Мирапекс® PD

General characteristics. Structure:

Active ingredient: 0,375 mg of a pramipeksol of dihydrochloride of monohydrate (that corresponds to 0,26 mg of a pramipeksol), 0,75 mg of a pramipeksol of dihydrochloride of monohydrate (that corresponds to 0,52 mg of a pramipeksol), 1,5 mg of a pramipeksol of dihydrochloride of monohydrate (that corresponds to 1,05 mg of a pramipeksol), 3 pramipeksol of dihydrochloride of monohydrate (that corresponds to 2,1 mg of a pramipeksol), 4,5 mg of a pramipeksol of dihydrochloride of monohydrate (that corresponds to 3,15 mg of a pramipeksol).

Excipients: gipromelloza 2208, starch corn, carbomer 941, silicon dioxide colloid, magnesium stearate.

Pharmacological properties:

Pharmacodynamics. Protivoparkinsonichesky drug - an agonist of dopamine receptors. With high selectivity and specificity contacts dopamine receptors of subgroup of D2 from which has the most expressed affinity to D3 to receptors. Reduces deficit of a physical activity at Parkinson's disease due to stimulation of dopamine receptors in a striate body. Pramipeksol inhibits synthesis, release and metabolism of a dopamine. Pramipeksol of in vitro protects dopamine neurons from the degeneration arising in response to ischemia or a metamfetaminovy neurotoxicity.

Pramipeksol of in vitro protects neurons from a levodopa neurotoxicity.

Reduces prolactin secretion (дозозависимо).

In clinical trials on healthy volunteers at whom increase in a dose of the drug Mirapeks® PD was carried out quicker than follows (each 3 days), up to 4.5 mg/days, increase in the ABP and ChSS was observed. In researches on patients this effect was not observed.

Pharmacokinetics. Absorption and distribution. Pramipeksol after intake is quickly and completely soaked up. Absolute bioavailability exceeds more than 90% and Cmax in plasma is reached approximately in 6 h. As a rule, meal does not influence bioavailability of a pramipeksol. After reception of greasy food small increase, approximately for 20%, Cmax and delay, approximately on 2 h, time of achievement of Cmax who do not have clinical value is observed.

Pramipeksol shows linear kinetics and rather small variability of levels in plasma between patients, irrespective of a pharmaceutical form. Pramipeksol contacts proteins of plasma in very insignificant degree (<20%), and has big Vd (400 l). High concentration of drug in tissues of a brain of rats were observed (about 8 times higher, than in plasma).

Metabolism and removal. Is exposed to metabolism in insignificant degree. About 90% of a dose are removed through kidneys (80% in not changed look) and less than 2% are found in Calais. The general clearance of a pramipeksol makes about 500 ml/min., the renal clearance makes about 400 ml/min. of T1/2 fluctuates of 8 h at young people and to 12 h at elderly people.

Indications to use:

— a symptomatic treatment of an idiopathic disease of Parkinson (drug can be used for monotherapy or in a combination with a levodopa).

Route of administration and doses:

It is necessary to take a pill of the prolonged action 1 times/days, approximately at the same time day. Tablets are swallowed entirely, washing down with water, tablets cannot be chewed, broken or crushed. A pill can be taken irrespective of meal.

If time of the next administration of drug was passed, then if from the moment of usual time of reception there did not pass more than 12 h, it is necessary to accept drug in a daily dose. If there passed more than 12 h, then it is not necessary to accept drug, the next reception has to take place in usual time next day.

Patients who already take a pill of Mirapeks can be translated reception of tablets of the prolonged action of Mirapeks® of PD within a day, in the same dose.

Initial therapy:

As it is given below, the dose should be increased gradually, since a starting dose of 0.375 mg/days and then to raise each 5-7 days. For prevention of undesirable side effects, the dose should be selected before achievement of the maximum therapeutic effect.

Weeks	Dose (mg)	Full daily dose (mg)
1	0.375	0.375
2	0.75	0.75
3	1.50	1.50

If further increase in a dose is necessary, a daily dose increase on 0.75 mg through week intervals to the maximum dose 4.5 mg/days.

The supporting treatment: the therapeutic dose has to be in the range from 0.375 mg to the maximum dose of 4.5 mg/days. In the main researches conducted in the initial and developed disease stages during increase in a dose, efficiency of treatment was observed, since a daily dose of 1.5 mg. It does not exclude that at certain patients the daily dose above can give 1.5 mg to additional therapeutic effect.

It partially concerns to patients with the developed stage of a disease to which the levodopa dose decline was shown.

Treatment termination: the dose of drug has to decrease by 0.75 mg/days until the daily dose does not reach 0.75 mg. After that the dose should be lowered by 0.375 mg/days.

Combined treatment by a levodopa. At simultaneous therapy with a levodopa, it is recommended in process of increase in a dose, and also during a maintenance therapy pramipeksoly to reduce a levodopa dose. It is necessary for prevention of excessive dopaminergic stimulation.

Use at a renal failure. Removal of a pramipeksol from an organism depends on function of kidneys.

At initial therapy at patients with KK decrease in a daily dose or frequency of reception is higher than 50 ml/min. it is not required.

At patients with KK from 30 to 50 ml/min. treatment it is necessary to begin with a dose 0.375 mg of drug every other day. In one week of therapy, before increase in a daily dose, it is necessary to take precautionary measures and to carefully estimate the therapeutic answer and tolerance. If further increase in a dose is necessary, the daily dose should be raised on 0.375 mg of a pramipeksol through week intervals to the maximum dose 2.25 mg прамипексола / days.

Data on treatment by tablets of the slowed-down release of patients with KK lower than 30 ml/min. are absent. It is necessary to study expediency of use of tablets with usual release.

If function of kidneys decreased during the supporting treatment, follow the recommendations given above.

Use at a liver failure. There is no need to reduce a dose at patients with a liver failure.

Use for children and teenagers. Safety and efficiency of drug at children and teenagers aged up to 18 years is not established.

Features of use:

Use at pregnancy and feeding by a breast. The possibility of use of drug at pregnancy and in the period of a lactation at the person is not investigated. Possible impact of a pramipeksol on reproductive function was investigated in experiments on animals. Pramipeksol does not show teratogenecity on rats and rabbits, however in doses, toxic for pregnant females, was embriotoksichny at rats. At pregnancy it is necessary to appoint drug only if the potential advantage for mother surpasses potential risk for a fruit. Removal of drug with breast milk was not studied. Concentration of drug in milk of rats was higher, than in plasma. As прамипексол inhibits prolactin secretion, it is possible to assume that it also suppresses a lactation. Therefore drug should not be accepted during feeding by a breast. Influences on fertility at the person were not studied. Results of the researches conducted on animals do not indicate existence of straight lines or indirect signs of adverse influences on fertility at males.

Use at abnormal liver functions. There is no need to reduce a dose at patients with a liver failure.

Use at renal failures. With care at a renal failure.

Use for children. It is contraindicated to children up to 18 years.

At purpose of the drug Mirapeks® PD, the dose decline is recommended to patients with a renal failure.

Hallucinations and confusion of consciousness - the known side effects at treatment by agonists of a dopamine and a levodopa.

Hallucinations are more often observed at treatment by the drug Mirapeks® PD in a combination with a levodopa at patients with the developed stage of a disease of Parkinson, than at monotherapy of patients with Parkinson's disease at an early stage of a disease. Patients should be informed that hallucinations can develop (preferential, visual). Patients have to be warned that the hallucinations influencing ability to driving can be observed.

Patients and persons who care for them have to know that in connection with treatment of patients dopaminergic means emergence of signs of abnormal behavior (symptoms of impulsive and compulsive actions), such as tendency to an overeating, persuasive desire to shop (pathological shopping), hyper sexuality and pathological thirst for gamblings is possible. In such cases the decision on decrease in a dose / the gradual termination of treatment has to be considered.

Patients with psychotic frustration have a purpose of dopamine agonists in combination with pramipeksoly perhaps only after preliminary estimate of possible risk advantage. The concomitant use of a pramipeksol with antipsychotic means should be avoided.

It is recommended to check sight through certain intervals of time or right after purpose of drug in the presence of such disturbances.

It is necessary to show care in the presence at a sick serious cardiovascular illness. Due to the risk of development of orthostatic hypotension when performing dopaminergic therapy it is recommended to control arterial pressure, in particular, in an initiation of treatment.

Patients should be warned about possible sedation of drug, including drowsiness and sudden backfilling during day activity. Patients should explain that in case of the increased drowsiness or episodes of sudden backfilling during day activity (for example, at a conversation, meal, etc.) which can happen during treatment at any time, they cannot conduct the car or to participate in potentially dangerous types of activity and it is necessary to consult with the doctor.

Epidemiological researches showed that patients with Parkinson's disease have a high risk (from 2 to, about, 6 times higher) development of a melanoma, than at the general population. Whether this increased risk is a consequence of a disease of Parkinson, or it is connected with other factors, such as drug intake which are used at Parkinson's disease, it is not known.

Owing to the reasons which are stated above, patients and persons who care for them have to be informed that during reception of a pramipeksol or other dopaminergic drugs it is necessary to show consideration for possible development of a melanoma.

There are messages that at the sudden termination of therapy symptoms of a malignant antipsychotic syndrome can be observed by dopaminergic drugs.

Influence on ability to driving of motor transport and to control of mechanisms. Patients have to be informed on possibility of hallucinations (generally visual) which can influence ability to driving of the car.

At use of drug development of sedations, including drowsiness and backfilling is possible during daily activity. As drowsiness is the frequent undesirable phenomenon with potentially serious effects, patients should not drive the car or work with other difficult mechanisms until they do not gain sufficient experience of treatment by the drug Mirapeks® PD whether to estimate it influences negatively or not their intellectual and/or physical activity. It has to be recommended to patients, that if during treatment they test the increased drowsiness or episodes of backfilling during daily activity (i.e. during the conversation, food, etc.), then they have to refuse driving, work with the equipment and to see a doctor.

Side effects:

At use of drug the following side effects are listed: abnormal behavior (symptoms of impulsive and compulsive actions), such as tendency to an overeating (hyperphagia), persuasive desire to shop (pathological shopping), hyper sexuality and pathological thirst for gamblings; abnormal dreams, amnesia, heart failure, confusion of consciousness, lock, nonsense, dizziness, dyskinesia, short wind, weakness, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, decrease in the ABP, disturbance of secretion of antidiuretic hormone, sleeplessness, frustration libido, nausea, paranoia, peripheral hypostases; pneumonia; itch, rash and other hypersensitivity reactions; concern, drowsiness, sudden backfilling, a syncope, deterioration in sight (including a diplopia, decrease in visual acuity and clearness of perception), vomiting, change of body weight, including a loss of appetite.

Frequency of cases of decrease in the ABP during treatment by the drug Mirapeks® PD is no more, than at placebo treatment. Nevertheless, hypotension can be observed at certain patients in an initiation of treatment, especially, if doses of drug raise too quickly. Frustration of a libido (increase or decrease) can be connected with treatment by the drug Mirapeks® PD.

The patients taking a pill of a pramipeksol reported about sudden backfilling during day activity, including driving that sometimes led to road incidents. At the same time some of them did not report about existence at themselves alarming signs, such as drowsiness, often observable the patients taking a pill of a pramipeksol in doses is higher than 1.5 have some which according to modern knowledge of dream physiology always lead to sudden backfilling. Accurate communication with duration of treatment did not come to light. At the same time a part of patients took also other medicine having potentially sedative properties. In most cases, where such information was available, there were no similar episodes after a dose decline or the termination of treatment. The patients with Parkinson's disease receiving therapy by dopamine agonists including Mirapeks® of PD, especially in high doses, reported about pathological thirst for gamblings, increase in a libido and hyper sexuality that usually passed after a dose decline or the termination of treatment.

During clinical trials and post-marketing observation it was reported about heart failure at the patients accepting прамипексол. Relationship of cause and effect between treatment pramipeksoly and heart failure was not proved.

In system and organ classes on the frequency of emergence of side effects the following categories are used: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); seldom (≥1/10 000, <1/1000); very seldom (<1/10 000); it is not established.

System and organ class	Side effect	Emergence frequency
Infections and invasions	Pneumonia	Infrequently
From endocrine system	Disturbance of secretion of antidiuretic hormone	It is not established
Psychotic disturbances	Abnormal behavior (symptoms of impulsive and compulsive actions)	Often
	Abnormal dreams	Often
	Tendency to an overeating	Infrequently
	Pathological shopping	Infrequently
	Confusion of consciousness	Often
	Nonsense	Infrequently
	Hallucinations	Often
	Hyperphagia	Infrequently
	Hyper sexuality	Infrequently
	Sleeplessness	Often
	Frustration of a libido (increase in a libido, decrease in a libido)	Infrequently
	Paranoia	Infrequently
	Pathological thirst for gamblings	Infrequently
	Concern	Infrequently
From a nervous system	Amnesia	Infrequently
	Dizziness	Very often
	Dyskinesia	Very often
	Headache	Often
	Hyperkinesia	Infrequently
	Drowsiness	Very often
	Sudden backfilling	Infrequently
	Syncope	Infrequently
From organs of sight	Deterioration in sight (including a diplopia, decrease in visual acuity and clearness of perception)	Often
From cardiovascular system	Decrease in the ABP	Often
	Heart failure	It is not established
From respiratory system	Asthma	Infrequently
	Hiccups	Infrequently
From a GIT	Lock	Often
	Nausea	Very often
	Vomiting	Often
From skin and hypodermic cellulose	Hypersensitivity reactions	Infrequently
	Itch	Infrequently
	Rash	Infrequently
General disturbances	Weakness	Often
	Peripheral hypostases	Often
The reactions revealed at special researches	Decrease in body weight, including a loss of appetite	Often
	Increase in body weight	Infrequently

Interaction with other medicines:

Pramipeksol in insignificant degree (<20%) contacts proteins of plasma and is exposed to biotransformation. Therefore interactions with other drugs influencing linkng with proteins of plasma, or removal at the expense of biotransformation are improbable.

Drugs which inhibit active secretion of cationic drugs through renal tubules (for example, Cimetidinum) or which are removed due to active secretion through renal tubules, can interact with pramipeksoly that is expressed in decrease in clearance of one or both drugs. In case of simultaneous use of such drugs (including an amantadina) and a pramipeksola it is necessary to pay attention to such signs of excess dopamine stimulation as dyskinesia, excitement or hallucinations. In similar cases it is necessary to lower a dose.

Selegilin and levodopa do not influence pharmacokinetics of a pramipeksol. Pramipeksol does not influence the total value of absorption or elimination of a levodopa. Interaction with anticholinergic medicines and amantadiny was not studied. However interaction with amantadiny is possible since drugs have the similar mechanism of removal. Anticholinergic medicines, are generally removed in the metabolic way therefore interaction with pramipeksoly is improbable.

At increase in a dose of drug at patients with Parkinson's disease the levodopa dose decline is recommended, at the same time the dose of other protivoparkinsonichesky medicines needs to be supported at the constant level.

Owing to possible cumulative effects, patients should recommend to show care at reception of other sedative medicines or alcohol in combination with the drug Mirapeks® PD, as well as at a concomitant use of the medicines increasing concentration of a pramipeksol in plasma (for example, Cimetidinum).

Contraindications:

— children's and teenage age up to 18 years;

— hypersensitivity to a pramipeksol or to any component of drug.

With care it is necessary to use drug at a renal failure, decrease in the ABP.

Overdose:

Cases of the expressed overdose are not described.

Estimated symptoms inherent to a pharmakodinamichesky profile of agonists of dopamine receptors: nausea, vomiting, hyperkinesia, hallucinations, excitement and decrease in the ABP.

Treatment: the established antidote does not exist, at overdose the gastric lavage, symptomatic therapy, dynamic observation is recommended. Efficiency of carrying out a hemodialysis is not established. At signs of excitement of TsNS purpose of neuroleptics is possible.

Storage conditions:

Drug should be stored in the place, dry, unavailable to children, at a temperature not above 25 °C. A period of validity - 3 years. Not to use drug after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in blisters, on 1 or 3 blisters in a cardboard pack.