Sifrol ER

/ Boehringer Ingelheim

PRAMIPEXOLE extended-release tablets are a once-a-day oral formulation of Pramipexolee.
Initial treatment: Doses should be increased gradually from a starting dose of 0.375 mg of salt (0.26 mg of base) 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 extended-release tablets:
Week 1: a daily dose of 0.375 (mg of salt) = 0.26 (mg of base).
Week 2: a daily dose of 0.75 (mg of salt) = 0.52 (mg of base).
Week 1: a daily dose of 1.5 (mg of salt) = 1.05 (mg of base).
If a further dose increase is necessary the daily dose should be increased by 0.75 mg of salt (0.52 mg of base) at weekly intervals up to a maximum dose of 4.5 mg of salt (3.15 mg of base) per day. However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg of salt (1.05 mg of base) per day. Patients already taking Pramipexole tablets may be switched to Pramipexole extended-release tablets overnight, at the same daily dose. After switching to Pramipexole extended-release tablets, the dose may be adjusted depending on the patient’s therapeutic response.
Maintenance treatment:  The individual dose of Pramipexolee should be in the range of 0.375 mg of salt (0.26 mg of base) to a maximum of 4.5 mg of salt (3.15 mg of base) per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.5 mg of salt (1.05 mg of base). 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 of salt (1.05 mg of base). In advanced Parkinson’s disease, Pramipexolee doses higher than 1.5 mg of salt (1.05 mg of base) 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.
Missed dose: When the intake of a dose is missed, Pramipexole 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. Pramipexole should be tapered off at a rate of 0.75 mg of salt (0.52 mg of base) per day until the daily dose has been reduced to 0.75 mg of salt (0.52 mg of base). Thereafter the dose should be reduced by 0.375 mg of salt (0.26 mg of base) per day.
Patients with renal impairment: The elimination of Pramipexolee 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 Pramipexole 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 Pramipexolee salt  at weekly intervals up to a maximum dose of 2.25 mg of salt (1.57 mg Pramipexolee base) per day. The treatment of patients with a creatinine clearance below 30 ml/min with PRAMIPEXOLE extended-release tablets is not recommended as no data are available for this patient population. The use of Pramipexole tablets should be considered. If renal function declines during maintenance therapy, the recommendations given above should be followed.
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.
Paediatric population: The safety and efficacy of Pramipexole in children below 18 years has not been established. There is no relevant use of Pramipexole extended-release tablets in the paediatric population in 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.

This product is indicated for treatment of signs and symptoms of idiopathic Parkinson’s disease, as monotherapy or in combination with levodopa.

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

When prescribing this product in a patient with Parkinson’s disease with renal impairment a reduced dose is suggested below in Dosage.
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 this product. 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 this product. 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.
Impulse control disorders: 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 this product. 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.
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. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including pramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain which may be severe. Patients should be informed about this before tapering the dopamine agonist, and monitored regularly thereafter. In case of persistent symptoms, it may be necessary to increase the pramipexole dose temporarily.
Remnants in stool: Some patients have reported the occurrence of remnants in faeces which may resemble intact SIFROL prolonged-release tablets. If patients report such an observation, the physician should reassess patient’s response to therapy.

Insomnia, hallucinations, abnormal dreams, confusion behavioural symptoms of impulse control disorders and compulsions, somnolence, dizziness
dyskinesia, headache, visual impairment including diplopia, vision blurred, visual acuity reduced, hypotension, nausea, constipation, vomiting, fatigue, peripheral oedema, weight decrease including decreased appetite.
For full details see prescribing information.

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 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.
Antipsychotic medicinal products: Co-administration of antipsychotic medicinal products with pramipexole should be avoided, e.g. if antagonistic effects can be expected.

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. this product 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, this product 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.

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.

Storage: Store below 25°C in the original package in order to protect from moisture.