Sifrol ER

Pramipexole dihydrochloride monohydrate.

Pharmacotherapeutic group: Dopamine agonist. ATC code: N04BC05.
Pharmacology: Mode of Action: 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 D₃ 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. Pramipexole protects dopamine neurones from degeneration in response to ischemia or metamphetamine neurotoxicity.
In vitro studies demonstrate that pramipexole protects neurones from levodopa neurotoxicity.
Pharmacodynamics: In human volunteers a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where Sifrol extended-release tablets were titrated faster than recommended (every 3 days) up to 4.5 mg per day, an increase in blood pressure and heart rate was observed. Such effect was not observed in patient studies.
Clinical Trials: Parkinson's disease: 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.
The efficacy and tolerability of an overnight switch from Sifrol tablets to Sifrol extended-release tablets at the same daily dose was evaluated in a double-blind clinical study in patients with early Parkinson's disease.
Efficacy was maintained in 87 of 103 patients switched to Sifrol extended-release tablets. Out of these 87 patients, 82.8% did not change their dose, 13.8% increased and 3.4% decreased their dose.
In half of the 16 patients who did not meet the criterion for maintained efficacy on UPDRS Part II+III score, the change from baseline was considered not clinically relevant.
One patient switched to Sifrol extended-release tablets experienced a drug-related adverse event leading to withdrawal.
Pharmacokinetics: Absorption: Pramipexole is rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90%.
The maximum plasma concentrations occur at about 6 hours. Generally, food does not affect the bioavailability of pramipexole. A slight increase of about 20% in peak concentration and a delay of about 2 hours in time to reach peak concentration after a high fat meal are not considered clinically relevant.
Pramipexole shows linear kinetics and a relatively small inter-patient variation of plasma levels irrespective of the pharmaceutical form.
Distribution: In humans the protein binding of pramipexole is very low (<20%) and the volume of distribution is large (400L). 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 and accounts for about 80% of dose. Approx. 90% of a 14C-labelled dose is excreted through the kidneys while less than 2% is found in the feces. The total clearance of pramipexole is approx. 500 ml/min and the renal clearance is approx. 400 ml/min. The elimination half-life (t ½) varies from 8 hours in the young to 12 hours in the elderly. Age - Pramipexole clearance is reduced by approximately 30% in the elderly (aged 65 years or older) compared with young healthy volunteers (age less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.

Sifrol extended-release tablet is indicated in the treatment of signs and symptoms of advanced idiopathic Parkinson's disease. It may be used as monotherapy or in combination with levodopa.

(all dose information refers to pramipexole salt form)
Parkinson's disease: Dosage: Initial treatment: As shown as follows, dosages should be increased gradually from a starting-dose of 0.375 mg 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. (See Table 1.)

Click on icon to see table/diagram/image

If a further dose increase is necessary the daily dose should be increased by 0.75 mg at weekly intervals up to a maximum dose of 4.5 mg per day.
Patients already taking Sifrol tablets may be switched to Sifrol extended-release tablets overnight, at the same daily dose.
Maintenance treatment: The individual dose should be in the range of 0.375 mg to a maximum of 4.5 mg per day. During dose escalation in pivotal studies both, in early and advanced disease efficacy was observed starting at a daily dose of 1.5 mg. This does not preclude that in individual patients doses higher than 1.5 mg per day can result in additional therapeutic benefit.
This applies particularly to patients with advanced disease where a reduction of the levodopa therapy is intended.
Treatment discontinuation: SIFROL tablets and extended-release tablets should be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter the dose should be reduced by 0.375 mg per day. (See Precautions.)
Missed dose: When the intake of a dose is missed, Sifrol extended-release tablets should be taken up to 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.
Dosing in patients with concomitant levodopa therapy: In patients with concomitant levodopa therapy it is recommended that the dosage of levodopa is reduced during both dose escalation and maintenance treatment with Sifrol. This may be necessary in order to avoid excessive dopaminergic stimulation.
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 or dosing frequency.
In patients with a creatinine clearance between 30 and 50 ml/min, treatment should be started with 0.375 mg Sifrol 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, daily doses should be increased by 0.375 mg pramipexole at weekly intervals up to a maximum dose of 2.25 mg pramipexole per day.
No data are available for the treatment of patients with a creatinine clearance below 30 ml/min with Sifrol extended-release tablets. The use of Sifrol tablets should be considered.
If renal function declines during maintenance therapy the recommendations given previously should be followed.
Dosing in patients with hepatic impairment: Dose reduction is not considered necessary in patients with hepatic impairment.
Method of Administration: The extended-release tablets should be taken once daily at about the same time each day. The extended-release tablets should be swallowed whole with water, and must not be chewed, divided or crushed. The extended-release tablets may be taken with or without food.
Paediatric Use: The pharmacokinetics, safety and efficacy of Sifrol in paediatric patients have not been evaluated.

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, agitation and hypotension.
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.
Haemodialysis has not been shown to be helpful.

Hypersensitivity to pramipexole or any other component of the product.

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 Driving and using machines under Precautions and Adverse Reactions).

Hallucinations and abnormal behaviour: Hallucinations and confusion are known side-effects of treatment with dopamine agonists and levodopa in Parkinson's disease patients. Hallucinations were more frequent when Sifrol was given in combination with levodopa in Parkinson's disease patients with advanced disease than in monotherapy in Parkinson's disease patients with early disease. Within the RLS clinical development program for registration, one case of hallucinations has been reported. Patients should be informed that (mostly visual) hallucinations can occur.
Patients should be aware of the fact that hallucinations can occur and may adversely affect their ability to drive.
Patients and caregivers should be made aware of the fact that abnormal behaviour (reflecting symptoms of impulse control disorders and compulsive behaviours) such as binge eating, compulsive shopping, hypersexuality and pathological gambling, have been reported in patients treated with dopaminergic drugs. Dose reduction/tapered discontinuation should be considered.
Patients with psychotic disorders: Patients with psychotic disorders should be treated with dopamine agonists only if the potential benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole is not recommended, e.g. if dopamine-antagonistic effects can be expected.
Retinal changes in albino rats: Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-years carcinogenicity study. Evaluation of the retinas of albino mice, pigmented rats, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (ie. disk shedding) may be involved.
Postural hypotension: 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.
Dystonia: Patients with Parkinson's disease may present with axial dystonia such as antecollis, camptocormia or pleurothotonus (Pisa Syndrome). Dystonia has occasionally been reported following initiation of dopamine agonists including pramipexole, although a clear causal relationship has not been established. Dystonia may also occur several months following medication initiation or adjustment. If dystonia occurs, the dopaminergic medication regimen should be reviewed and an adjustment considered.
Sudden onset of sleep and somnolence: Patients should be alerted to the potential sedating effects associated with Sifrol, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor operate other complex machinery until they have gained sufficient experience with Sifrol to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities and should contact their physician.
Melanoma: Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
For the reasons stated previously, patients and providers are advised to monitor for melanoma when using pramipexole or other dopaminergic drugs.
Treatment Discontinuation in Parkinson's disease: Symptoms suggestive of a neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy. (See Dosage & Administration).
Dopamine agonist withdrawal syndrome (DAWS): DAWS has been reported with dopamine agonists, including pramipexole (see Adverse Reactions). To discontinue treatment with patients with Parkinson's disease, pramipexole should be tapered off (see Dosage & Administration). Limited data suggests that patients with impulse control disorders and those receiving high daily dose and/or high cumulative doses of dopamine agonists may be at higher risk for developing DAWS. Withdrawal symptoms may include apathy, anxiety, depression, fatigue, sweating and pain and do not respond to levodopa. Prior to tapering off and discontinuing pramipexole, patients should be informed about potential withdrawal symptoms. Patients should be closely monitored during tapering and discontinuation. In case of severe and/or persistent withdrawal symptoms, temporary readministration of pramipexole at the lowest effective dose may be considered.
Remnants in stool: Some patients have reported the occurrence of remnants in faeces which may resemble intact Sifrol extended-release tablets. If patients report such an observation, the physician should reassess patient's response to therapy.
Rhabdomyolysis: In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.
Ophthalmologic monitoring: Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occurs.
Renal impairment: When prescribing Sifrol in a patient with renal impairment a reduced dose is suggested in line with section Dosage & Administration.
Driving and using machines: Patients should be aware of the fact that hallucinations can occur and may adversely affect their ability to drive.
Patients should be alerted to the potential sedating effects associated with Sifrol, including somnolence and the possibility of falling asleep while engaged in activities of daily living. (See Precautions).

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.
Sifrol should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Lactation: 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. As Sifrol treatment inhibits secretion of prolactin in humans inhibition of lactation is expected. In consequence, Sifrol should not be used during breast-feeding.
Fertility: No studies on the effect on human fertility have been conducted. Animal studies did not indicate direct or indirect harmful effects with respect to male fertility.

Tabulated summary of adverse reactions: The following adverse reactions have been reported during use of Sifrol in the clinical trials and in the post-marketing experience.

Click on icon to see table/diagram/image

Description of selected adverse reactions: Sudden onset of sleep and somnolence: Patients treated with pramipexole 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, 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.
Hypotension: 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 rapidly.
Libido disorders: Sifrol may be associated with disorders of libido (increase or decrease).
Dopamine agonist withdrawal syndrome: Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including pramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain (see Precautions).
Cardiac failure: In clinical studies and post-marketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole. A causal relationship between pramipexole and cardiac failure has not been demonstrated.

Pramipexole is bound to plasma proteins to a very low (<20%) extent and little biotransformation is seen in man. Therefore, interactions with other medications affecting plasma protein binding or elimination by biotransformation are unlikely.
Medication that inhibit the active renal tubular secretion of basic (cationic) drugs, such as cimetidine, or are themselves eliminated by active renal tubular secretion, may interact with Sifrol resulting in reduced clearance of either or both medication. In case of concomitant treatment with these kind of drugs (including amantadine) attention should be paid to signs of dopamine overstimulation, such as dyskinesias, agitation or hallucinations. In such cases a dose reduction is necessary.
Selegeline and levodopa do not influence the pharmacokinetics of pramipexole. The overall extent of absorption or elimination of levodopa is not changed by pramipexole. The interaction with anticholinergics and amantadine has not been examined. As anticholinergics are mainly eliminated by hepatic metabolism, pharmacokinetic drug-drug interactions with pramipexole are rather unlikely. With amantadine, an interaction is possible via the same system of excretion in the kidney.
Antipsychotic medicinal products: Co-administration of antipsychotic medicinal products with pramipexole is not recommended, e.g. if dopamine-antagonistic effects can be expected. (See Precautions.)
While increasing the dose of Sifrol in Parkinson's disease patients it is recommended that the dosage of levodopa is reduced and the dosage of other anti-parkinsonian medication kept constant.
Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with Sifrol and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine).

Instructions for use/handling: N/A.

Store below 30°C.

Antiparkinsonian Drugs

N04BC05 - pramipexole ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.

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