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

active substance: pramipexole dihydrochloride monohydrate 0.25 mg or 1 mg; Excipients: mannitol, corn starch, silicon dioxide colloid (aerosil), povidone K-30, magnesium stearate.

Description:

Dosage of 0.25 mg: biconvex tablets oblong with rounded ends with a risk, white or almost white.

Dosage 1 mg: round flat-cylindrical tablets of white or almost white color with a facet and a risk.

Pharmacotherapeutic group:An antiparkinsonian agent - a 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 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 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 using positron emission tomography (PET) have shown that the moderate presynaptic dopaminergic dysfunction in the striatum can be involved in the pathogenesis of the restless leg syndrome.

Pramipexole in vitro protects neurons from the neurotoxicity of levodopa.

Reduces the secretion of prolactin (dose-dependent).

With prolonged use (more than 3 years) of pramipexole in patients with Parkinson's disease, there was no evidence of a decrease in efficacy.

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

Pharmacokinetics:

Suction.

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

Distribution.

Pramipexole binds to proteins to a very small extent (less than 20%). Volume of distribution (Vd) is 400 liters.

Metabolism and excretion.

It is exposed to a metabolism to an insignificant degree. About 90% of the dose is excreted through the kidneys (80% in unchanged form) and less than 2% through the intestine. The total clearance of pramipexole is about 500 ml / min, the renal clearance is about 400 ml / min. T1 / 2 ranges from 8 hours in young and up to 12 hours in the elderly.

Indications:

Symptomatic treatment of idiopathic Parkinson's disease as monotherapy or in combination with levodopa preparations at a late stage of the disease,when the effects of levodopa are weakened or become unstable and fluctuations of the therapeutic effect (on-off) occur.

Symptomatic treatment of idiopathic syndrome of restless legs.

Contraindications:

- Hypersensitivity to pramipexole and other components that make up the drug.

- Children's age (up to 18 years).

Carefully:

Renal failure, hepatic insufficiency, arterial hypotension, cardiovascular diseases, simultaneous reception of dopamine receptor agonists, sedatives, cimetidine, amantadine, ethanol.

Pregnancy and lactation:

The possibility of using the drug during pregnancy and during the breast feeding 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 food intake, washing down with water.

The daily dose is evenly divided into 3 divided 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 1

Scheme of increasing the dose of Mipexol®

A week	Dose (mg)	The total daily dose (mg)
1	3 х 0,125	0,375
2	3 x 0.25	0,75
3	3 x 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. The 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 therapy. The drug should be canceled gradually over several days. 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.

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.

Patients with renal insufficiency. For initial therapy in patients with creatinine clearance (CK) above 50 ml / min, a decrease in the daily dose or frequency of admission is not required. For patients with creatinine clearance from 20 to 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. Patients with creatinine clearance less than 20 ml / min daily dose prescribed once a day, starting with 0.125 mg. Do not exceed the maximum daily dose of 1.5 mg pramipexole.

If during the maintenance therapy the kidney function 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 doses 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.

Patients with hepatic insufficiency.

In patients with hepatic insufficiency, dose adjustment is not required.

Symptomatic treatment of idiopathic syndrome of 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 Table 2 below).

table 2

Scheme of increasing the dose of Mipexol®

Steps to increase	Dose for reception once 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.

Patients with renal insufficiency. Removal of the drug depends on the function of the kidneys and directly correlates with the clearance of creatinine. For patients with creatinine clearance greater than 20 ml / min, a daily dose reduction is not required. The use of pramipexole in patients with restless legs syndrome, suffering from renal insufficiency, has not been studied.

Patients with hepatic insufficiency. In patients with hepatic insufficiency, dose adjustment is not required.

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 (pathological shopping), hypersexuality, pathological craving for gambling; heart failure, confusion, constipation, delirium, dizziness, dyskinesia, shortness of breath, fatigue, hallucinations, headache, hiccups, hyperkinesia,lowering blood pressure, insomnia, libido disorders, impaired secretion of antidiuretic hormone, nausea, paranoia, peripheral edema, pneumonia, pruritus, rash and other hypersensitivity reactions, anxiety, drowsiness, sudden falling asleep, fainting, visual impairment, including visual acuity and sharpness reduction perception, vomiting, weight loss, loss of appetite.

Tables 3 and 4 show the most common side effects with pramipexole in patients with Parkinson's disease and restless legs syndrome. Most of the side effects were mild or moderate, usually manifested in the early stages of therapy and disappeared with continued use of the drug.

For the system-organ classes, the following classification (WHO) is 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); not is established.

Table 3. Parkinson's disease

System of organs	Frequency	By-effect
Infectious and parasitic diseases	Infrequently	pneumonia
Disorders from the endocrine system	Infrequently	violation of the secretion of antidiuretic hormone¹
Disorders of the psyche	Often	abnormal dreams, behavioral disorders, confusion, hallucinations, sleep disturbance, insomnia
Disorders of the psyche	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
Disturbances on the part of the organ of sight	Often	visual impairment, including diplopia, decreased visual acuity and clarity of perception
Heart Disease	Infrequently	heart failure¹
Vascular disorders	Often	lowering of blood pressure
Disturbances from the respiratory system	Infrequently	shortness of breath, hiccough
Disorders from the gastrointestinal tract	Often	nausea
Disorders from the gastrointestinal tract	Often	constipation, vomiting
Disturbances from the skin and subcutaneous tissues	Infrequently	itching, rash and other signs hypersensitivity
General disorders and disorders at the site of administration	Often	fatigue, peripheral edema, 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 "infrequently", but it can be lower. An accurate assessment of the frequency category is not possible, since the side effect is not recorded in the clinical trials database containing information on 2762 patients with Parkinson's disease who received pramipexole.

Table 2. Syndrome of "restless legs"

System of organs	Frequency	By-effect
Infectious and parasitic diseases	Infrequently	pneumonia
Disorders from the endocrine system	Infrequently	violation of the secretion of antidiuretic hormone¹
Disorders of the psyche	Often	abnormal dreams, insomnia
Disorders of the psyche	Infrequently	behavior disorders, such as compulsive overeating, obsessive desire to shop, delirium¹, hyperphagia¹, hypersexuality, violations of sexual desire, paranoia¹, pathological craving for gambling¹, anxiety
Disturbances from the nervous system	Often	dizziness, drowsiness, headache
Disturbances from the nervous system	Infrequently	amnesia, dyskinesia, hyperkinesia, sudden falling asleep, fainting
Disturbances on the part of the organ of sight	Infrequently	visual impairment, including diplopia, decreased 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
Disorders from the gastrointestinal tract	Often	constipation, vomiting
Disturbances from the skin and subcutaneous tissues	Infrequently	itching, rash and other symptoms of hypersensitivity
General disorders and disorders at the site of administration	Often	fatigue
	Infrequently	peripheral edema, weight loss, decreased appetite, weight gain

¹This side effect was observed in the process of post-registration observation. With a probability of 95%, the frequency category does not exceed "infrequently", but it can be lower. An accurate assessment of the frequency category is not possible, since the side effect is not recorded in the clinical trials database containing information on 1395 patients with restless legs syndrome who received pramipexole.

Overdose:

Cases of severe overdose are not described.

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

Treatment: there is no specific antidote, overdose recommended gastric lavage, 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 minor extent (less than 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 through active secretion through the renal tubules, can interact with pramipexole, which is expressed 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, excitation or hallucinations. In such cases, it is necessary to reduce the dose.

Selegiline and levodopa do not affect the pharmacokinetics of pramipexole. Pramipexole does not affect the total amount of absorption or elimination of levodopa. Pramipexole increases C_m_Oh levodopa by 40% and reduces the time it reaches from 2.5 to 0.5 hours. 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.

Interaction with anticholinergic drugs and amantadine has not been studied. However, interaction with amantadine is possible, because drugs have similar removal mechanism. Anticholinergic drugs The drugs are generally metabolized, so interaction with pramipexole is unlikely.

Because of possible cumulative effects, patients should be cautioned when taking other sedativesdrugs or alcohol in combination with the drug, as well as with the simultaneous use of drugs that increase the concentration of pramipexole in the plasma (for example, cimetidine).

It is necessary to avoid simultaneous administration of pramipexole with antipsychotic drugs (possibly antagonistic action).

Special instructions:

When appointing the drug to patients with Parkinson's disease and renal dysfunction, it is recommended to reduce the dose in accordance with the recommendations (see section "Method of administration").

Hallucinations and confusion are known side effects when treated with dopamine agonists and levodopa. When pramipexole was used 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 receiving pramipexole and persons caring for them should be informed about the possibility of hallucinations (mainly visual) and confusion of consciousness.

During the treatment of Parkinson's disease, dopamine receptor agonists, including pramipexole, there are cases of pathological craving for gambling, increased libido, hypersexuality, compulsive obsessive overeating, obsessive desire to shop. Patients and caregivers should be informed of possible changes in behavior. In such cases, a decision should be taken to reduce the dose of the drug or to gradually stop treatment.

When using pramipexole in combination with levodopa in the late stages of Parkinson's disease, at the initial stage of dose selection, dyskinesia may develop, in the case of which the dose of levodopa should be reduced.

In patients with psychotic disorders, simultaneous use of antipsychotics in combination with pramipexole is only possible if the potential benefit exceeds the possible risk. Simultaneous administration of pramipexole and antipsychotics is not recommended, for example, if a dopamine antagonistic effect is possible.

In the event of visual impairment, it is recommended to monitor the eyesight at regular intervals or immediately after the administration of the drug in the presence of such disorders.

Care should be taken when a patient has a severe 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 drowsiness and sudden falling asleep during daily activities can occur at any time during the treatment period and patients should be informed about this.

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

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 devoted 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:

In connection with the possibility of developing drowsiness and hallucinations, in order to avoid episodes of falling asleep, patients taking the drug must refuse for the period of treatment or until the symptoms of relapse of the disease disappear and signs of drowsiness from driving and working with mechanisms requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, 0.25 mg and 1 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1, 3 contour cell packs along with the instruction for use are placed in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004541

Date of registration:15.11.2017

Expiration Date:15.11.2022

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Information update date: & nbsp07.12.2017

Illustrated instructions

Instructions

Mipexol® (Mipexole)