SIFROL â. Contraindications Hypersensitivity to pramipexole or any other component of the product.

Transcription

1 SIFROL â Composition 1 tablet contains 0.088, 0.18 & 0.7 mg (S) 2 amino 4,5,6,7-tetrahydro-6-propylamino-benzothiazole (= pramipexole base) equivalent to 0.125, 0.25 & 1 mg of pramipexole dihydrochloride monohydrate respectively. Properties Pramipexole, the active ingredient of SIFROL, is a dopamine agonist and binds with high selectivity and specificity to the dopamine D2 subfamily receptors and has a preferential affinity to D 3 receptors; it has full intrinsic activity. SIFROL 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 vitro studies demonstrate that pramipexole protects neurons from levodopa neurotoxicity. In human volunteers a dose-dependent decrease in prolactin was observed. In patients SIFROL alleviates signs and symptoms of idiopathic Parkinson s disease. Controlled clinical trials included approximately 1500 patients of Hoehn and Yahr stages I IV. Out of these, approximately 900 were in more advances stages, received concomitant levodopa therapy, and suffered from motor complications. Efficacy of SIFROL in the controlled clinical trials was maintained for the duration of the trials, approximately six months. In open continuation trials lasting for more than three years there were no signs of decreasing efficacy. Indication SIFROL â tablets are indicated for treatment of the signs and symptoms of advanced idiopathic Parkinson s disease in combination with levodopa i.e. over the course of the disease, when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or on off fluctuations). Contraindications Hypersensitivity to pramipexole or any other component of the product. Side Effects Undesirable Effects The following adverse events have been reported more frequently during the use of SIFROL than under placebo: nausea, constipation, somnolence, hallucinations and insomnia. The incidence of somnolence is increased at doses higher than 1.5 mg/day (salt) (see section Posology and

2 method of administration). More frequent adverse reactions in early disease were somnolence and constipation and in advanced disease, in combination with levodopa treatment, dyskinesias and hallucinations. These adverse events decreased with continued therapy; constipation, nausea and dyskinesia tended to disappear. The incidence of hypotension under SIFROL, compared to placebo treatment, was not increased. However, in individual patients, hypotension may occur at the beginning of treatment, especially if SIFROL is titrated too fast. Insomnia and peripheral oedema have been reported. Patients treated with pramipexole tablets have reported falling asleep during activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Some of them did not report a warning sign such as somnolence, which is a common occurrence in patients receiving pramipexole tablets at doses above 1.5 mg (salt)/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. Overdose Symptoms There is no clinical experience with massive overdose. The expected adverse events should be those related to the pharmacodynamic profile of a dopamine agonist including nausea, vomiting, hyperkinesia, hallucinations, agitations and hypotensions. Therapy 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, and electrocardiogram monitoring. Special Warnings and Precautions When prescribing SIFROL tablets in a patient with renal impairment a reduced dose is suggested in line with section 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. Dyskinesias can occur during the initial titration of SIFROL. The incidence of initial dyskinesia may be higher in women. If they occur, the dose of levodopa should be decreased.

3 Sudden onset of sleep during daily activities has been reported in rare cases. This can be life threatening to the patient or others depending on the circumstances. These episodes have been reported in some cases without awareness of warning signs. If this occurs, reduction of dosage or termination of therapy should be considered. Patients being treated with pramipexole must be informed not to drive or engage in other activities where impaired alertness could put themselves or others at risk of serious injury or death (e.g. operating machines). Because of possible additive effects, caution should be advised when patients are taking other sedating medication or alcohol in combination with pramipexole (see Effects on Ability to Drive and Operate Machines and Undesirable Effects). Patients with psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks. 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 a neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy (see Posology and Method of Administration : Treatment Discontinuation). Pregnancy and Lactation 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. SIFROL should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. As SIFROL treatment inhibits secretion of prolactine in humans inhibition of lactation is expected. The excretion of SIFROL into the breast milk has not been studied in women. In rats, the concentration of drug was higher in the breast milk than in plasma. However, if its use is unavoidable, breast-feeding should be discontinued. Effects on ability to drive and use machine Hallucinations or somnolence can occur.

4 Rare cases of sudden onset of sleep have also been reported (see Special Warnings and Precautions for Use and Undesirable Effects). These episodes can be life threatening depending on the circumstances and have been reported in some cases without awareness of warning signs. Patients being treated with pramipexole must be informed not to drive or engaged in other activities where impaired alertness could put themselves or others at risk of serious injury or death (e.g. operating machines). (See Interaciton with other medicinal products and other forms of interaction). Drug Interactions Pramipexole is bound to plasma proteins to a very low (<20%) extent and little biotransformation is seen in man. Therefore, interactions with other medication 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. Selegiline and levodopa do not influence the pharmacokinetics of pramipexole. In a small pharmacokinetic study (n=9) the overall extent of absorption or elimination of levodopa was not changed by concomitant administration of pramipexole. Levodopa absorption rate was increased in 4 of 9 healthy volunteers, all of whom were female. Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by inhibition of the cationic secretory transport system of the renal tubules. Therefore, medications that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, may interact with pramipexole resulting in reduced clearance of either or both drugs. Drugs included in this category are Cimetidine, Diltiazem, Quinidine, Quinine, Ranitidine, Triamterene, Verapamil, Digoxin, Procainamide and Trimethoprim. Amantadine is also eliminated by this renal pathway. Reduction of the pramipexole dose should be considered when these drugs are administered concomitantly with SIFROL. While increasing the dose of SIFROL it is recommended that the dosage of levodopa is reduced and the dosage of other antiparkinsonian medication kept constant. Because of possible additive effects, caution should be advised when patients are taking other sedating medication or alcohol in combination with pramipexole. Dosage and Administration The tablets should be taken orally, swallowed with water, and can be taken either with or without food. The daily dosage is administered in equally divided doses 3x per day. Initial treatment: Dosages should be increased gradually from a starting-dose of mg of base (0.375 mg of salt) per day and then increased every 5-7 days. Providing patients do not experience intolerable side effects, the dosage should be titrated to achieve a maximal therapeutic effect.

5 Ascending-Dose Schedule of SIFROL Week Dosage (mg of base) Total Daily Dose (mg of base) Dosage (mg of salt) Total Daily Dose (mg of salt) 1 3x x x x x x If a further dose increase is necessary, the daily dose should be increased by 0.54 mg base (0.75 mg salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) per day. However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg/day (salt) (see Undesirable Effects). Maintenance treatment: The individual dose should be in the range of mg of base (0.375 mg of salt) to a maximum of 3.3 mg of base (4.5 mg of salt) per day. During dose escalation in three pivotal studies, efficacy was observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). Further dose adjustment should be done based on the clinical response and tolerability. In clinical trials approximately 5% of patients were treated at doses below 1.1 mg (1.5 mg of salt). Doses higher than 1.1 mg (1.5 mg of salt) per day can be useful in patients where reduction of the levodopa therapy is intended. It is recommended that the dosage of levodopa is reduced during both the dose escalation and the maintenance treatment with SIFROL, dependent on reactions in individual patients. Treatment discontinuation: Abrupt discontinuation dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Therefore pramipexole should be tapered off at a rate of 0.54 mg of base (0.75 mg of salt) per day until the daily dose has been reduced to 0.54 mg of base (0.75 mg of salt). Thereafter the dose should be reduced mg of base (0.375 mg of salt) per day (see Special Warnings and Precautions for use). For potential pharmacokinetic interaction with levodopa, which may be different in men and women. (see Interactions). Dosing in 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 50 ml/min require no reduction in daily dose. In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of SIFROL should be administered in two divided doses, starting at mg of base (0.125 mg of

6 salt) twice a day (0.176 mg of base/0.25 mg of salt daily). In patients with a creatinine clearance less than 20 ml/min, the daily dose of SIFROL should be administered in a single dose, starting at mg of base (0.125 mg of salt daily). If renal function declines during maintenance therapy reduce SIFROL daily dose by the same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then reduce SIFROL daily dose 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. Dosing in patients with hepatic impairment: Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed drug is excreted through the kidneys. However, the potential influence of hepatic insufficiency on SIFROL pharmacokinetics has not been investigated. Availability Tablets mg Box contains 3 strips of 10 tablets Reg. No. Tablets 0.25 mg Box contains 3 strips of 10 tablets Reg. No. Tablets 1 mg Box contains 3 strips of 10 tablets Reg. No. Store in a safe place out of the reach of children! Sensitive to light. Store below 30 C Only on doctor s prescription. Harus dengan resep dokter Manufactured by Boehringer Ingelheim Pharma KG Ingelheim am Rhein Germany Imported by: PT Boehringer Ingelheim Indonesia Bogor, Indonesia