Instructions for Pramipexole Asino tablets 1 mg No. 30
Composition
active ingredient: pramipexole;
1 tablet contains pramipexole dihydrochloride monohydrate 0.25 mg or 1.0 mg;
Excipients: mannitol (E 421), corn starch, colloidal anhydrous silicon dioxide, povidone, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
0.25 mg tablets – white or almost white, with a flat surface, round shape with a bevel, with a cross on one side;
1.0 mg tablets – white or almost white, with a flat surface, round shape with a bevel, with a score on one side and marking “1” on the other side.
Pharmacotherapeutic group
Dopaminergic drugs. Dopamine agonists.
ATX code N04B C05.
Pharmacological properties
Pharmacodynamics.
Pramipexole is a dopamine agonist with high selectivity and specificity for dopamine receptors of the D2 subtype and has a preferential affinity for D3 receptors, and is characterized by full intrinsic activity.
Pramipexole alleviates parkinsonian movement disorders by stimulating dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits the synthesis, release and turnover of dopamine.
The exact mechanism of action of the drug in the treatment of restless legs syndrome is unknown. Although the pathophysiology of restless legs syndrome is largely unknown, neuropharmacological evidence suggests involvement of the primary dopaminergic system.
Pharmacokinetics.
Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability is over 90%. Peak plasma concentrations are achieved between 1 and 3 hours after administration. The rate of absorption is not reduced by concomitant food intake, but the overall extent of absorption is reduced. Pramipexole exhibits linear kinetics and, regardless of the dosage form, there is relatively little variation in plasma levels between patients. In humans, protein binding of pramipexole is very low (< 20%) and the volume of distribution is large (400 l).
Pramipexole is metabolized in humans only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of the 14C-labeled dose is excreted renally, while less than 2% is recovered 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) ranges from 8 hours in young subjects to 12 hours in the elderly.
Indication
Treatment of the signs and symptoms of idiopathic Parkinson's disease in adults as monotherapy (without levodopa) or in combination with levodopa throughout the course of the disease until the late stages when the effect of levodopa decreases or becomes unstable and there is fluctuation in the therapeutic effect (the "on-off" phenomenon).
Symptomatic treatment of moderate to severe idiopathic restless legs syndrome in adults at doses not exceeding 0.75 mg.
Contraindication
Hypersensitivity to pramipexole or to any other component of the drug.
Interaction with other medicinal products and other types of interactions
Binding to blood plasma proteins
Pramipexole is very poorly bound to plasma proteins (< 20%) and has low biotransformation. Therefore, interactions with other drugs that affect plasma protein binding or elimination by biotransformation are unlikely. Since anticholinergics are eliminated primarily by hepatic metabolism, interactions are unlikely. Interactions with anticholinergics have not been studied. There is no pharmacokinetic interaction with selegiline or levodopa.
Inhibitors/competitors of the active renal elimination pathway
Cimetidine reduces the renal clearance of pramipexole by approximately 34%, probably by inhibiting the cationic renal tubular secretion transport system. Drugs that inhibit active renal tubular secretion or are themselves eliminated by this route, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine and procainamide, may interact with pramipexole and lead to a decrease in pramipexole clearance. A reduction in the pramipexole dose should be considered when these drugs are co-administered with pramipexole.
Combination with levodopa
When increasing the dose of pramipexole in patients with Parkinson's disease, it is recommended to reduce the dose of levodopa, while leaving the doses of other antiparkinsonian drugs unchanged.
Due to possible additive effects, caution should be exercised if the patient is taking other sedative medicinal products in combination with pramipexole or drinking alcohol (see sections 4.4, 4.8 and 4.8).
Antipsychotic medications
The concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section 4.4) as antagonistic effects are possible.
Application features
Hallucinations: Hallucinations are a known adverse reaction of dopamine agonist and levodopa treatment. Patients should be advised of the possibility of hallucinations (mostly visual) while taking the drug.
Dyskinesia: In combination therapy with levodopa in progressive Parkinson's disease, dyskinesia may develop at the beginning of pramipexole titration. In such cases, the levodopa dose should be reduced.
Dystonia: Axial dystonia, including antecollis, camptocormia and pleurothotonus (Pisa syndrome), has occasionally occurred in patients with Parkinson's disease following initial or gradual dose increases of pramipexole. Although dystonia may be a symptom of Parkinson's disease, symptoms of dystonia in patients with Parkinson's disease resolve after dose reduction or discontinuation of pramipexole.
If dystonia occurs, consideration should be given to reviewing the dopaminergic treatment regimen and adjusting the pramipexole dose.
Sudden onset of sleep and somnolence. Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. There have been uncommon reports of sudden onset of sleep onset during daily activities, in some cases without awareness or warning signs. Therefore, patients should be advised to exercise caution when driving or operating machinery during treatment with pramipexole. Patients experiencing somnolence and/or episodes of sudden sleep onset should refrain from driving or operating machinery. In addition, a dose reduction or a reduction in the duration of treatment should be considered. Due to possible additive effects, caution should be exercised if the patient is taking other sedative medicinal products in combination with pramipexole or drinking alcohol (see sections “Interaction with other medicinal products and other types of interactions”, “Ability to influence the speed of reactions when driving vehicles or using other mechanisms” and “Adverse reactions”).
Impulse control disorders: Patients should be monitored closely for the development of impulse control disorders. Patients and caregivers should be made aware that symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating, may occur during treatment with dopamine agonists, including pramipexole.
If such symptoms develop, dose reduction/discontinuation of the drug should be considered.
Mania and delirium: Patients should be monitored closely for the development of mania and delirium. Patients and caregivers should be made aware that mania and delirium can occur in patients receiving pramipexole therapy. If such symptoms develop, dose reduction/discontinuation of the drug should be considered.
Severe cardiovascular disease. In case of severe cardiovascular disease, the drug should be prescribed with particular caution. Monitoring of blood pressure is recommended, especially at the beginning of treatment, taking into account the general risk of postural hypotension associated with dopaminergic therapy.
Patients with psychiatric disorders: Patients with psychiatric disorders should only be treated with dopamine agonists if the potential benefits of treatment outweigh the risks. The concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section 4.5).
Neuroleptic malignant syndrome: Symptoms resembling neuroleptic malignant syndrome have been observed after abrupt withdrawal of dopaminergic treatment (see section 4.2).
Ophthalmological examination: Regular ophthalmological examination is recommended in case of visual impairment.
Augmentation (worsening of symptoms) in restless legs syndrome. Reports indicate that treatment of restless legs syndrome with dopaminergic drugs may cause augmentation. Augmentation is manifested by an early onset of symptoms in the evening (or even during the day), an increase in symptoms and the spread of symptoms to the upper limbs. Augmentation was specifically investigated in a controlled clinical trial of 26 weeks. Augmentation was observed in 11.8% of patients in the pramipexole (N = 152) and placebo (N = 149) groups. Kaplan-Meier analysis of time to augmentation did not show any significant difference between the pramipexole and placebo groups.
The risk of augmentation may increase with increasing dose. Before starting treatment, patients should be informed of the possibility of augmentation and advised to seek medical advice if they experience symptoms of augmentation. If augmentation is suspected, consideration should be given to adjusting the dose to the lowest effective dose or discontinuing pramipexole (see sections 4.2 and 4.8).
Renal impairment: Pramipexole should be administered with caution to patients with renal impairment, as pramipexole is excreted by the kidneys.
Rhabdomyolysis: A case of rhabdomyolysis has been reported in a patient with advanced Parkinson's disease treated with pramipexole. The patient had an elevated creatine phosphokinase (CPK) level (10,631 IU/L). The symptoms resolved after discontinuation of treatment.
Use during pregnancy or breastfeeding
Pregnancy
The effect on pregnancy has not been studied in humans. Pramipexole should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding period
Since treatment with pramipexole inhibits prolactin secretion, a decrease in lactation is possible. The excretion of pramipexole into breast milk has not been studied in women, therefore the drug is not recommended for use during breastfeeding. If pramipexole cannot be avoided, breastfeeding should be discontinued.
Fertility
No studies have been conducted on the effects on human fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Pramipexole may have a significant influence on the ability to drive or use machines. Hallucinations or drowsiness may occur. Patients with drowsiness and/or episodes of sudden onset of drowsiness should refrain from driving and other potentially hazardous activities where impaired alertness increases the risk of serious injury or death while taking pramipexole.
Method of administration and doses
All dosage information refers to pramipexole as pramipexole dihydrochloride.
Parkinson's disease
The daily dose is divided into 3 equal doses.
Initial treatment
As outlined below, the dose should be increased gradually, starting at 0.375 mg/day every 5-7 days. In cases where patients do not experience intolerable adverse reactions, the dose should be titrated to achieve the maximum therapeutic effect.
Table 1
| Pramipexole Asino dose escalation schedule |
| Week | Dose (mg) | Total daily dose (mg) |
| 1st | 3 x 0.125 | 0.375 |
| 2nd | 3 x 0.25 | 0.75 |
| 3rd | 3 x 0.5 | 1.5 |
If further dose increases are necessary, the daily dose should be increased by 0.75 mg every week to a maximum of 4.5 mg/day. However, it should be noted that the incidence of drowsiness increases with doses above 1.5 mg/day.
Supportive therapy
The individual dose ranges from 0.375 mg/day to a maximum of 4.5 mg/day. When increasing the dose, the treatment effect was observed starting from a daily dose of 1.5 mg. Further dose adjustment should be carried out taking into account the clinical response and the occurrence of adverse reactions. It is known that in clinical trials approximately 5% of patients took a dose of less than 1.5 mg. In progressive Parkinson's disease, a dose above 1.5 mg/day may be appropriate for patients who are planning to reduce the dose of levodopa in combination therapy with levodopa. It is recommended to reduce the dose of levodopa when increasing the dose of Pramipexole Asino and during maintenance therapy depending on the patient's response (see section "Interaction with other medicinal products and other types of interactions").
Treatment discontinuation
Abrupt discontinuation of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome. The dose of pramipexole should be reduced according to the mg/day scheme to a daily dose of 0.75 mg/day. The dose should then be reduced to 0.375 mg per day (see section "Special instructions for use"). Dopamine agonist withdrawal syndrome may occur during dose reduction, therefore a temporary increase in the dose may be necessary before the dose reduction is resumed (see section "Special instructions for use").
Dosage for patients with renal impairment
Patients with creatinine clearance above 50 ml/min do not require a reduction in daily dose or dosing frequency.
For patients with creatinine clearance 20-50 ml/min, the initial daily dose of Pramipexole Asino is administered in two divided doses, starting at 0.125 mg twice daily (0.25 mg/day). The maximum daily dose of pramipexole should not be exceeded, 2.25 mg.
For patients with creatinine clearance below 20 ml/min, the daily dose of Pramipexole Asino is prescribed in a single dose, starting from 0.125 mg/day. The maximum daily dose of pramipexole should not be exceeded, which is 1.5 mg.
In case of renal impairment on supportive therapy, the daily dose of Pramipexole Asino is reduced by the percentage of the decrease in creatinine clearance. For example, if creatinine clearance is reduced by 30%, the daily dose of Pramipexole Asino is reduced by 30%. The daily dose can be administered in two divided doses if creatinine clearance is between 20 and 50 ml/min, and in one divided dose if creatinine clearance is below 20 ml/min.
Dosage for patients with hepatic impairment
For patients with hepatic impairment, dose reduction is not considered necessary, as almost 90% of the absorbed drug is excreted by the kidneys. The potential effect of hepatic impairment on the pharmacokinetics of pramipexole has not been studied.
Restless legs syndrome
The recommended starting dose of Pramipexole is 0.125 mg once daily, 2-3 hours before bedtime. For patients requiring additional relief of symptoms, the dose may be increased every 4-7 days to a maximum dose of 0.75 mg/day (as shown in Table 2 below). The lowest effective dose should be used (see section 4.4).
Table 2
| Pramipexole Asino dose escalation schedule |
| Titration stage | Single daily evening dose (mg) |
| 1 | 0.125 |
| 2* | 0.25 |
| 3* | 0.50 |
| 4* | 0.75 |
| *If necessary. |
The patient's response to treatment should be assessed after 3 months and the need for continued therapy should be reconsidered. If treatment is interrupted for more than a few days, it should be restarted at the dose indicated above.
Treatment discontinuation
Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg, Pramipexole can be discontinued without tapering the dose. Relapse of restless legs syndrome symptoms (increased severity of symptoms compared to baseline) may occur in 10% of patients after abrupt discontinuation of pramipexole. This effect is possible with all doses.
Dosage for patients with renal impairment
The elimination of Pramipexole Asino from the body depends on renal function. For patients with creatinine clearance above 20 ml/min, there is no need to reduce the daily dose.
Pramipexole has not been studied in patients undergoing haemodialysis or in patients with severe renal impairment.
Dosage for patients with hepatic impairment
For patients with impaired liver function, dose reduction is not considered necessary, since almost 90% of the absorbed drug is excreted by the kidneys.
Method of application
The tablets should be taken orally with water, regardless of food intake.
Children.
Parkinson's disease. The safety and efficacy of Pramipexole Accord in children (under 18 years of age) have not been established. There is no evidence to support the use of Pramipexole Accord in children with Parkinson's disease.
Restless legs syndrome: Pramipexole is not recommended for use in children (under 18 years of age) due to insufficient data on safety and efficacy.
Tourette's syndrome: Pramipexole Accord should not be used in children (under 18 years of age) with Tourette's syndrome due to the negative benefit/risk ratio for this condition.
Overdose
There is no clinical experience of significant overdose. Expected adverse reactions related to the pharmacodynamic profile of a dopamine agonist include nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension. No antidote for dopamine agonist overdose has been established. Neuroleptics may be administered if signs of central nervous system excitation occur. Treatment of patients with overdose may require general supportive measures, including gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram monitoring.
Side effects
Based on an analysis of pooled placebo-controlled trials involving a total of 1,923 patients taking pramipexole and 1,354 patients taking placebo, adverse reactions were commonly reported in both groups. 63% of patients taking pramipexole and 52% of patients taking placebo reported at least one adverse drug reaction.
Most adverse drug reactions usually begin early in treatment and tend to disappear even with continued therapy.
Parkinson's disease
In patients with Parkinson's disease, the most common adverse reactions (≥5%) when treated with pramipexole compared to placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache and fatigue. The incidence of somnolence increases with doses above 1.5 mg/day (see section 4.2). The most common adverse reaction when used in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.
Infections and infestations: uncommon – pneumonia.
Endocrine system: uncommon – impaired secretion of antidiuretic hormone1.
Psychiatric disorders: common: sleep disorders, symptoms of impulse control disorder and compulsive behavior, confusion, hallucinations, sleep disorders; uncommon: binge eating1, pathological shopping, hyperphagia1, hypersexuality, libido disorders, paranoia, pathological gambling, anxiety, delusions, delirium; rare: mania.
From the nervous system: very often - dizziness, dyskinesia, drowsiness; often - headache; infrequently - amnesia, hyperkinesia, sudden onset of drowsiness, syncope.
On the part of the organs of vision: often - visual disturbances, including diplopia, blurred vision and deterioration of visual acuity.
Cardiac disorders: uncommon – heart failure1.
From the vascular system: often - arterial hypotension.
On the part of the respiratory system: infrequently - shortness of breath, hiccups.
On the part of the digestive system: very often - nausea; often - constipation, vomiting.
Skin and subcutaneous tissue disorders: infrequently - hypersensitivity, itching, rash.
From the reproductive system and mammary glands: rarely - spontaneous erection.
General disorders: often - increased fatigue, peripheral edema; frequency unknown - dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, increased sweating and pain).
Investigations: common: weight loss, including decreased appetite; uncommon: weight gain.
1 This adverse reaction has been reported in the post-marketing setting. In 95% of patients, the frequency was no higher than uncommon, but may be lower. It is not possible to establish a precise frequency as no adverse reactions were observed in clinical trials among 2762 patients with Parkinson's disease treated with pramipexole.
Restless legs syndrome
In patients with restless legs syndrome treated with pramipexole, the most common adverse reactions (≥ 5%) were nausea, headache, dizziness and fatigue. Nausea and fatigue were more frequently observed in women (20.8% and 10.5%, respectively) compared to men (6.7% and 7.3%, respectively) treated with pramipexole.
Infections and infestations: uncommon – pneumonia2.
Endocrine system: uncommon – impaired secretion of antidiuretic hormone2.
Psychiatric disorders: common: sleep disorders, insomnia; uncommon: symptoms of impulse control disorders and compulsive behavior2, such as binge eating, pathological shopping, hypersexuality and pathological gambling; confusion, mania2, hallucinations, hyperphagia2, libido disorders, paranoia2, anxiety, delusions2, delirium2.
Nervous system disorders: very common: restless legs syndrome increased; common: dizziness, headache, drowsiness; uncommon: amnesia2, dyskinesia, hyperkinesia2, sudden onset of drowsiness, syncope.
On the part of the organs of vision: often - visual disturbances, including diplopia, blurred vision and deterioration of visual acuity.
Cardiac disorders: uncommon – heart failure2.
Vascular disorders: infrequently - arterial hypotension.
On the part of the respiratory system: infrequently - shortness of breath, hiccups.
On the part of the digestive system: very often - nausea; often - constipation, vomiting.
Skin and subcutaneous tissue disorders: infrequently - hypersensitivity, itching, rash.
From the reproductive system and mammary glands: rarely - spontaneous erection.
General disorders: often - increased fatigue; infrequently - peripheral edema; frequency unknown - dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, increased sweating and pain).
Investigations: uncommon – weight loss, including decreased appetite, weight gain.
2 This adverse reaction has been reported in the post-marketing period. In 95% of patients, the frequency is not higher than uncommon, but may be lower. It is not possible to establish the exact frequency, as the adverse reaction was not observed in clinical trials among 1395 patients with restless legs syndrome treated with pramipexole.
Description of selected adverse reactions
Somnolence: Pramipexole is commonly associated with somnolence and uncommonly with excessive daytime sleepiness and episodes of sudden onset of somnolence (see section 4.4).
Impulse control disorders: Symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating, may occur during treatment with dopamine agonists, including pramipexole (see section 4.4).
In a retrospective cross-sectional screening study of 3090 patients with Parkinson's disease, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms of an impulse control disorder in the previous six months. Manifestations observed included pathological gambling, compulsive shopping, binge eating, and compulsive sexual behavior (hypersexuality). Possible independent risk factors for impulse control disorders include dopaminergic treatment and higher doses of dopaminergic medications, younger age (≤ 65 years), singleness, and a self-reported family history of gambling.
Dopamine agonist withdrawal syndrome: Non-motor adverse reactions may occur when the dose of dopamine agonists (including pramipexole) is reduced or discontinued. Symptoms include apathy, anxiety, depression, fatigue, increased sweating and pain (see section 4.4).
Heart failure
Heart failure has been reported in patients treated with pramipexole in clinical trials and in the post-marketing setting. In a pharmacoepidemiological study, pramipexole was associated with an increased risk of heart failure compared with no treatment (hazard ratio 1.86; 95% CI 1.21–2.85).
Reporting of suspected adverse reactions
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
3 years.
Storage conditions
Store out of the reach of children, in the original packaging at a temperature not exceeding 25 °C.
Packaging
10 tablets in a blister; 3 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
"Pharma Start" LLC.
Location of the manufacturer and address of its place of business.
Ukraine, 03124, Kyiv, Vaclav Havel Boulevard, 8.
Applicant
LLC "ASINO UKRAINE".
Location of the applicant.
Ukraine, 03124, Kyiv, Vaclav Havel Boulevard, building 8.
In case of adverse reactions or questions regarding the safety and effectiveness of the medicinal product, please contact the Pharmacovigilance Department of ASINO UKRAINE LLC at the address: Vaclav Havel Boulevard, 8, Kyiv, 03124, tel/fax: +38 044 281 2333.
