Sifrol

Pramipexole diHCl.

1 tablet contains 0.125, 0.25 mg (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole dihydrochloride monohydrate equivalent to 0.088, 0.18, 0.35 mg pramipexole base.
Excipients/Inactive Ingredients: mannitol, maize starch, anhydrous colloidal silica, polyvidone, magnesium stearate.

Pharmacotherapeutic group: dopamine agonist. ATC code: N04BC05
Pharmacology: Pramipexole dihydrochloride monohydrate, 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 dihydrochloride monohydrate inhibits dopamine synthesis, release, and turnover. Pramipexole dihydrochloride monohydrate protects dopamine neurones from degeneration in response to ischemia or methamphetamine neurotoxicity.
The precise mechanism of action of SIFROL as a treatment for Restless Legs Syndrome is not known. Although the pathophysiology of Restless Legs Syndrome is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of Restless Legs Syndrome.
In vitro studies demonstrate that pramipexole dihydrochloride monohydrate protects neurones from levodopa neurotoxicity.
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.
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 prolonged-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 prolonged-release tablets experienced a drug-related adverse event leading to withdrawal.
Restless Legs Syndrome: The efficacy of SIFROL was evaluated in four placebo controlled trials in approximately 1000 patients with moderate to very severe Restless Legs Syndrome. Efficacy was demonstrated in controlled trials in patients treated for up to 12 weeks and sustained efficacy was shown over a period of 9 months.
The efficacy of SIFROL was maintained during open continuation trials lasting for up to 1 year. In a placebo controlled clinical trial over 26 weeks, the efficacy of pramipexole dihydrochloride monohydrate was confirmed in patients with moderate to severe RLS.
Pharmacokinetics: Pramipexole dihydrochloride monohydrate is rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90 %.
Tablets: The maximum plasma concentrations occur between 1 and 3 hours. The rate of absorption is reduced by food intake but not the overall extent of absorption.
Pramipexole dihydrochloride monohydrate shows linear kinetics and a relatively small inter-patient variation of plasma levels irrespective of the pharmaceutical form.
In humans the protein binding of pramipexole dihydrochloride monohydrate 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).
Pramipexole dihydrochloride monohydrate is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole dihydrochloride monohydrate 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 faeces. The total clearance of pramipexole dihydrochloride monohydrate 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.
Toxicology: Repeated dose toxicity studies showed that pramipexole dihydrochloride monohydrate exerted functional effects, mainly involving the CNS and, in the rat, the female reproductive system, probably resulting from an exaggerated pharmacodynamic effect of pramipexole dihydrochloride monohydrate.
Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to a hypotensive effect was discerned in the monkey.
The potential effects of pramipexole dihydrochloride monohydrate on reproductive function have been investigated in rats and rabbits. Pramipexole dihydrochloride monohydrate was not teratogenic in rats and rabbits but was embryotoxic in the rat at maternally toxic doses. Due to the hypoprolactinaemic effect of the compound and the special role of prolactin in reproductive function in the female rat, the effects of pramipexole dihydrochloride monohydrate on pregnancy and female fertility were not fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats. The relevance for humans is unknown.
Pramipexole dihydrochloride monohydrate was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole dihydrochloride monohydrate. This finding is not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of the salt form) and higher, pramipexole dihydrochloride monohydrate was associated with retinal degeneration in albino rats. The latter finding was not observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study, or in any other species investigated.

SIFROL tablets and Extended-release tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose "on off" fluctuations). It may be used alone (without levodopa) or in combination with levodopa.
SIFROL tablets are indicated for the symptomatic treatment of idiopathic Restless Legs Syndrome.

Parkinson's Disease: Tablets: 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: As shown below 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).


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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 prolonged-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.
Further dose adjustments 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). In advanced Parkinson's disease, doses higher than 1.1 mg (1.5 mg of salt) per day can be useful in patients where a 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, depending on reactions in individual patients.
Treatment discontinuation: Abrupt discontinuation of dopaminergic therapy can lead to development of aneuroleptic malignant syndrome. Therefore, pramipexole dihydrochloride monohydrate should be tapered off at 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).
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 dihydrochloride monohydrate 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.
Tablets: In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of SIFROL tablets should be administered in two divided doses, starting at 0.125 mg twice a day (0.25 mg daily). A maximum daily dose of 2.25 mg pramipexole dihydrochloride monohydrate should not be exceeded.
In patients with a creatinine clearance less than 20 ml/min, the daily dose of SIFROL tablets should be administered in a single dose, starting at 0.125 mg daily. A maximum daily dose of 1.5 mg pramipexole dihydrochloride monohydrate should not be exceeded.
If renal function declines during maintenance therapy reduce SIFROL daily dose by same percentage as 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 of SIFROL pharmacokinetics has not been investigated.
Restless Legs Syndrome: The tablets should be taken orally, swallowed with water, and can be taken either with or without food.
The recommended starting dose of SIFROL is 0.125 mg 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 per day (as shown in the table as follows, see Table 2).


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As long-term efficacy of SIFROL in the treatment of RLS has not been sufficiently tested, 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: SIFROL can be discontinued without tapered dose reduction. In a 26 week placebo controlled clinical 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 pramipexole dihydrochloride monohydrate. This effect was found to be similar across all doses.
Dosing in patients with renal impairment: The elimination of SIFROL is dependent on renal function and closely related to the creatinine clearance. Based on a pharmacokinetic study in renally impaired subjects, patients with creatinine clearance above 20 ml/min require no reduction in daily dose. The use of SIFROL in RLS patients with renal impairment has not been studied.
Dosing in patients with hepatic impairment: Dose reduction is not considered necessary in patients with hepatic impairment, as approx. 90% of absorbed drug is excreted through the kidneys.
Dosing in children and adolescents: Safety and efficacy of SIFROL have not been established in children and adolescents up to 18 years.

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.
Treatment: 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 dihydrochloride monohydrate or any other component of the product.

Renal impairment: When prescribing SIFROL in a patient with renal impairment a reduced dose is suggested in line with section Dosage & Administration.
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 made aware of the fact that hallucinations can occur and may adversely affect their ability to drive.
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 dihydrochloride monohydrate is not recommended, e.g. if dopamine-antagonistic effects can be expected.
Patients and caregivers should be made aware of the fact that abnormal behavior (reflecting symptoms of impulse control disorders and compulsive behaviors) 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.
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 (i.e. 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.
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 above, patients and providers are advised to monitor for melanoma when using pramipexole dihydrochloride monohydrate 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). Augmentation in RLS: Reports in the literature that indicate treatment of RLS with dopaminergic medications 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. Kaplan-Meier analysis of time to augmentation showed no significant difference between pramipexole dihydrochloride monohydrate (N = 152) and placebo groups (N = 149).
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.
Effects on Ability to Drive and Use 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).
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.

Pregnancy: The effect on pregnancy and lactation has not been investigated in humans. Pramipexole dihydrochloride monohydrate 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.

Infections and infestations: Pneumonia.
Endocrine disorders: Inappropriate antidiuretic hormone secretion.
Psychiatric disorders: Abnormal behavior (reflecting symptoms of impulse control disorders and compulsions) such as binge eating, compulsive shopping, hyper sexuality and pathological gambling. Abnormal dreams. Confusion. Delusion. Hallucinations. Hyperphagia. Insomnia. Libido disorders. Paranoia. Restlessness.
Nervous system disorders: Amnesia. Dizziness. Dyskinesia. Headache. Hyperkinesia. Somnolence. Sudden onset of sleep. Syncope.
Eye disorders: Visual impairment including diplopia, vision blurred and visual acuity reduced.
Cardiac disorders: Cardiac failure.
Vascular disorders: Hypotension.
Respiratory, thoracic and mediastinal disorders: Dyspnoea. Hiccups. Gastrointestinal disorders: Constipation. Nausea. Vomiting.
Skin and subcutaneous tissue disorders: Hypersensitivity. Pruritus. Rash.
General disorders and administration site conditions: Fatigue. Peripheral oedema.
Investigations: Weight decrease including decreased appetite. Weight increase.
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.
SIFROL may be associated with disorders of libido (increase or decrease).
Patients treated with pramipexole dihydrochloride monohydrate 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 dihydrochloride monohydrate tablets at doses above 1.5 mg/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.
Patients treated with dopamine agonists for Parkinson's disease, including SIFROL, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.
In clinical studies and post-marketing experience cardiac failure has been reported in patients with pramipexole dihydrochloride monohydrate. In a pharmacoepidemiological study pramipexole dihydrochloride monohydrate use was associated with an increased risk of cardiac failure compared with non-use of pramipexole dihydrochloride monohydrate. A causal relationship between pramipexole dihydrochloride monohydrate and cardiac failure has not been demonstrated.

Pramipexole dihydrochloride monohydrate 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.
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 kinds of drugs (incl. amantadine) attention should be paid to signs of dopamine over stimulation, such as dyskinesias, agitation or hallucinations. In such cases a dose reduction is necessary.
Selegiline and levodopa do not influence the pharmacokinetics of pramipexole dihydrochloride monohydrate. The overall extent of absorption or elimination of levodopa is not changed by pramipexole dihydrochloride monohydrate. The interaction with anticholinergics and amantadine has not been examined.
As anticholinergics are mainly eliminated by hepatic metabolism, pharmacokinetic drug-drug interactions with pramipexole dihydrochloride monohydrate are rather unlikely. With amantadine, an interaction is possible via the same system of excretion in the kidney.
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 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 SIFROL and when taking concomitant medication that increase plasma levels of pramipexole dihydrochloride monohydrate (e.g. cimetidine).
Antipsychotic medicinal products: Co-administration of antipsychotic medicinal products with pramipexole dihydrochloride monohydrate should be avoided, e.g. if dopamine-antagonistic effects can be expected. (see Precautions).

Sensitive to light. Store below 30°C. Store in the original package.
Store in a safe place out of the reach of children.

Antiparkinsonian Drugs

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

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