Instructions Pramipexole IS tablets 1 mg blister No. 30
Composition
active ingredient: pramipexole;
1 tablet contains 1 mg pramipexole dihydrochloride monohydrate (equivalent to 0.7 mg pramipexole);
excipients: mannitol (E 421), potato starch, povidone, colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: white tablets, flat-cylindrical in shape with a bevel; on one surface of the tablet there is a trademark of the company, on the other surface of the tablet there is a dividing line.
Pharmacotherapeutic group
Dopaminergic agents. Dopamine agonists. Pramipexole. 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 pramipexole 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
Absorption
Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability is over 90%. Peak plasma concentrations are reached 1–3 hours after administration. Concomitant administration with food does not reduce the extent of absorption of pramipexole, but does reduce the rate of absorption. Pramipexole exhibits linear kinetics and relatively small interpatient plasma level fluctuations.
Distribution
In humans, the binding of pramipexole to plasma proteins is very low (< 20%) and the volume of distribution is large (400 l).
Metabolism
Pramipexole is only slightly metabolized in humans.
Elimination
Renal excretion of unchanged pramipexole is the major route of drug elimination. Approximately 90% of the 14C-labeled dose is excreted renally, while less than 2% is recovered in the feces.
The total clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life varies from 8 hours in young people to 12 hours in the elderly.
Indication
Treatment of the 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 fluctuations in the therapeutic effect occur (the "on-off" phenomenon).
Symptomatic treatment of moderate to severe idiopathic restless legs syndrome in adults at doses not exceeding 0.75 mg pramipexole dihydrochloride monohydrate.
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 undergoes minimal biotransformation. Therefore, interactions with other medicinal products that affect plasma protein binding or elimination by biotransformation are unlikely. Since anticholinergics are eliminated primarily by biotransformation, the potential for interactions is limited, although 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%, presumably by inhibiting the cationic secretory transport system of the renal tubules. Therefore, drugs that inhibit active renal elimination 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 the possible additive effect, caution should be exercised if the patient uses other sedative medicines or drinks alcohol in combination with pramipexole (see sections "Special instructions for use", "Ability to influence the speed of reactions when driving vehicles or using other mechanisms" and "Adverse reactions").
Antipsychotic medications
The concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section 4.4), particularly if antagonistic effects are possible.
Application features
Patients with Parkinson's disease who have impaired renal function should be prescribed reduced doses of Pramipexole IC in accordance with the section "Method of administration and dosage".
Hallucinations
Hallucinations are known side effects of dopamine agonist and levodopa treatment. Patients should be informed that hallucinations (mostly visual) may occur.
Dyskinesia
In combination therapy with levodopa in progressive Parkinson's disease, dyskinesia may develop at the beginning of pramipexole titration. In this case, the levodopa dose should be reduced.
Dystonia
Axial dystonia, including antecollis, camptocormia and pleurothotonus (leaning tower syndrome), has occasionally been reported in patients with Parkinson's disease following initial or dose-escalation of pramipexole. Although dystonia can be a symptom of Parkinson's disease, the severity of dystonia in patients with Parkinson's disease has been reported to decrease after dose reduction or discontinuation of pramipexole. If dystonia occurs, the dopaminergic treatment regimen should be reviewed and the pramipexole dose adjusted.
Sudden onset of sleep and drowsiness
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 sleep onset during daytime 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 who experience somnolence and/or episodes of sudden sleep onset should refrain from driving or operating machinery. In addition, a dose reduction or discontinuation of treatment should be considered. Due to possible additive effects, caution should be exercised if the patient is taking other sedative medicinal products or drinking alcohol during treatment with pramipexole (see sections 4.5, 4.8 and 4.8).
Impulse control disorders
Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be made aware that behavioural 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/gradual discontinuation of the medicinal product should be considered.
Mania and delirium
Patients should be closely monitored for the development of mania and delirium. Patients and caregivers should be aware that mania and delirium can occur in patients receiving pramipexole therapy. If such symptoms develop, dose reduction/gradual discontinuation of the drug should be considered.
Patients with mental disorders
Dopamine agonists should only be used in patients with psychiatric disorders 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).
Ophthalmological examination
Ophthalmological examination is recommended at regular intervals or in case of visual impairment.
Neuroleptic malignant syndrome
Symptoms resembling neuroleptic malignant syndrome have been observed after abrupt withdrawal of dopaminergic treatment (see section 4.2).
Dopamine agonist withdrawal syndrome
Dopamine agonist withdrawal syndrome has been observed with dopamine agonists, including pramipexole (see section 4.8). To discontinue treatment, patients with Parkinson's disease should have their dose of pramipexole tapered gradually according to the recommendations in section 4.2. Limited data suggest that patients with impulse control disorders and patients receiving high daily doses and/or high cumulative doses of dopamine agonists may be at increased risk of developing dopamine agonist withdrawal syndrome. Symptoms of withdrawal syndrome may include apathy, anxiety, depression, fatigue, sweating, pain and lack of response to levodopa. Before reducing the dose and discontinuing pramipexole, patients should be informed of the possible withdrawal symptoms. Patients should be closely monitored during dose reduction and discontinuation of pramipexole. In case of severe and/or persistent symptoms of dopamine agonist withdrawal syndrome, temporary re-administration of pramipexole at the lowest effective dose may be considered.
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 an extension of symptoms to the upper extremities. Augmentation was specifically investigated in a controlled clinical trial of 26 weeks duration. Augmentation was observed in 11.8% of patients in the pramipexole group (n=152) and in 9.4% of patients in the placebo group (n=149). Kaplan–Meier analysis of time to onset of augmentation did not show any significant difference between the pramipexole and placebo groups.
Severe cardiovascular diseases
Pramipexole should be administered with particular caution to patients with severe cardiovascular disease. Monitoring of blood pressure is recommended, especially at the beginning of treatment, given the general risk of postural hypotension associated with dopaminergic therapy.
Kidney failure
Pramipexole IC should be administered with caution to patients with renal insufficiency, as pramipexole is excreted by the kidneys.
Rhabdomyolysis
A single case of rhabdomyolysis has been reported in a 49-year-old man with advanced Parkinson's disease treated with pramipexole. The patient was hospitalized with elevated creatine phosphokinase (CPK) levels (10,631 IU/L). Symptoms resolved after discontinuation of treatment.
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 who experience somnolence and/or sudden sleep onset episodes while taking pramipexole should be advised 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 machinery) until the recurrence and somnolence have resolved (see sections 4.5, 4.8, and 4.8).
Use during pregnancy or breastfeeding
Pregnancy period
The effects of pramipexole on pregnancy and lactation have not been studied in humans. Pramipexole should not be used during pregnancy unless clearly necessary, i.e. when the potential benefit to the woman outweighs the potential risk to the foetus.
Breastfeeding period
Since treatment with pramipexole inhibits prolactin secretion, a decrease in lactation may occur. The excretion of pramipexole into breast milk in women has not been studied. In the absence of data, pramipexole should not be used in women who are breastfeeding. If the use of pramipexole cannot be avoided, breastfeeding should be discontinued.
Fertility
Studies on the effect of pramipexole on human fertility have not been conducted.
Method of administration and doses
All dosage information refers to pramipexole as pramipexole dihydrochloride monohydrate.
Parkinson's disease
The daily dose should be administered in 3 equal doses.
Initial treatment
As outlined below, the dose should be increased gradually, starting at 0.375 mg/day every 5–7 days. If patients do not experience intolerable side effects, the dose should be titrated to achieve the maximum therapeutic effect (see Table 1).
Table 1
| Pramipexole IC dose escalation schedule | | |
| Week | Dose (mg) | Total daily dose (mg) |
| 1st | 3 × 0.125 | 0.375 |
| 2nd | 3 × 0.25 | 0.75 |
| 3rd | 3 × 0.5 | 1.5 |
If further dose increases are necessary, the daily dose should be increased by 0.75 mg weekly up to a maximum of 4.5 mg/day. However, it should be noted that the incidence of somnolence increases with doses above 1.5 mg/day (see section 4.8).
Supportive therapy
The individual dose ranges from 0.375 mg to a maximum of 4.5 mg per day. During dose escalation in the pivotal studies, a therapeutic effect was observed starting from a daily dose of 1.5 mg. Further dose adjustments should be made based on clinical response and the occurrence of adverse reactions. In clinical studies, approximately 5% of patients received doses below 1.5 mg. In progressive Parkinson's disease, a dose above 1.5 mg per day may be beneficial in patients for whom a reduction in the levodopa dose is planned in combination therapy with levodopa. It is recommended to reduce the levodopa dose when increasing the pramipexole dose and during maintenance therapy depending on the response of each individual patient (see section "Interaction with other medicinal products and other forms of interaction").
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 gradually reduced by 0.75 mg per day until a daily dose of 0.75 mg is reached. The dose should then be reduced to 0.375 mg per day (see section 4.4). Dopamine agonist withdrawal syndrome may occur during gradual dose reduction. Therefore, a temporary increase in dose may be necessary before resuming the dose reduction (see section 4.4).
Dosage for patients with renal impairment
The elimination of pramipexole from the body depends on renal function. The following dosage regimen is suggested for initial therapy.
Patients with creatinine clearance above 50 ml/min do not require a reduction in daily dose or frequency of administration.
For patients with creatinine clearance 20-50 ml/min, the initial daily dose of pramipexole should be administered in 2 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.
In patients with creatinine clearance below 20 ml/min, the daily dose of pramipexole should be administered in a single dose, starting at 0.125 mg per day. The maximum daily dose of pramipexole should not exceed 1.5 mg.
In case of deterioration of renal function on the background of maintenance therapy, the daily dose of pramipexole should be reduced by the same percentage as the decrease in creatinine clearance. For example, if creatinine clearance decreases by 30%, the daily dose of pramipexole should be 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
In patients with hepatic impairment, dose reduction is not considered necessary as approximately 90% of absorbed pramipexole is excreted renally. 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 symptom relief, the dose may be increased every 4–7 days to a maximum dose of 0.75 mg daily (see Table 2).
Table 2
| Pramipexole IC dose escalation schedule | |
| Titration stage | Single daily evening dose (mg) |
| 1 | 0.125 |
| 2* | 0.25 |
| 3* | 0.50 |
| 4* | 0.75 |
The patient's therapeutic response should be assessed after 3 months of treatment and the need for continued therapy should be reconsidered. If treatment is interrupted for more than a few days, resumption of the drug should be carried out by gradually increasing the dose according to the scheme indicated above.
Treatment discontinuation
Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg, Pramipexole IC can be discontinued without tapering. In a 26-week placebo-controlled clinical trial, relapse of restless legs syndrome symptoms (increased severity of symptoms compared to baseline) was observed in 10% of patients after abrupt discontinuation of pramipexole. This effect was observed at all doses.
Dosage for patients with renal impairment
The elimination of pramipexole from the body depends on renal function. Patients with creatinine clearance above 20 ml/min do not need to reduce the daily dose.
The use of pramipexole in patients undergoing hemodialysis or in patients with severe renal impairment has not been studied.
Dosage for patients with hepatic impairment
For patients with hepatic impairment, dose reduction is not considered necessary, as approximately 90% of absorbed pramipexole is excreted by the kidneys.
Method of application
The tablets should be taken orally with water, regardless of meals.
Children
Parkinson's disease
The safety and efficacy of pramipexole in children (under 18 years of age) have not been established. There is no evidence to support the use of pramipexole in children with Parkinson's disease.
Restless legs syndrome
The use of pramipexole is not recommended in children (under 18 years of age) due to insufficient data on safety and efficacy.
Tourette syndrome
Pramipexole should not be used in children (under 18 years of age) with Tourette syndrome due to a 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.
There is no known antidote for dopamine agonist overdose. 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, activated charcoal, and electrocardiogram monitoring.
Adverse reactions
Most adverse reactions are usually observed at the beginning of therapy, a significant part of them disappear even if therapy is continued.
Adverse reactions are classified by system organ class and frequency. The frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 - < 1/10), uncommon (≥ 1/1000 - < 1/100), rare (≥ 1/10000 - < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).
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 increased 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 hormone*.
Psychiatric disorders: often - insomnia, hallucinations, abnormal dreams, confusion, symptoms of impulse control disorder and compulsive behavior; infrequently - pathological shopping, pathological gambling, anxiety, hypersexuality, delusions, libido disorders, paranoia, delirium, binge eating*, hyperphagia*; rarely - mania.
From the nervous system: very often - drowsiness, dizziness, dyskinesia; often - headache; infrequently - sudden onset of sleep, amnesia, hyperkinesia, syncope.
On the part of the organs of vision: often - visual disturbances, including diplopia, blurred vision and deterioration of visual acuity.
Cardiovascular system: often - arterial hypotension; infrequently - heart failure*.
Respiratory, thoracic and mediastinal disorders: infrequently - shortness of breath, hiccups.
From the gastrointestinal tract: very often - nausea; often - constipation, vomiting.
Skin and subcutaneous tissue disorders: uncommon – hypersensitivity, itching, rash.
General disorders: often - 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.
* This adverse reaction has been reported during post-marketing surveillance. With 95% confidence, the frequency category is not higher than "uncommon", but may be lower. A precise estimate of the frequency category is not possible, as the adverse reaction was not observed in clinical trials involving 2762 patients with Parkinson's disease who took 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 – pneumonia**.
Endocrine system: uncommon – impaired secretion of antidiuretic hormone**.
Psychiatric disorders: often - insomnia, abnormal dreams; infrequently - anxiety, confusion, hallucinations, libido disorders, delusions**, hyperphagia**, paranoia**, mania**, delirium**, symptoms of impulse control disorders and compulsive behavior** (such as pathological shopping, pathological gambling, hypersexuality, binge eating).
Nervous system disorders: often - headache, dizziness, drowsiness; infrequently - sudden onset of sleep, syncope, dyskinesia, amnesia**, hyperkinesia**.
On the part of the organs of vision: infrequently - visual disturbances, including deterioration of visual acuity, diplopia and blurred vision.
Cardiovascular system: infrequently - heart failure**, arterial hypotension.
Respiratory, thoracic and mediastinal disorders: infrequently - shortness of breath, hiccups.
From the gastrointestinal tract: very often - nausea; often - constipation, vomiting.
Skin and subcutaneous tissue disorders: infrequently - hypersensitivity, itching, rash.
General disorders: often - increased fatigue; infrequently - peripheral edema; frequency unknown - dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, increased fatigue, increased sweating and pain).
Investigations: uncommon – weight loss, including decreased appetite; weight gain.
** This adverse reaction has been reported during post-marketing surveillance. With 95% confidence, the frequency category is not higher than "uncommon", but may be lower. A precise estimate of the frequency category is not possible, as the adverse reaction was not observed in clinical trials involving 1395 patients with restless legs syndrome who took pramipexole.
Description of selected adverse reactions
Libido disorders: Pramipexole may be uncommonly associated with libido disorders (increased or decreased).
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).
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, sweating and pain (see section 4.4).
Heart failure: Heart failure has been observed in patients treated with pramipexole in clinical trials and during the post-marketing period. In a pharmacoepidemiological study, pramipexole was associated with an increased risk of heart failure compared to no treatment.
Reporting of suspected adverse reactions
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system in order to monitor the benefit/risk balance of the medicinal product.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3 blisters in a pack.
Vacation category
According to the recipe.
Producer
Additional Liability Company "INTERCHEM".
Location of the manufacturer and its business address
Ukraine, 65025, Odessa, 21st km. Starokyivska Road, 40-A.
