Sifrol

/ Boehringer Ingelheim

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 0.375 mg salt (0.264 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 Pramipexol:
Week 1: 3 x 0.125 (mg of salt) = 3 x 0.0088 (mg of base).
Week 2: 3 x 0.25 (mg of salt) = 3 x 0.18 (mg of base).
Week 3: 3 x 0.5 (mg of salt) = 3 x 0.35 (mg of base).
See prescribing information for full details.
If a further dose increase is necessary the daily dose should be increased by 0.75 mg of salt (0.54 mg base) at weekly intervals up to a maximum dose of 4.5 mg of salt (3.3 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) per day.
Maintenance treatment : The individual dose of pramipexole should be in the range of 0.375 mg salt (0.264 mg base) to a maximum of 4.5 mg salt (3.3 mg base) per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.5 mg salt (1.1 mg 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 salt (1.1 mg base). In advanced Parkinson’s disease, pramipexole doses higher than 1.5 mg salt (1.1 mg 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.
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 salt (0.54 mg base) per day until the daily dose has been reduced to 0.75 mg salt (0.54 mg base). Thereafter the dose should be reduced by 0.375 mg salt (0.264 mg base) per day.
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 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 should be administered in two divided doses, starting at 0.125 mg salt (0.088 mg base) twice a day (0.25 mg salt/0.176 mg base daily). A maximum daily dose of 2.25 mg salt (1.57 mg base) should not be exceeded. In patients with a creatinine clearance less than 20 ml/min, the daily dose of Pramipexole should be administered in a single dose, starting at 0.125 mg salt (0.088 mg base) daily. A maximum daily dose of 1.5 mg salt (1.1 mg base) 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 50 ml/min and as a single daily dose if creatinine clearance is less than 20 ml/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. There is no relevant use of Pramipexole in the paediatric population in Parkinson’s Disease.
Restless Legs Syndrome: The recommended starting dose of Pramipexole is 0.125 mg salt (0.088 mg base) 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 0.75 mg salt (0.54 mg base) per day (as shown below).
Dose Schedule of Pramipexol:  1^st Titration step: 0.125 Once Daily Evening Dose (mg of salt) = 0.088 Once Daily Evening Dose (mg of base).
2^nd* Titration step: 0.25 Once Daily Evening Dose (mg of salt) = 0.18 Once Daily Evening Dose (mg of base).
3^rd* Titration step: 0.5 Once Daily Evening Dose (mg of salt) = 0.35 Once Daily Evening Dose (mg of base).
4^th* Titration step: 0.75 Once Daily Evening Dose (mg of salt) = 0.54 Once Daily Evening Dose (mg of base). * 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. Treatment discontinuation: Since the daily dose for the treatment of Restless Legs Syndrome will not exceed 0.75 mg salt (0.54 mg base) Pramipexole can be discontinued without tapering off. In a 26 week placebo controlled trial, rebound of RLS symptoms (worsening of symptom severity as compared to baseline) was observed in 10% of patients (14 out of 135) after abrupt discontinuation of treatment. This effect was found to be similar across all doses.
Renal impairment: The elimination of pramipexole is dependent on renal function. Patients with a creatinine clearance above 20 ml/min require no reduction in daily dose. The use of Pramipexole has not been studied in haemodialysis patients, or in patients with severe renal impairment.
Hepatic impairment: Dose adjustment in patients with hepatic failure is not required, as approx. 90% of absorbed active substance is excreted through the kidneys.
Paediatric population: Pramipexole is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.
Tourette Disorder:
Paediatric population: Pramipexole is not recommended for use in children and adolescents below 18 years since the efficacy and safety has not been established in this population. Pramipexole should not be used in children or adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder.
Method of administration: The tablets should be taken orally, swallowed with water, and can be taken either with or without food.

Pramipexol 0.25 mg and 1 mg are indicated for the treatment of signs and symptoms of idiopathic Parkinson’s disease, as monotherapy or in combination with levodopa.
Pramipexol 0.25 mg is also indicated for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome.

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.
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.
Augmentation: Reports in the literature indicate that treatment of Restless Legs Syndrome with dopaminergic medicinal products can result in augmentation. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks. Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no significant difference between pramipexole and placebo groups.

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.
See prescribing information for full details.   

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 this product.
Combination with levodopa: When 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. 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.
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 in the original package below 25°C, protected from light.