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Instruction for use: Mirapex

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Dosage form: tablets

Active substance: Pramipexole*

ATX

N04BC05 Pramipexole

Pharmacological groups:

Dopamine receptor agonist [Dophaminomimetics]

Dopamine receptor agonist [Antiparkinsonian means]

The nosological classification (ICD-10)

G20 Parkinson's disease: A trembling paralysis; Idiopathic Parkinsonism; Parkinson's disease; Symptomatic Parkinsonism

G25.8 Other specified extrapyramidal and motor disorders: Restless legs syndrome; Idiopathic Restless Leg Syndrome; Attention Deficit Hyperactivity Disorder

Composition and release form

Tablets - 1 table.

active substance: Pramipexole dihydrochloride monohydrate 0.25 mg; 1 mg

(Equivalent to 0.18 mg or 0.7 mg of pramipexole base, respectively)

Auxiliary substances: mannitol; corn starch; Silicon dioxide colloid; Povidone; Magnesium stearate

In a blister of PA / aluminum foil / PVC 10 pieces; In a pack of cardboard 3 blisters.

Description of dosage form

Tablets of 0.25 mg: oval, white, with bevelled edge, flat on both sides. On one side of the tablet is a deep risk, on both sides of which marking is "P7", on the other side of the risk pills, on both sides of which is the company logo marking.

Tablets 1 mg: round, white, with bevelled edge, flat on both sides. On one side of the tablet is a deep risk, on both sides of which marking is "P9", on the other side of the risk pills, on both sides of which is the company logo marking.

Pharmachologic effect

Mode of action - antiparkinsonian, dopaminergic.

Pharmacodynamics

Pramipexole, a dopamine receptor agonist, with high selectivity and specificity binds to the dopamine receptors of the D2 subgroup, of which it has the most pronounced affinity for D3 receptors. Reduces the lack of motor activity in Parkinson's disease by stimulating dopamine receptors in the striatum. Pramipexole inhibits the synthesis, release and metabolism of dopamine. Pramipexole in vitro protects dopamine neurons from degeneration arising in response to ischemia or methamphetamine neurotoxicity.

The exact mechanism of action of the drug in the treatment of restless legs syndrome is not currently known. Despite the fact that the pathophysiology of restless leg syndrome is not fully understood, there are neuropharmacological data on the primary involvement of the dopaminergic system in the process. Studies using positron emission tomography (PET) have shown that moderate pre-synaptic dopaminergic dysfunction in the striatum can be involved in the pathogenesis of restless leg syndrome.

Pramipexole in vitro protects neurons from the neurotoxicity of levodopa.

Reduces the secretion of prolactin (dose-dependent).

With long-term use (more than 3 years) of pramipexole in patients with Parkinson's disease, there were no signs of a decrease in efficacy.

When using pramipexole in patients with restless legs syndrome for 1 year, the effectiveness of the drug persisted.

Pharmacokinetics

Pramipexole after ingestion is quickly and completely absorbed. Absolute bioavailability is more than 90%, and Cmax in plasma is observed in 1-3 hours. The rate of absorption decreases with food intake, however, the total intake is not affected by food intake. Pramipexole is characterized by linear kinetics and a relatively small variability in concentrations between patients.

Pramipexole binds to proteins to a very small extent (<20%), and has a large Vd (400 L). It is exposed to a metabolism to an insignificant degree. About 90% of the dose is excreted through the kidneys (80% - unchanged) and less than 2% is found in the stool. The total clearance of pramipexole is about 500 ml / min, the renal clearance is about 400 ml / min. T1 / 2 ranges from 8 h in young and up to 12 h in the elderly.

Indications of the drug Mirapex

Symptomatic treatment of idiopathic Parkinson's disease (monotherapy or in combination with levodopa) and idiopathic restless legs syndrome.

Contraindications

Hypersensitivity to pramipexole or to any component of the drug;

Children's age (under 18 years).

With caution: renal failure, lowering blood pressure.

Application in pregnancy and breastfeeding

The effect on pregnancy and lactation in humans has not been investigated.

The possible effect of pramipexole on reproductive function was studied in animal experiments. Pramipexole does not show teratogenicity in rats and rabbits, but at doses toxic to pregnant females, it was embryotoxic in rats.

During pregnancy, the drug should be administered only if the potential benefit to the mother exceeds the potential risk to the fetus.

Excretion of the drug with breast milk has not been studied. Since pramipexole inhibits the secretion of prolactin, it can be assumed that it also suppresses lactation. Therefore, the drug should not be taken during breastfeeding.

Side effects

When using the drug, the following side effects are listed: abnormal behavior (symptoms of impulsive and compulsive actions), such as a tendency to overeating (hyperphagia), obsessive desire to shop (pathological shopping), hypersexuality and pathological craving for gambling; Abnormal dreams, amnesia, confusion, constipation, delirium, dizziness, dyskinesia, dyspnoea, weakness, hallucinations, headache, hyperkinesia, lowering blood pressure, insomnia, libido disorders, nausea, paranoia, peripheral edema; pneumonia; Itching, rash and other hypersensitivity reactions; Anxiety, drowsiness, sudden falling asleep, fainting, vision disorders, including decreased visual acuity and clearness of perception, vomiting, weight change.

The incidence of hypotension during treatment with Mirapex® is not greater than with placebo. However, a reduction in blood pressure can be observed in individual patients at the beginning of treatment, especially if the dose of the drug is increased too quickly. With the treatment of Mirapex®, libido disorders (increase or decrease) can be associated.

Patients taking pramipexole tablets reported a sudden fall asleep during daytime activity, including driving, which sometimes led to traffic accidents. At the same time, some of them did not report having anxious signs such as drowsiness, often observed in patients taking pramipexole tablets at doses above 1.5 mg / day, which according to modern knowledge of the physiology of sleep always lead to sudden falling asleep . A clear connection with the duration of treatment was not revealed. At the same time, some patients took other drugs that had potentially sedative properties. In most cases, where such information was available, there were no such episodes after a dose reduction or cessation of treatment.

Patients with Parkinson's disease who received dopamine receptor agonists, including Mirapex®, especially in high doses, reported a pathological craving for gambling, increased libido and hypersexuality, which usually occurred after a dose reduction or discontinuation of treatment.

Within the system-organ classes, the following categories are used according to the incidence of side effects: very often (≥1 / 10); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <1/1000); Very rarely (<1/10000); not installed.

Table 1

System-Organ Class Side effect Frequency of occurrence
Parkinson's disease Idiopathic restless leg syndrome
Infections and invasions Pneumonia Infrequently Not installed
Psychotic disorders Abnormal behavior (symptoms of impulsive and compulsive actions) Often Not installed
Abnormal dreams Often Often
Propensity to overeating Not installed Not installed
Pathological Shopping Infrequently Not installed
Confusion of consciousness Often Infrequently
Rave Infrequently Not installed
Hallucinations Often Infrequently
Hyperphagia Not installed Not installed
Hypersexuality Infrequently Not installed
Insomnia Often Often
Disorders of libido (increased libido, decreased libido) Infrequently Infrequently
Paranoia Infrequently Not installed
Pathological craving for gambling Infrequently Not installed
Anxiety Often Infrequently
Disturbances from the nervous system Amnesia Infrequently Often
Dizziness Often Often
Dyskinesia Often Infrequently
Headache Often Often
Hyperkinesia Infrequently Not installed
Drowsiness Often Often
Sudden falling asleep Infrequently Infrequently
Fainting Infrequently Infrequently
Vision disorders Visual disturbances, including reduced visual acuity and clarity of perception Often Infrequently
Violations by the CAS Decreased blood pressure Often Infrequently
Disturbances from the respiratory system Dispnoe Infrequently Infrequently
Disorders from the digestive tract Constipation Often Often
Nausea Often Often
Vomiting Often Often
Disturbances from the skin and subcutaneous tissue Hypersensitivity reactions Infrequently Infrequently
Itching Infrequently Infrequently
Rash Infrequently Infrequently
Common violations Weakness Often Often
Peripheral edema Often Infrequently
Reactions identified by special studies System-Organ Class Weight loss Often Infrequently
Weight gain Infrequently Infrequently
InteractionPramipexole to a small extent (<20%) binds to plasma proteins and undergoes biotransformation. Therefore, interactions with other drugs that affect binding to plasma proteins, or excretion due to biotransformation are unlikely.

Drugs that inhibit the active secretion of cationic drugs through the renal tubules (for example cimetidine), or are themselves excreted by active secretion through the renal tubules, can interact with pramipexole, which is manifested in a decrease in the clearance of one or both drugs. In case of simultaneous use of such drugs (including amantadine) and pramipexole, it is necessary to pay attention to such signs of excessive dopamine stimulation, like dyskinesia, agitation or hallucinations. In such cases, it is necessary to reduce the dose.

Selegiline and levodopa do not affect the pharmacokinetics of pramipexole. Paramipexole does not affect the total amount of absorption or elimination of levodopa. Interaction with anticholinergic drugs and amantadine has not been studied. However, interaction with amantadine is possible, because Drugs have a similar elimination mechanism. Anticholinergic drugs are generally metabolized, so interaction with pramipexole is unlikely.

With an increase in the dose of pramipexole, a reduction in the dose of levodopa is recommended, while the dose of other antiparkinsonian drugs should be maintained at a constant level.

Because of the possible cumulative effects, patients should be cautioned when taking other sedative drugs or alcohol in combination with the Mirapex® drug, and also while taking medications that increase the concentration of pramipexole in plasma (eg, cimetidine).

It is necessary to avoid the simultaneous administration of pramipexole with antipsychotic drugs (for example, if antagonism is expected).

Dosing and Administration

Inside, regardless of food intake, washing down with water.

The daily dose is evenly divided into 3 doses.

Symptomatic treatment of Parkinson's disease

Initial therapy. As indicated below, the initial daily dose of 0.375 mg is increased every 5-7 days. To reduce side effects, the dose should be selected gradually until the maximum therapeutic effect is achieved.

table 2

Scheme of increasing the dose of Mirapex ®

Weak Dose, mg Total daily dose, mg
1-st 3 × 0,125 0,375
2-d 3 × 0,25 0,75
3-d 3 × 0,5 1,5
If you need to further increase the daily dose, add 0.75 mg per week to a maximum dose of 4.5 mg / day.Supportive therapy. Individual dose should be in the range from 0.375 mg to 4.5 mg / day. Both at the early and late stages of the disease, the drug was effective starting at a daily dose of 1.5 mg. It is not excluded that in some patients doses above 1.5 mg / day can provide an additional therapeutic effect, especially at a late stage of the disease, when a decrease in the dose of levodopa is indicated.

Termination of treatment. Pramipexole should be discontinued gradually over several days.

Doses for patients receiving both levodopa therapy. With simultaneous therapy with levodopa, it is recommended to reduce the dose of levodopa as the dose increases, and during maintenance therapy with pramipexole. This is necessary to avoid excessive dopaminergic stimulation.

Doses for patients with renal insufficiency. For initial therapy: in patients with Cl creatinine above 50 ml / min, a daily dose or frequency of reduction is not required. With Cl creatinine 20-50 mg / ml, the initial daily dose of the drug is prescribed in 2 divided doses, starting with 0.125 mg twice daily (0.25 mg / day). Do not exceed the maximum daily dose of 2.25 mg of pramipexole. At Cl creatinine <20 ml / min, the daily dose of the drug is prescribed 1 time per day, starting with 0.125 mg. Do not exceed the maximum daily dose - 1.5 mg pramipexole.

If during the maintenance therapy the kidney function decreases, the daily dose of the drug is reduced by the same percentage, which decreases the creatinine clearance, i.å. If the clearance of creatinine is reduced by 30%, then the daily dose of the drug should be reduced by 30%. The daily dose can be divided into two doses if Cl creatinine is in the range of 20-50 ml / min, and taken once a day if Cl creatinine is less than 20 ml / min.

Doses for patients with hepatic insufficiency. There is no need to reduce the dose in patients with hepatic insufficiency.

Symptomatic treatment of idiopathic restless leg syndrome:

Initial therapy. The recommended initial daily dose is 0.125 mg, 2-3 hours before bedtime. If patients require additional symptomatic relief, the dose can be increased every 4-7 days to a maximum dose of 0.75 mg per day (as shown in Table 3 below).

Table 3

Scheme of increasing the dose of Mirapex

Steps of increasing Dose for reception 1 time a day, in the evening, mg
1 0,125
2* 0,25
3* 0,5
4* 0,75

* If necessary.

Supportive therapy. The individual dose should be in the range from 0.125 to 0.75 mg / day.

Termination of treatment. Treatment can be stopped without a gradual dose reduction. In clinical trials, only 10% of patients showed signs of weight gain after a sharp cessation of treatment, this effect was manifested at any dosage.

Doses for patients with renal insufficiency. Removal of the drug depends on the function of the kidneys and directly correlates with the clearance of creatinine. Based on pharmacokinetic studies in patients with renal insufficiency, for patients with Cl creatinine more than 20 ml / min, a daily dose reduction is not required. The use of Mirapecx® in patients with restless legs syndrome suffering from renal failure has not been studied.

Doses for patients with hepatic insufficiency. The need for dose reduction in patients with hepatic insufficiency is not considered, since approximately 90% of the absorbed drug is released through the kidneys.

Dose for children and adolescents. The safety and efficacy of Mirapec ® in children and adolescents under the age of 18 years is not established.

Overdose

Cases of severe overdose are not described.

Presumptive symptoms inherent in the pharmacodynamic profile of dopamine receptor agonists: nausea, vomiting, hyperkinesia, hallucinations, excitation and reduction of blood pressure.

Treatment: the established antidote does not exist, with overdosage recommended gastric lavage, symptomatic therapy, dynamic observation. The effectiveness of hemodialysis is not established.

When signs of CNS excitement possible appointment of antipsychotics.

Special instructions

Hallucinations and confusion are known side effects when treated with dopamine agonists and levodopa. When using Mirapex ® in combination with levodopa in late stages of the disease, hallucinations were more frequent than with monotherapy with pramipexole in patients at an early stage of the disease. Patients should be informed of the possibility of hallucinations (mainly visual), which can affect the ability to drive a car.

Patients and people who care about them should be aware that in connection with the treatment of patients with dopaminergic drugs, signs of abnormal behavior (symptoms of impulsive and compulsive actions), such as a tendency to overeating (hyperphagia), obsessive desire to shop (pathological Shopping), hypersexuality and pathological craving for gambling. In such cases, a decision should be made to reduce the dose / gradually stop treatment.

In patients with psychotic disorders, the appointment of dopamine agonists in combination with pramipexole is only possible after a preliminary assessment of the possible risk-benefit. Simultaneous administration of pramipexole with antipsychotic drugs should be avoided.

It is recommended to check eyesight at regular intervals or immediately after the administration of the drug in the presence of such disorders.

Care must be taken when a patient has a serious cardiovascular disease. In connection with the risk of orthostatic hypotension during the treatment with dopaminergic drugs, it is recommended to control blood pressure, especially at the beginning of treatment.

Patients should be warned about a possible sedative effect of the drug. It has been reported that cases of drowsiness and sudden falling asleep during daily activities, (including when driving a car or managing complex mechanisms) can occur at any time during treatment, and patients should be informed about it.

Epidemiological studies have shown that patients with Parkinson's disease have a high risk (2 to about 6 times higher) of melanoma than the general population. Whether this increased risk is a consequence of Parkinson's disease, or is associated with other factors, such as taking medications that are used in Parkinson's disease, is not known.

Due to the reasons given above, patients and persons who care for them should be informed that during the period of taking pramipexole or other dopaminergic drugs, one should carefully consider the possible development of melanoma.

Parkinson's disease

It was reported that with a sharp discontinuation of therapy, there was a symptom complex resembling a malignant neuroleptic syndrome.

Strengthening the syndrome of "restless legs"

The reports in the literature indicate that treatment of the "restless legs" syndrome with dopaminergic drugs can lead to its amplification.

This reinforcement was an earlier onset of symptoms in the evening (or even in the afternoon), an increase in this symptom and the spread of symptoms to other extremities. However, in a 26-week controlled clinical trial specifically devoted to the study of this effect, there was no significant difference in the clinical symptoms between pramipexole and placebo groups.

Influence on the ability to drive and technique. Patients should be informed of the possibility of hallucinations (mainly visual), which may affect the ability to drive.

When applying the drug, it is possible to develop sedative effects, including drowsiness and falling asleep during daily activities. Since drowsiness is a frequent undesirable phenomenon with potentially serious consequences, patients should not drive the car or work with other complex mechanisms until they have acquired sufficient experience with Mirapex® to assess whether it affects negatively or not on their mental and / Or motor activity. If during the treatment patients experience increased drowsiness or episodes of falling asleep during their daily activities (ie during a conversation, eating, etc.), they should refuse to drive, work with equipment, and consult a doctor.

Terms of leave from pharmacies

On prescription.

Storage conditions of the drug Mirapex

At a temperature of 15-30 ° C.

Keep out of the reach of children.

Shelf life of Mirapex

3 years.

Do not use after the expiry date printed on the package.

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