Sifrol

Sifrol

pramipexole

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Boehringer Ingelheim
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Contents
Pramipexole dihydrochloride monohydrate.
Description
One tablet contains 0.25 mg of pramipexole dihydrochloride monohydrate (as 0.18 mg of pramipexole base).
Each prolonged-release tablet contains pramipexole dihydrochloride monohydrate 0.75 or 0.375 mg equivalent to pramipexole base 0.52 or 0.26 mg, respectively.
All tablets can be divided into equal halves.
Excipients/Inactive Ingredients: Immediate-Release Tablet: mannitol, maize starch, anhydrous colloidal silica, polyvidone, magnesium stearate. Prolonged-Release Tablet: hypromellose 2208, maize starch, carbomer 941, anhydrous colloidal silica and magnesium stearate.
Action
Pharmacotherapeutic Group: dopamine agonist. ATC Code: N04BC05.
Pharmacology: Pharmacodynamics: Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic activity.
Pramipexole alleviates Parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release and turnover.
The mechanism of action of pramipexole as treatment for Restless Legs Syndrome is unknown. Neuropharmacological evidence suggests primary dopaminergic system involvement.
In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where SIFROL prolong-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 for Sifrol Immediate-Release Tablet in Parkinson's Disease: In patients, SIFROL alleviates signs and symptoms of idiopathic Parkinson's disease.
Controlled clinical trials included approximately 2100 patients of Hoehn and Yahr stages I-IV. Out of these, approximately 900 were in more advanced stages, received concomitant levodopa therapy and suffered from motor complications.
In early and advanced Parkinson's disease, efficacy of SIFROL in the controlled clinical trials was maintained for approximately six months. In open continuation trials lasting for more than three years there were no signs of decreasing efficacy. In a controlled, double blind clinical trial of 2 year duration, initial treatment with pramipexole significantly delayed the onset of motor complications, and reduced their occurrence compared to initial treatment with levodopa. This delay in motor complications with pramipexole should be balanced against a greater improvement in motor function with levodopa (as measured by the mean change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally higher in the escalation phase with the pramipexole group. However, there was no significant difference during maintenance phase. These points should be considered when initiating pramipexole treatment in patients with Parkinson's disease.
Clinical Trials for Sifrol Immediate-Release Tablet in Restless Leg Syndrome: The efficacy of Sifrol was evaluated in 4 placebo-controlled trials in approximately 1000 patients with moderate to very severe idiopathic Restless Legs Syndrome. Efficacy was demonstrated in controlled trials in patients treated for up to 12 weeks. Maintenance of effect has not been sufficiently tested.
In a placebo controlled clinical trial over 26 weeks, the efficacy of pramipexole was confirmed in patients with moderate to severe RLS.
The mean change from baseline in the Restless Legs Syndrome rating scale (IRLS) and the Clinical Global Impression-Improvement (CGI-I) were the primary efficacy outcome measures. For both primary endpoints, statistically significant differences have been observed for the pramipexole dose groups 0.25 mg, 0.5 mg and 0.75 mg in comparison to placebo. After 12 weeks of treatment, the baseline IRLS score improved from 23.5 to 14.1 points for placebo and from 23.4 to 9.4 points for pramipexole (doses combined). The adjusted mean difference was -4.3 points (CI 95%: -6.4; -2.1 points, p-value <0.0001). CGI-I responder rates (improved, very much improved) were 51.2% and 72% for placebo and pramipexole, respectively (difference 20% CI 95%: 8.1%; 31.8%, p<0.0005).
Efficacy was observed with 0.088 mg of base (0.125 mg of salt) per day after the first week of treatment.
In a placebo-controlled polysomnography study over 3 weeks, SIFROL significantly reduced the number of periodic limb movements during time in bed.
Clinical Studies for Sifrol Prolonged-Release Tablet: In patients, pramipexole alleviates signs and symptoms of idiopathic Parkinson's disease. Placebo-controlled clinical trials included approximately 1800 patients of Hoehn and Yahr stages I-V treated with pramipexole. Out of these, approximately 1000 were in more advanced stages, received concomitant levodopa therapy and suffered from motor complications.
In early and advanced Parkinson's disease, efficacy of pramipexole in the controlled clinical trials was maintained for approximately 6 months. In open continuation trials lasting for >3 years, there were no signs of decreasing efficacy. In a controlled double-blind clinical trial of 2-year duration, initial treatment with pramipexole significantly delayed the onset of motor complications and reduced their occurrence compared to initial treatment with levodopa. This delay in motor complications with pramipexole should be balanced against a greater improvement in motor function with levodopa (as measured by the mean change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally higher in the escalation phase with the pramipexole group. However there was no significant difference during the maintenance phase. These points should be considered when initiating pramipexole treatment in patients with Parkinson's disease.
The safety and efficacy of Sifrol prolonged-release tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of 3 randomised, controlled trials. Two trials were conducted in patients with early Parkinson's disease and 1 trial was conducted in patients with advanced Parkinson's disease.
Superiority of Sifrol prolonged-release tablets over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS parts II+III score) and the key secondary (CGI-I and PGI-I responder rates) efficacy endpoints in a double-blind, placebo-controlled trial including a total of 539 patients with early Parkinson's disease. Maintenance of efficacy was shown in patients treated for 33 weeks. Sifrol prolonged-release tablets were non-inferior to pramipexole immediate release tablets as assessed on the UPDRS parts II+III score at week 33.
In a double-blind placebo-controlled trial including a total of 517 patients with advanced Parkinson's disease who were on concomitant levodopa therapy, superiority of Sifrol prolonged-release tablets over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS parts II+III score) and the key secondary (off-time) efficacy endpoints.
The efficacy and tolerability of an overnight switch from Sifrol tablets to Sifrol prolonged-release tablets at the same daily dose were 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 ½ 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. Only 1 patient switched to Sifrol prolonged-release tablets experienced a drug-related adverse event leading to withdrawal.
Pharmacokinetics: Sifrol Immediate-Release Tablet: Pramipexole is rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3 hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels.
In humans, the protein binding of pramipexole is very low (<20%) and the volume of distribution is large (400 L). High brain tissue concentrations were observed in the rat (approx. 8-fold compared to plasma).
Pramipexole is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of 14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
Sifrol Prolonged-Release Tablet: Pramipexole is completely absorbed following oral administration. The absolute bioavailability is greater than 90%.
In a Phase I trial, where pramipexole immediate-release and prolonged-release tablets were assessed in fasted state, the minimum and peak plasma concentration (Cmin, Cmax) and exposure (AUC) of the same daily dose of Sifrol prolonged-release tablets given once daily and Sifrol tablets given 3 times daily were equivalent.
The once-daily administration of Sifrol prolonged-release tablets causes less frequent fluctuations in the pramipexole plasma concentration over 24 hrs compared to the 3 times daily administration of pramipexole immediate-release tablets.
The maximum plasma concentrations occur at about 6 hrs after administration of Sifrol prolonged-release tablets once daily. Steady state of exposure is reached at the latest after 5 days of continuous dosing.
Concomitant administration with food generally does not affect the bioavailability of pramipexole. Intake of a high-fat meal induced an increase in peak concentration (Cmax) of about 24% after a single dose administration and about 20% after multiple dose administrations and a delay of about 2 hrs in time to reach peak concentration in healthy volunteers.
Total exposure (AUC) was not affected by concomitant food intake. The increase in Cmax is not considered clinically relevant. In the phase III studies that established safety and efficacy of Sifrol prolonged-release tablets, patients were instructed to take study medication without regard to food intake.
While body weight has no impact on the AUC, it was found to influence the volume of distribution and therefore, the peak concentrations, Cmax. A decreased body weight by 30 kg results in an increase in Cmax of 45%. However, in phase III trials in Parkinson's disease patients, no clinically meaningful influence of body weight on the therapeutic effect and tolerability of Sifrol prolonged-release tablets was detected.
Pramipexole shows linear kinetics and a small interpatient variation of plasma levels. In humans, the protein-binding of pramipexole is very low (<20%) and the volume of distribution is large (400 L). High brain tissue concentrations were observed in the rat (approximately 8-fold compared to plasma).
Pramipexole is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of 14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
Indications/Uses
SIFROL is indicated for treatment of signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or "on off" fluctuations).
SIFROL is indicated for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome in dosages up to 0.75 mg of salt (see Dosage & Administration).
Dosage/Direction for Use
Parkinson's Disease: Sifrol Immediate-Release Tablet: 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 3 times a day.
Sifrol Prolonged-Release Tablet: SIFROL prolonged-release tablets are a once-a-day oral formulation of pramipexole. 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.
When the intake of a dose is missed, SIFROL prolonged-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.  
Initial treatment: Dosages should be increased gradually from a starting-dose of 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. (See Table 1.)


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If a further dose increase is necessary the daily dose should be increased by 0.75 mg salt at weekly intervals up to a maximum dose of 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 (see Adverse Reactions).
Sifrol Prolonged-Release Tablet: Patients already taking Sifrol tablet may be switched to Sifrol prolonged-release tablets overnight, at the same daily dose. After switching to Sifrol prolonged-release tablets, the dose may be adjusted depending on the patient's therapeutic response (see Pharmacology under Actions).  
Maintenance treatment: The individual dose of pramipexole should be in the range of 0.375 mg of salt to a maximum of 4.5 mg of salt per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.5 mg of salt. Further dose adjustments should be done based on the clinical response and the occurrence of undesirable effects. In clinical trials, approximately 5% of patients were treated at doses below 1.5 mg of salt. In advanced Parkinson's disease, doses higher than 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 dose 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 the development of a neuroleptic malignant syndrome. Therefore, pramipexole should be tapered off at a rate of 0.75 mg of salt per day until the daily dose has been reduced to 0.75 mg of salt. Thereafter, the dose should be reduced by 0.375 mg of salt per day (see Precautions).
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.
Sifrol Immediate-Release Tablet: 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 0.125 mg of salt twice a day (0.25 mg of salt daily). A maximum daily dose of 2.25 mg of salt should not be exceeded.
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 0.125 mg of salt daily. A maximum daily dose of dose of 1.5 mg of salt should not be exceeded.
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 the 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.
Prolonged-Release Tablet: CrCl between 30 and 50 mL/min: Treatment should be started with 0.375 mg of salt every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after 1 week. If a further dose increase is necessary, doses should be increased by pramipexole salt 0.375 mg at weekly intervals up to a maximum dose of pramipexole 2.25 mg of salt per day.
The treatment of patients with a creatinine clearance below 30 mL/min with SIFROL prolonged-release tablets is not recommended as no data are available for this patient population. 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 adjustment in patients with hepatic failure is probably not necessary, as approximately 90% of absorbed active substance is excreted through the kidneys. However, the potential influence of hepatic insufficiency on SIFROL pharmacokinetics has not been investigated.
Restless Legs Syndrome (RLS) (only for Immediate-Release Tablet): 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 of salt taken once daily 2-3 hrs before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days to a maximum of 0.75 mg of salt 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 reinitiated by dose titration carried out as previously mentioned.
Treatment discontinuation: Since daily dose for the treatment of RLS will not exceed 0.75 mg of salt, SIFROL can be discontinued without tapering off. 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. This effect was found to be similar across all doses.
Dosing in patients with renal impairment: The elimination of pramipexole is dependent on renal function. Patients with CrCl above 20 mL/min require no reduction in daily dose. The use of SIFROL has not been studied in hemodialysis patients or in patients with severe renal impairment.
Dosing in patients with hepatic impairment: Dose adjustment in patients with hepatic failure is not required, as approx. 90% of absorbed active substance is excreted through the kidneys.
Dosing in children and adolescents: SIFROL is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.
Overdosage
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.
Contraindications
Hypersensitivity to pramipexole or to any other component of the product.
Special Precautions
Renal impairment: When prescribing SIFROL tablets in a patient with Parkinson's disease with renal impairment a reduced dose is suggested in line with Dosage & Administration.
Hallucinations and abnormal behaviour: Hallucinations are known as a side-effect of treatment with dopamine agonists and levodopa. Patients should be informed that (mostly visual) hallucinations can occur.
Immediate-Release Tablet: Patients and caregivers should be made aware of the fact that abnormal behaviour (reflecting symptoms of impulsive 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.
Prolonged-Release Tablet: Impulse Control Disorders and Compulsive Behaviours: Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including Sifrol. Furthermore, patients and caregivers should be aware of the fact that other behavioural symptoms of impulse control disorders and compulsions eg, binge eating and compulsive shopping can occur. Dose reduction/tapered discontinuation should be considered.
Dyskinesia: In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesia can occur during the initial titration of SIFROL. If they occur, the dose of levodopa should be decreased.
Sudden onset of sleep and somnolence: SIFROL 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 SIFROL. 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 (see Effects on ability to drive and use machines as follows and Adverse Reactions).
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. Coadministration of antipsychotic medicinal products with pramipexole is not recommended, e.g. if dopamine-antagonistic effects can be expected.
Ophthalmologic monitoring: Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
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 asscociated 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 casual 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.
Treatment discontinuation in Parkinson's disease: Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy (see Dosage & Administration).
Dopamine agonist withdrawal syndrome: To discontinue treatment in patients with Parkinson's disease, pramipexole should be tapered off (see Dosage & Administration). 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 (see Adverse Reactions).
Augmentation in RLS: 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. Kaplan-Meier analysis of time to augmentation showed no significant difference between pramipexole (N = 152) and placebo groups (N = 149).
Effects on the ability to drive and use machines: SIFROL can have a major influence on the ability to drive and use machines. Hallucinations or somnolence can occur.
Patients being treated with SIFROL and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see Precautions, Interactions, and Adverse Reactions).
Use In Pregnancy & Lactation
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 not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.
Lactation: As SIFROL treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected. The excretion of SIFROL 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, SIFROL 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. Animal studies did not indicate direct or indirect harmful effects with respect to male fertility.
Adverse Reactions
Expected Adverse Reactions: The following side effects are listed under the use of Sifrol: Abnormal dreams, amnesia, cardiac failure, behavioural symptoms of impulse control disorders and compulsions e.g., binge eating, compulsive shopping, hypersexuality and pathological gambling; confusion, constipation, delirium, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, hypotension, inappropriate antidiuretic hormone secretion, insomnia, libido disorders, mania, nausea, paranoia, peripheral oedema, pneumonia, pruritus, rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual impairment including diplopia, blurred vision and reduced visual acuity, vomiting, decreased weight including decreased appetite, weight increase.
The most commonly (≥5%) reported adverse drug reactions in patients with Parkinson's disease more frequent with Sifrol treatment than with placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of somnolence is increased at doses >1.5 mg/day (see Dosage & Administration). A more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if Sifrol is titrated too fast.
Sifrol Immediate-Release Tablet: Based on the analysis of pooled placebo-controlled trials, comprising a total of 1923 patients on SIFROL and 1354 patients on placebo. adverse drug reactions were frequently reported for both groups. 63% of patients on SIFROL and 52% of patients on placebo reported at least one adverse drug reaction.
The majority of adverse reactions usually start early in therapy and most tend to disappear even as therapy is continued.
The most commonly (≥5%) reported adverse drug reactions in patients with Parkinson's disease more frequent with SIFROL treatment than with Placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinatin, headache and fatigue. The incidence of somnolence is increased at doses higher than 1.5 mg/day (see Dosage & Administration). More frequent adverse drug reactions in combination with levodopa were dyskinesia. Hypotension may occur at the beginning of treatment, especially if SIFROL is titrated too fast. (See Table 3.)


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The most commonly (≥5%) reported adverse drug reactions in patients with Restless Legs Syndrome treated with SIFROL were nausea, headahe, dizziness, and fatigue. Nausea and fatigue were more often reported in female patients treated with SIFROL (20.8% and 10.5%, respectively) compared to males (6.7% and 7.3%, respectively). (See Table 4.)


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SIFROL is associated with somnolence (8.6%) and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes (0.1%). (See Precautions.)
SIFROL may be associated with libido disorders (increased (0.1%) or decreased (0.4%)).
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.
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).
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.
Inform the doctor or pharmacist immediately about side effects that occur while taking the drug.
Sifrol Prolonged-Release Tablet: Based on the analysis of pooled placebo-controlled trials, comprising a total of 1778 Parkinson's disease patients on pramipexole and 1297 patients on placebo, adverse drug reactions were frequently reported for both groups. Sixty-seven percent of patients on pramipexole and 54% of patients on placebo reported at least 1 adverse drug reaction.
The adverse drug reactions reported as follows are those events that occurred in ≥0.1% of patients treated with pramipexole and were reported significantly more often in patients taking pramipexole than placebo, or where the event was considered clinically relevant. The majority of adverse drug reactions were mild to moderate; they usually start early in therapy and most tended to disappear even as therapy was continued.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Infections and Infestations: Uncommon: Pneumonia.
Psychiatric Disorders: Common: Abnormal dreams, behavioural symptoms of impulse control disorders and compulsions, confusion, hallucinations, insomnia, restlessness, delirium.
Uncommon: Compulsive shopping, delusion, hypersexuality, libido disorder, paranoia, pathological gambling.
Rare: Mania.
Not Known: Binge eating, hyperphagia.
Nervous System Disorders: Very Common: Dizziness, dyskinesia, somnolence.
Common: Amnesia, headache.
Uncommon: Hyperkinesia, sudden onset of sleep, syncope.
Eye Disorders: Common: Visual disturbance including vision blurred and visual acuity reduced.
Vascular Disorders: Very Common: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnoea.
Gastrointestinal Disorders: Very Common: Nausea.
Common: Constipation, vomiting.
Skin and Subcutaneous Tissue Disorders: Uncommon: Hypersensitivity, pruritus, rash.
General Disorders and Administration Site Conditions: Common: Fatigue, peripheral oedema.
Investigations: Common: Weight decrease.
Uncommon: Weight increase.
Somnolence: Pramipexole is commonly associated with somnolence (8.6%) and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes (0.1%) (see Precautions).
Libido Disorders: Pramipexole may uncommonly be associated with libido disorders [increased or decreased].
Impulse Control Disorders and Compulsive Behaviours: 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 (see Precautions).
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. In a cross-sectional, retrospective screening and case-control study including 3090 Parkinson's disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms of an impulse control disorder during the past 6 months. Manifestations observed include pathological gambling, compulsive shopping, binge eating and compulsive sexual behaviour (hypersexuality). Possible independent risk factors for impulse control disorders included dopaminergic treatments and higher doses of dopaminergic treatment, younger age (≤65 years), not being married and self-reported family history of gambling behaviours.
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 medicinal products affecting plasma protein binding 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.
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 and amantadine may interact with pramipexole resulting in reduced clearance of either or both medicinal products. Reduction of the pramipexole dose should be considered when these medicinal products are administered concomitantly with SIFROL.
When SIFROL is given in combination with levodopa, it is recommended that the dose of levodopa is reduced and the dose of other antiparkinsonian medicinal products is kept constant while increasing the dose of SIFROL.
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: Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see Precautions).
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store below 30°C. Store in original package in order to protect from light.
Shelf-Life: 36 months since manufactured date.
ATC Classification
N04BC05 - pramipexole ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.
Presentation/Packing
Tab (immediate-release) 0.25 mg (white, oval, both faces flat, with bevelled edges and markings: P7/deep breakline/P7 on one face, Boehringer Ingelheim Company symbol/breakline/Boehringer Ingelheim Company symbol on other face) x 3 x 10's. Prolonged-release tab 0.75 mg x 3 x 10's. 0.375 mg x 3 x 10's.
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