secretion, compulsive shopping, pathological gambling, restlessness, hypersexuality, delusion, libido disorder, paranoia, delirium, binge eating1, hyperphagia, sudden onset of sleep amnesia, hyperkinesia, syncope, cardiac failure, Dyspnoea, hiccups, hypersensitivity, pruritus, rash, weight increase.

Dosage And Administration

Parkinson's disease:

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 per day and then increased every 5-7 days, the dose should be titrated to achieve a maximal therapeutic effect.

Ascending dose schedule of Pramipexole
Week	Dose (mg of base)	Total Daily Dose (mg of base)	Dose (mg of salt)	Total Daily Dose (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 of base (0.75mg of 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.

-Maintenance treatment: The individual dose of pramipexole should be in the range of 0.264mg of base to a maximum of 3.3mg of base per day.

-Treatment discontinuation: Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Pramipexole should be tapered off at a rate of 0.54mg of base per day until the daily dose has been reduced to 0.54mg of base. Thereafter the dose should be reduced by 0.264mg of base per day.

Restless Legs Syndrome:

The recommended starting dose of Pramipexole is 0.088mg of base (0.125mg of salt) taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days to a maximum of 0.54mg of base (0.75mg of salt) per day (as shown in the table below).

Dose Schedule of Mirapexin
Titration Step	Once Daily Evening Dose (mg of base)	Once Daily Evening Dose (mg of salt)
1	0.088	0.125
2*	0.18	0.25
3*	0.35	0.50
4*	0.54	0.75
* if needed

Patient's response should be evaluated after 3 months treatment and the need for treatment continuation should be reconsidered. If treatment is interrupted for more than a few days it should be          re-initiated by dose titration carried out as above.

Renal impairment:

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 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 20 ml/min, the daily dose of MIRAPEXIN 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.

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.

Paediatric population:

The safety and efficacy of Pramipexole in children below 18 years has not been established.

Overdose:

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.

 

 

Drug and Food Interactions:

•  Cimetidine reduced the renal clearance of pramipexole by approximately 34%.
• Interactions with other medicinal products affecting plasma protein binding or elimination by biotransformation are unlikely.
• Co-administration of antipsychotic medicinal products with pramipexole   should be avoided.

Pregnancy & Lactation:

The effect of Pramipexol on pregnancy and lactation has not been investigated in humans, it should not be used during pregnancy unless clearly necessary (if the potential benefit justifies the potential risk to) the foetus.

Pramipexole inhibits secretion of prolactin in humans, inhibition of lactation is expected