Expiration date: 11/2025

The composition and form of issue:

Extended-release tablets, 1 tablet contains active substance:

pramipeksola dihydrochloride monohydrate 0.375, 0.75, 1.5, 3 or 4.5 mg

(equivalent to 0.26, and 0.52, of 1.05, 2.1 or pramipeksola of 3.15 mg base, respectively) 

excipients: hypromellose 2208 — 112,5/148,5/157,5/191,25/225 mg of corn starch— 119,375/160,62/169,65/209,075/250 mg carbomer 941 — 15/16,5/17,5/17/15 mg silica colloidal anhydrous— 1,5/1,98/2,1/2,55/3 mg of magnesium stearate— 1,25/1,65/1,75/2,125/2,5 mg 

blister foil aluminum/foil aluminum 10 PCs the paper cartons 1, or 3 blisters.

Description pharmaceutical form:

Tablets 0.375 mg: biconvex with beveled edges, round, white or almost white, engraved with the company logo on one side and engraved "P1" on the other.

Tablets 0.75 mg: biconvex with beveled edges, round, white or almost white, engraved with the company logo on one side and engraved "P2" on the other.

Tablets 1.5 mg: oval biconvex, white or almost white, engraved with the company logo on one side and engraved "P3" on the other.

Tablets 3 mg: oval biconvex, white or almost white, engraved with the company logo on one side and engraved "R4" on the other.

Pills 4.5 mg: oval biconvex, white or almost white, engraved with the company logo on one side and engraved "R5" on the other.

Pharmacokinetics:

Pramipexole once inside quickly and completely absorbed. The absolute bioavailability exceeds 90% and the Tmax in plasma is about 6 h. generally, eating does not affect the bioavailability pramipeksola. After a fatty meal there is a slight increase of about 20%, Cmax, and a reduction of about 2 hours, Tmax, having no clinical importance.

Pramipexole shows linear kinetics and a relatively small variability of plasma levels between the patients, regardless of the pharmaceutical form. Pramipexole is bound to plasma proteins to a very small extent (<20%) and has a large Vd — 400 L. there is a high concentration of the drug in the brain tissue of rats (approximately 8 times higher than in plasma). Metabolized to a small extent.

About 90% of the dose is excreted via the kidneys (80% unchanged) and less than 2% found in the feces. Pramipeksola total clearance is about 500 ml/min, renal clearance is about 400 ml/min. T1/2 varies from 8 hours in the young to 12 hours in the elderly.

Description pharmacological action:

Pramipexole — dopamine receptor agonist with high selectivity and specificity associated with dopamine receptors of the D2 family, which has the most pronounced affinity for the D3 subtype of receptors. Reduces the deficit of motor activity in Parkinson's disease by stimulating dopamine receptors in the striatum. Pramipexole inhibits synthesis, release and metabolism of dopamine. In vitro pramipexole protects dopamine neurons from degeneration that occurs in response to ischemia or methamphetamine neurotoxicity. In vitro pramipexole protects neurons from neurotoxicity of levodopa.

Reduces the secretion of prolactin (dose-dependent).

In clinical studies, data from healthy volunteers, in whom increasing the dose of the drug Mirapex PD (pills prolonged action) was carried out faster than every 3 days up to 4.5 mg per day, there was an increase in BP and HR. In studies of these patients (increase dose was proizvodilas with a one week interval), this effect was not observed.

Indications:

Symptomatic treatment of idiopathic Parkinson's disease: monotherapy or in combination with levodopa.

Contraindications:

• hypersensitivity to pramipexole or any component of the drug
  
• children under 18 years of age.
  

Caution: renal failure, decrease in blood pressure.

Application of pregnancy and breast-feeding:

Effect on pregnancy and lactation in humans has not been investigated.

Pramipeksola possible impacts on reproductive function was studied in experiments on animals. Pramipexole has shown no teratogenicity in rats and rabbits, however, at doses toxic to the pregnant female was embryotoxic. During pregnancy, the drug should be administered only if the potential benefit to the mother outweighs the potential risk to the fetus.

Excretion of the drug in breast milk has not been studied. The concentration of the drug in the milk of rats was higher than in plasma. Since pramipexole inhibits the secretion of prolactin, it can be assumed that it also suppresses lactation. Therefore, the drug should not be taken during the period of lactation.

Side effects:

When using the drug the following side effects: abnormal behaviour (symptoms of impulsive and compulsive actions), such as the tendency to overeat (hyperphagia), the compulsive desire to shop (pathological shopping), hypersexuality and pathological gambling abnormal dreams, amnesia, confusion, constipation, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesis, hyperphagia, hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus, rash and other hypersensitivity reactions restlessness, drowsiness, sudden falling asleep, fainting, blurred vision (including diplopia, reduced visual acuity and clarity of perception), vomiting, weight changes, including decreased appetite.

The incidence of hypotension during treatment with the drug Mirapex PD is not greater than in the placebo treatment. However, hypotension can occur in individual patients at the beginning of treatment, especially if the dose increase too quickly. With drug treatment Mirapex PD can be related to disorders of libido (increase or decrease).

Patients taking pills pramipeksola, have reported a sudden falling asleep during daily activities, including driving, which sometimes led to road accidents. At the same time some of them did not report having warning signs such as drowsiness, which is often observed in patients taking pramipeksola tablets at doses above 1.5 mg/day, which according to present knowledge about the physiology of sleep will always lead to a sudden fall asleep. A clear relationship with the duration of treatment was not detected. In this part of the patients took other drugs with potentially sedating properties. In most cases, where they were available such information, no such episodes after dose reduction or discontinuation of treatment.

Patients with Parkinson's disease receiving therapy with dopamine agonists, including Mirapex PD, especially in large doses, reported a pathological craving for gambling, increased libido and hypersexuality, which usually took place after dose reduction or discontinuation of treatment.

Inside the system-organ classes according to the frequency of side effects are used the following categories: very common (&ge1/10) frequently (&GE. 1/100, <1/10) uncommon (&ge1/1000, <1/100) rare (&ge1/10000, <1/1000) very rare (<1/10,000) uninstalled.

Infections and invasions: rare — pneumonia.

Psychotic disorders: often — anomalous behavior (the symptoms of impulsive and compulsive actions), abnormal dreams, confusion, hallucinations, insomnia uncommon — the tendency to overeating, pathological shopping, nonsense, hyperphagia, hypersexuality, libido disorders (increased or decreased libido), paranoia, pathological gambling, restlessness.

From the nervous system: very often — dizziness, dyskinesia, drowsiness often — headache infrequent: amnesia, hyperkinesis, sudden falling asleep, fainting.

From the side of organs of vision: often — blurred vision (including diplopia, decreased visual acuity and clarity of perception).

From the CCC: often — decreased blood pressure.

The respiratory system: rarely — dyspnea, hiccups.

With the reversal of the gastrointestinal tract: very often — nausea often — constipation, vomiting.

With the reversal of skin and subcutaneous tissue: rare — hypersensitivity reactions, pruritus, rash.

Common: often — fatigue, peripheral edema.

Reactions have been identified during special investigations: frequent — weight loss including decreased appetite uncommon — increase in body weight.

Drug interactions:

Pramipexole to a small extent (<20%) bound to plasma proteins and biotransformation. Therefore, interaction with other drugs affecting plasma protein binding or elimination by biotransformation are unlikely.

Drugs that inhibit the active secretion of cationic drugs through the renal tubules (such as cimetidine) or themselves derived by active secretion via the renal tubules, can interact with pramipexole, resulting in reduced clearance of one or both drugs. In the case of the simultaneous use of these drugs, including amantadine and pramipeksola, you need to pay attention to such signs of excess dopamine stimulation as dyskinesia, agitation or hallucinations. In such cases it is necessary to reduce the dose.

Selegiline and l-DOPA do not affect the pharmacokinetics pramipeksola. Pramipexole does not affect the total amount of absorption or elimination of levodopa. Interaction with anticholinergic drugs and amantadine has not been studied. However, the interaction with amantadine is possible, because the drugs have a similar mechanism of excretion. Anticholinergic drugs are mainly removed by metabolic, interaction with pramipexole unlikely.

With increasing doses of the drug in patients with Parkinson's disease, it is recommended to decrease the dose of levodopa, the dose of other antiparkinsonian drugs must be maintained at a constant level.

Because of the possible cumulative effects, patients are advised to exercise caution when taking other sedative drugs or alcohol in combination with drug Mirapex PD, but also the simultaneous administration of drugs that increase the concentration pramipeksola in plasma (e.g. cimetidine).

Method of application and dose:

Inside.

Extended-release tablets should be taken 1 time a day, at approximately the same time of day regardless of meals. Swallow the tablet whole with water, not chew, break, or shred.

Missed dose of the drug should be taken in the case, if after the usual time of admission is not passed more than 12 hours If it has been more than 12 hours, the missed dose should not be accepted, the next dose should be taken the next day at the usual time.

Patients who are already taking pills Mirapex can be transferred to tablets of the prolonged action of Mirapex PD during the day, at the same dose.

The initial therapy. As shown below, the dose should be gradually increased from the starting dose of 0.375 mg per day and then increased every 5-7 days. To prevent unwanted side effects the dose should be selected to achieve maximum therapeutic effect.

Weeks	Dose, mg	The total daily dose, mg
1	0,375	0,375
2	0,75	0,75
3	1,5	1,5

If necessary further dose increase, increase daily dose by 0.75 mg at weekly intervals to a maximum dose of 4.5 mg per day.

With supportive treatment. Individual dose should be in the range from 0.375 mg to a maximum dose of 4.5 mg per day. In major studies conducted in the initial and developed stages of the disease in the course of increasing doses, treatment efficacy was observed starting with a daily dose of 1.5 mg. This does not preclude that in individual patients doses higher than 1.5 mg per day may lead to additional therapeutic effect.

This partly relates to patients with extensive-stage disease, which has been shown to decrease the dose of levodopa.

The cessation of treatment. The dose should be reduced to 0.75 mg per day until until the daily intake reaches 0.75 mg. After that dose should be reduced by 0.375 mg per day.

The dose for patients receiving concomitant treatment with levodopa. In concurrent therapy with levodopa is recommended with increasing dose and during maintenance therapy pramipexole to reduce the dose of levodopa. This is to prevent excessive dopaminergic stimulation.

Dose for patients with renal insufficiency. Pramipeksola excretion from the body depends on renal function.

For initial therapy in patients with creatinine Cl >50 ml/min, decrease daily dose or frequency of administration is not required.

Patients with Cl creatinine clearance 30 to 50 ml/min, treatment should be initiated with a dose of 0.375 mg of the drug every other day. After 1 week of therapy before increasing the daily dose, you should take precautions and carefully assess therapeutic response and tolerance. If necessary further dose increase, the dose should be increased by 0.375 mg pramipeksola at weekly intervals to a maximum dose of 2.25 mg pramipeksola a day.

Information about treatment pills time-release patients with Cl creatinine below 30 mg/min do not exist. Should explore the feasibility of using tablets Mirapex PD.

If renal function is decreased during maintenance treatment, follow the recommendations presented above.

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

The dose for children and adolescents. The safety and efficacy of the drug in children and adolescents under the age of 18 years not installed.

Overdose:

Cases of severe overdose not described.

The alleged symptoms peculiar pharmacodynamic profile of a dopamine receptor agonists: nausea, vomiting, hyperkinesis, hallucinations, agitation and decrease in blood pressure.

Treatment: installed there is no antidote to overdose, it is recommended gastric lavage, symptomatic therapy, dynamic monitoring. The effectiveness of hemodialysis is not established. When signs of CNS excitation may prescription of neuroleptics.

Precautions:

In the appointment of Mirapex PD patients with renal insufficiency recommended dose reduction (see "Method of application and dosage").

Hallucinations and confusion — known side effects during treatment with dopamine agonists and levodopa.

Hallucinations are more often seen in the treatment of drug Mirapex PD in combination with levodopa in patients with extensive-stage Parkinson's disease than in monotherapy in patients with Parkinson's disease at an early stage of the disease. Patients should be informed about what can develop hallucinations (mainly visual).

Patients and persons who take care of them, should know that in connection with the treatment of patients dopaminergic means you may experience signs of abnormal behavior (the symptoms of impulsive and compulsive actions), such as a tendency to overeat, compulsive desire to shop (pathological shopping), hypersexuality, and pathological gambling. In such cases, should be considered the decision on reduction of the dose or gradual discontinuation of treatment.

In patients with psychotic disorders the purpose of dopamine agonists in combination with pramipexole possible only after a preliminary assessment of the possible risk-benefit. Simultaneous reception pramipeksola with antipsychotic medicines should be avoided.

It is recommended to check your vision at regular intervals of time, or immediately after the appointment of the drug in the presence of such violations.

Caution should be exercised if patients with severe cardiovascular disease. In connection with the risk of orthostatic hypotension when conducting dopaminergic therapy is recommended to control the AD especially at the beginning of treatment.

Patients should be warned about the possible sedative effect of the drug, including sleepiness and sudden falling asleep during daytime activities.

Epidemiological studies have shown that patients with Parkinson's disease have a high risk, from 2 to about 6 times higher of developing melanoma than the General population. Is this increased risk the result of Parkinson's disease or is associated with other factors such as intake of drugs used in Parkinson's disease is unknown.

For the reasons given above, patients and persons who take care of them, should be informed that the reception is pramipeksola or other dopaminergic drugs, pay attention to possible development of melanoma.

There are reports that the sudden discontinuation of therapy, dopaminergic drugs may be symptoms of neuroleptic malignant syndrome.

Effects on ability to drive or to perform work requiring high speed physical and mental reactions. Patients should be informed of the possibility of hallucinations, mainly visual, which can affect the ability to drive a car.

In applying the drug may develop sedative effects, including drowsiness and falling asleep during daily activities. Since somnolence is a frequent adverse event with potentially serious consequences, patients should not drive a car or operate other complex machinery until they have enough experience of drug treatment, Mirapex PD to assess affect whether it is negative or not on their mental and/or physical activity. Patients should be advised that if during the treatment they experience increased somnolence or episodes of falling asleep during daily activities (i.e. during speaking, eating, etc.), they should refrain from driving, working with machinery and contact your doctor.