Mirapex - instructions for use, dose, side effects, contraindications

Excipients: mannitol 61.0 mg (121.50 mg), corn starch 39.90 mg (79.85 mg), silicon dioxide colloid 1.20 mg (2.30 mg), povidone 1.15 mg (2.35 mg ), magnesium stearate 1.50 mg (3.00 mg).

Description:

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

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

Pharmacotherapeutic group:Dopamine receptor agonist

ATX: & nbsp

N.04.B.C.05 Pramipexole

Pharmacodynamics:

Pramipexole, a dopamine receptor agonist, with high selectivity and specificity binds to subgroup dopamine receptors D₂, of which has the most pronounced affinity for D₃ receptors. Reduces the lack of motor activity in Parkinson's disease due to the stimulation of 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 the syndrome of restless legs is not currently known. Despite the fact that the pathophysiology of the "restless legs" syndrome has not been fully studied, there are neuropharmacological data on the primary involvement of the dopaminergic system in the process. Studies performed with the use of positron emission tomography (PET)that the pathogenesis of the "restless leg" syndrome may involve moderate presynaptic dopaminergic dysfunction in the striatum.

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 decreased efficacy.

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

Pharmacokinetics:

Pramipexole is quickly and completely absorbed after ingestion. Absolute bioavailability is more than 90%, and maximum plasma concentrations are observed after 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 the concentrations between patients. Pramipexole binds to proteins to a very small extent (<20%), and has a large volume of distribution (400 liters). 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 detected in the stool.The total clearance of pramipexole is about 500 ml / min, the renal clearance is about 400 ml / min. The half-life (T_1/2) ranges from 8 h in young and up to 12 h in the elderly.

Indications:

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 under 18 years.

Carefully:

Renal failure, lowering blood pressure.

Pregnancy and lactation:

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 given 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. Because the pramipexole inhibits the secretion of prolactin, we can assume that it also suppresses lactation. Therefore, the drug should not be taken during breastfeeding.

Dosing and Administration:

Inside, regardless of the reception of food, washed down with water.

The daily dose is evenly divided into 3 divided doses. Calculation of doses is done by pramipexole dihydrochloride monohydrate.

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.

Scheme of increasing the dose MIRAPEX®

a week	dose (mg)	total daily dose (mg)
1	3x0,125	0,375
2	3 x 0.25	0,75
3	3x0.5	1,50

If you need to further increase the daily dose, add 0.75 mg per week to a maximum dose of 4.5 mg per day.

Supportive therapy

The individual dose should be in the range of 0.375 mg to 4.5 mg per 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 per day can give an additional therapeutic effect, especially at a late stage of the disease, when a decrease in the dose of levodopa is indicated.

Discontinuation of treatment

The dose of the drug should be reduced by 0.75 mg per day, until the daily dose reaches 0.75 mg. After that, the dose should be reduced by 0.375 mg per day.

Doses for patients receiving concurrent therapy with levodopa

At 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 creatinine clearance above 50 ml / min, a daily dose or frequency of reduction is not required. When creatinine is cleared 20-50 ml / min, the initial daily dose of the drug is prescribed in two divided doses, starting with 0.125 mg twice a day (0.25 mg per day). Do not exceed the maximum daily dose of 2.25 mg of pramipexole. When the creatinine clearance is less than 20 ml / min, the daily dose of the drug is prescribed once a day, starting at 0.125 mg. Do not exceed the maximum daily dose of 1.5 mg pramipexole.

If during maintenance therapy the function of the kidneys decreases, then the daily dose of the drug is reduced by the same percentage, which decreases the creatinine clearance, i.e.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 steps if the creatinine clearance is in the range of 20-50 ml / min, and taken once a day, if the creatinine clearance is less than 20 ml / min.

Doses for patients with liver failure: there is no need to reduce the dose in patients with liver failure.

Symptomatic treatment of idiopathic syndrome "restless legs"

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 the table below).

Scheme of increasing the dose of MIRAPEX®

Steps to increase	The dose for reception once a day, in the evening (mg)
1	0,125
2*	0,25
3*	0,50
4*	0,75

* if necessary

Supportive therapy

Individual dose should be in the range from 0.125 mg to 0.75 mg per day.

Discontinuation 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 dose.

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 individuals with renal insufficiency, for patients with creatinine clearance greater than 20 ml / min, a daily dose reduction is not required. The use of Mirapex ® in patients with restless legs syndrome, suffering from renal insufficiency, 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 excreted by the kidneys.

Dose for children and adolescents

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

Side effects:

Alleged side effects

When using the drug, the following side effects are expected: abnormal dreams, amnesia, impaired behavior (symptoms of impulsive and compulsive actions), such as compulsive overeating, obsessive desire to shop,Hypersexuality and pathological craving for gambling; heart failure, confused consciousness, constipation, delirium, dizziness, dyskinesia, dyspnea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, lowering blood pressure, impaired secretion of antidiuretic hormone, insomnia, disorders of sexual desire, nausea, paranoia, peripheral edema , pneumonia, pruritus, rash and other signs of hypersensitivity; anxiety, drowsiness, sudden falling asleep, fainting, visual impairment, including diplopia, decreased visual acuity and sharpness of perception, vomiting, weight loss, including decreased appetite, weight gain.

Based on an analysis of pooled data from placebo-controlled studies, including a total of 1,923 patients receiving pramipexole and 1,354 patients taking placebo, side effects were reported frequently in both groups. 63% of patients receiving pramipexole and 52% of patients taking placebo reported no less than one adverse drug reaction.

Tables 1 and 2 show the incidence of side effects from placebo-controlled clinical trials for Parkinson's disease and restless leg syndrome.The adverse drug reactions listed in these tables are those observed in 0.1% or more patients who received pramipexole, who were registered significantly more often in patients taking pramipexole, compared with the placebo group, or those events that have been clinically significant. Most side effects were mild or moderate, usually manifested in the early stages of therapy, and most tended to be eliminated even with continued therapy.

Within the system-organ classes, the following categories are used for 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).

Parkinson's disease, the most common side effects

The most common (≥5%) reported adverse drug reactions in patients with Parkinson's disease, more often with pramipexole compared with placebo, were nausea, dyskinesia, lower blood pressure, dizziness, drowsiness, insomnia, constipation, hallucinations, headache and fatigue.The incidence of somnolence is elevated at a dose exceeding 1.5 mg of pramipexole in the form of salt per day. More frequent side effect when combined with levodopa was dyskinesia. A decrease in blood pressure may develop at the beginning of therapy, especially if the dose of pramipexole is increased too quickly.

Table 1. Parkinson's disease

System Organ Class	Frequency	By-effect
Infectious and parasitic diseases
	Infrequently	pneumonia
Disorders from the endocrine system
	Infrequently	violation of the secretion of antidiuretic hormone¹
Mental disorders
	Often	abnormal dreams, impaired behavior (symptoms of impulsive and compulsive actions), confusion, hallucinations, insomnia
	Infrequently	compulsive overeating¹, obsessive desire to shop, delirium, hyperphagia¹, hypersexuality, violations of sexual desire, paranoia, pathological craving for gambling, anxiety
Disturbances from the nervous system
	Often	dizziness, dyskinesia, drowsiness
	Often	headache
	Infrequently	amnesia, hyperkinesia, sudden falling asleep, fainting
Vision disorders
	Often	visual impairment, including diplopia, reduced visual acuity and clarity of perception
Disorders from the cardiovascular system
	Infrequently	heart failure¹
	Often	lowering of blood pressure
Disturbances from the respiratory system
	Infrequently	shortness of breath, hiccough
Disorders from the gastrointestinal tract
	Often	nausea
	Often	constipation, vomiting
Disturbances from the skin and subcutaneous tissue
	Infrequently	itching, rash and other signs of hypersensitivity
Common violations
	Often	fatigability, peripheral edema
Violations revealed in special studies
	Often	weight loss, loss of appetite
	Infrequently	weight gain

¹ This side effect was observed in the process of post-registration observation. With a probability of 95%, the frequency category does not exceed "infrequent". but may be lower. An accurate assessment of the frequency category is not possible, because the side effect is not recorded in the clinical research database containing information on 2762 patients with Parkinson's disease who received pramipexole.

Restless legs syndrome, the most common side effects The most common (> 5%) reported side effects in patients with restless leg syndrome who received pramipexole, there was nausea, headache, dizziness and fatigue. Nausea and fatigue were more common in female patients. (20.8% and 10.5%, respectively) compared with men (6.7% and 7.3%, respectively).

Table 2. Restless legs syndrome

System Organ Class	Frequency	By-effect
Infectious and parasitic diseases
	Infrequently	pneumonia
Disorders from the endocrine system
	Infrequently	violation of the secretion of antidiuretic hormone¹
Mental disorders
	Often	abnormal dreams, insomnia
	Infrequently	impaired behavior (symptoms of impulsive and com- pulsive actions), such as compulsive overeating, obsessive desire to shop, nonsense¹, hyperphagia¹, hypersexuality, confusion, hallucinations, violations of sexual desire, paranoia¹, pathological craving for gambling¹, anxiety
Disturbances from the nervous system
	Often	dizziness, headache, drowsiness
	Infrequently	amnesia, dyskinesia, hyperkinesia, sudden falling asleep, fainting
Vision disorders
	Infrequently	visual impairment, including diplopia,reduced visual acuity and clarity of perception
Heart Disease
	Infrequently	heart failure¹
Vascular disorders
	Infrequently	lowering of blood pressure
Disturbances from the respiratory system
	Infrequently	shortness of breath, hiccough
Disorders from the gastrointestinal tract
	Often	nausea
	Often	constipation, vomiting
Disturbances from the skin and subcutaneous tissue
	Infrequently	itching, rash and other symptoms of hypersensitivity
Common violations
	Often	fatigue
	Infrequently	peripheral edema
Violations revealed in special studies
	Infrequently	weight loss, decreased appetite, weight gain

This side effect was observed in the process of post-registration observation. With a probability of 95%, the frequency category does not exceed "infrequent", but may be lower. An accurate assessment of the frequency category is not possible, because the side effect is not recorded in the clinical research database containing information on 1395 patients with Restless Leg Syndrome who received pramipexole.

Drowsiness

Taking pramipexole is often accompanied by drowsiness and infrequent excessive sleepiness during the day and episodes of sudden falling asleep.

Disorders of sexual desire

With the intake of pramipexole, disorders of sexual desire (weakening or enhancement) can rarely be associated.

Symptoms of impulsive and compulsive actions

Patients receiving dopamine agonists, including Mirapex®, may have a pathological passion for gambling, increased libido, hypersexuality, pathological shopping, compulsive overeating.

In an inter-group retrospective case-control screening study involving 3090 patients with Parkinson's disease, 13.6% of all patients receiving dopaminergic or nedopharminial therapy had symptoms of impulse control disorders during the past six months. Observable manifestations included a pathological passion for gambling, an irresistible passion for shopping, compulsive overeating and compulsive sexual behavior (hypersexuality). Possible independent risk factors for impulse control disorders included dopaminergic therapy and a large dose of dopaminergic drugs, a younger age (≤ 65 years), non-marital status, and a self-assessment of the presence of a pathological passion for gambling in a family history.

Heart failure

In clinical studies and in the process of post-registration observation, heart failure was recorded in patients taking pramipexole.

A pharmacoepidemiological study using pramipexole was associated with an increased risk of heart failure compared to the non-use of pramipexole (risk ratio was 1.86, 95% CI 1.21-2.85).

Overdose:

Cases of severe overdose are not described.

Proposed symptoms, characteristic of the pharmacodynamic profile of dopamine receptor agonists: nausea, vomiting, hyperkinesia, hallucinations, agitation and lowering blood pressure.

Treatment: The established antidote does not exist, with an overdose recommended washing stomach, symptomatic therapy, dynamic observation. The effectiveness of hemodialysis is not established.

With signs of CNS excitation, the administration of neuroleptics is possible.

Interaction:

Pramipexole 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 (eg, cimetidine), or which 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 as 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 overall 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.

Due to the possible cumulative effects, patients should be encouraged to exercise caution when receiving other sedating drugs or alcohol in combination with a preparation Mirapeks® and simultaneous reception and drugs that increase the concentration in plasma pramipexole (e.g., cimetidine).

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

Special instructions:

Hallucinations and confusion are known side effects when treated with dopamine agonists and levodopa. In applying Mirapeks® preparation in combination with levodopa in the later stages of the disease hallucinations were observed more frequently 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 those who care for them, should know that in connection with dopaminergic drugs treatment of patients may experience abnormal behavior symptoms (symptoms of impulsive and compulsive actions), such as the propensity 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 certain intervals or immediately after the appointment of the drug in the presence of such violations.

Care should be taken when a patient has a serious cardiovascular disease. In connection with the risk of orthostatic hypotension during therapy 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 was reported that cases of drowsiness and sudden falling asleep during daily activities, (incl.when driving a car or managing complex machinery) can occur at any time during the treatment period, and patients should be informed of this.

Epidemiological studies have shown that in patients with Parkinson's disease there is a high risk (from 2 before, approximately, 6 times higher) of melanoma than in 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 people 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 the 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 dedicated to the study of this effect, there was no significant difference in the increase in clinical symptoms between pramipexole and placebo groups.

Effect on the ability to drive transp. cf. and fur:

Patients should be informed of the likelihood of hallucinations (mainly visual), which may affect the ability to drive a car.

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 must refuse to drive the car, work with the equipment, and consult a doctor.

Form release / dosage:

Tablets, 0.25 mg or 1 mg.

Packaging:

For 10 tablets in a blister of PA / aluminum foil / PVC.

3 blisters with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 30 ° C, protected from light and out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:П N015908 / 01

Date of registration:20.07.2009 / 02.08.2010

Expiration Date:Unlimited

The owner of the registration certificate:Behringer Ingelheim Ellas A.E.Behringer Ingelheim Ellas A.E. Greece

Manufacturer: & nbsp

BOEHRINGER INGELHEIM PHARMA, GmbH Austria

Representation: & nbspBERINGER INGELCHAIM INTERNATIONAL GmbH BERINGER INGELCHAIM INTERNATIONAL GmbH Germany

Information update date: & nbsp09.06.2018

Illustrated instructions

Instructions

Mirapex® (Mirapex®)