Рамипекс

General characteristics. Structure:

Active ingredient: 0,25 mg of a pramipeksol of dihydrochloride of monohydrate that is equivalent to 0,18 mg of a pramipeksol.

Excipients: mannitol (E 421), starch corn, silicon dioxide colloid anhydrous, starch prezhelatinizirovanny, povidone (K-30), magnesium stearate.

Pharmacological properties:

Pharmacodynamics. Pramipeksol is a dopamine agonist with high selectivity and specificity to dopamine receptors of the D2 subtype among which it has preferential affinity to D3 receptors and total internal activity.

Pramipeksol facilitates parkinsonichesky motive disturbances by stimulation of dopamine receptors of a striatum (striate body). Researches on animals showed what прамипексол suppresses synthesis, release and exchange of a dopamine.

Mekhaniz of action of a pramipeksol at treatment of a syndrome of uneasy legs is unknown. Neuropharmacological data confirm participation primary dopaminergic systems.

During the researches conducted with participation healthy volunteers dozozavisimy decrease in level of prolactin was observed.

Pharmacokinetics. Pramipeksol is quickly and completely absorbed after oral administration. Absolute bioavailability makes more than 90%, the maximum concentration in plasma is reached between the 1st and 3 hours. Speed of absorption decreases against the background of meal, but extent of absorption does not decrease. Pramipeksol shows linear kinetics and insignificant fluctuations of plasma levels at different patients.

At people linkng of a pramipeksol with proteins is very low (less than 20%), and distribution volume – big (400 l). During the researches on rats high concentration of drug in brain fabric was observed (about 8 times higher in comparison with plasma).

Pramipeksol is metabolized at people in a small amount.

Removal by kidneys of not changed pramipeksol is the main way of elimination. About 90% of the 14C-marked dose are removed by kidneys whereas less than 2% are defined in Calais. The general clearance of a pramipeksol makes about 500 ml/min., and renal – about 400 ml/min. An elimination half-life – of 8 o'clock at young faces till 12 o'clock at elderly people.

Indications to use:

Treatments of signs and symptoms of an idiopathic disease of Parkinson adults as monotherapy (without levodopa) or in a combination with a levodopa throughout the course of a disease to late stages when the effect of a levodopa decreases or becomes unstable and have a fluctuation of therapeutic effect (a phenomenon of "inclusion switching off").

The symptomatic treatment of an idiopathic syndrome of uneasy legs from moderated to heavy degree at adults by doses is not higher than 0,75 mg.

Route of administration and doses:

Parkinson's disease. A pill should be taken inside, to swallow, washing down with water, irrespective of meal.

The daily dose is accepted in 3 receptions by equal shares. Initial treatment: the dose of drug needs to be increased gradually, as shown in table 1, since an initial dose of 0,375 mg of salt a day each 5-7 days. On condition of absence at patients of neperenosimy by-effects the dose needs to be titrated before achievement of the maximum therapeutic effect.

Table 1

Scheme of increase in a dose of drug
Week	Dose (salt mg)	General daily dose (salt mg)
The 1st	3×0,125	0,375
The 2nd	3×0,25	0,75
The 3rd	3×0,5	1,50

In case of need further increase in a dose the daily dose needs to be increased by 0,75 mg of salt weekly to the maximum dose of 4,5 mg of salt a day.

However it should be noted that at doses more than 1,5 mg of salt the frequency of cases of drowsiness increases.

Maintenance therapy. The individual dose has to be ranging from (0,375 mg) to the maximum dose of 4,5 mg a day. At increase in a dose in three main researches efficiency was observed, since a daily dose of 1,5 mg of salt. The further correcting of a dose should be carried out according to the clinical answer and emergence of undesirable effects. During the researches about 5% of patients treated doses lower than 1,5 mg. At the progressing Parkinson's disease of a dose higher than 1,5 mg a day can be effective for patients to whom therapy reduction is planned by a levodopa. It is recommended to reduce a levodopa dose at increase in a dose and carrying out a maintenance therapy drug, depending on reaction of each certain patient.

Treatment termination. The sudden termination dopaminergic can lead therapies to development of a malignant antipsychotic syndrome. Therefore the dose of a pramipeksol should be reduced gradually, by 0,75 mg a day, before decrease in a daily dose to 0,75 mg. After that the dose should be reduced by 0,375 mg a day.

Renal failure. A conclusion of a pramipeksol depends on function of kidneys. To start therapy such scheme is offered:

• patients with clearance of creatinine more than 50 ml/min. do not need to reduce a daily dose,
• patients with clearance of creatinine of 20-50 ml/min. should apply an initial daily dose of drug for 2 separate receptions, since 0,125 mg 2 times in days of 0,25 mg a day,
• patients with clearance of creatinine less than 20 ml/min. should apply a daily dose of drug for 1 reception, since 0,125 mg a day. It is not necessary to exceed the maximum daily dose to a pram_peksol of 1,5 mg.

At depression of function of kidneys during a maintenance therapy the daily dose of drug is lowered by the same percent by which the clearance of creatinine decreased i.e. if the clearance of creatinine decreased by 30%, then a daily dose of drug it is necessary to lower by 30%. The daily dose can be applied in 2 receptions if the clearance of creatinine is in limits of 20-50 ml/min., and at one time if the clearance of creatinine is lower than 20 ml/min.

Abnormal liver function. Correction of a dose is not required to patients with an abnormal liver function as about 90% of the absorbed active ingredient are allocated with kidneys though potential influence of a liver failure on pharmacokinetics to a pram_peksol it was not studied.

Syndrome of uneasy legs. A pill should be taken inside, to swallow washing down with water, irrespective of meal.

The recommended initial dose of drug makes 0,125 mg of 1 times a day in 2-3 hours prior to a dream. Patients who need additional symptomatic simplification can increase a dose each 4-7 days to the maximum dose of 0,75 mg a day (as shown in table 2).

Table 2

Scheme of dosing
Titration stage	One-time daily evening
1	0,125
2 *	0,25
3 *	0,50
4 *	0,75

* If necessary

As long-term efficiency of a pramipeksol at treatment of a syndrome of uneasy legs is studied insufficiently, in 3 months of treatment it is necessary to carry out assessment of the answer of the patient and to reconsider expediency of continuation of therapy. If treatment is interrupted more than for several days, it should be begun with titration of a dose as it is described above.

Treatment termination. As the daily dose for treatment of a syndrome of uneasy legs does not exceed 0,75 mg, use of drug can be stopped without gradual dose decline. It is not necessary to exclude effect of cancellation (deterioration in symptoms after the sudden termination of treatment).

Renal failure. A conclusion to a pram_peksol depends on function of kidneys. Patients with clearance of creatinine more than 20 ml/min. do not need to reduce a daily dose.

Use to a pram_peksol to the patients who are on a hemodialysis, or patients with a heavy renal failure was not studied.

Abnormal liver function. Correction of a dose is not required to patients with an abnormal liver function as about 90% of the absorbed active ingredient are allocated with kidneys.

Children. Drug is not recommended for use to children due to the lack of data on safety and efficiency for this age category of patients.

Features of use:

Use during pregnancy or feeding by a breast. Influence on pregnancy and a lactation at people it is unknown. It is possible to apply during pregnancy only in case the expected advantage for mother exceeds potential risk for a fruit.

As treatment pramipeksoly suppresses secretion of prolactin at people, decrease in a lactation is possible. Data on excretion of a pramipeksol in breast milk at people are unknown. Drug is not recommended to be used during feeding by a breast. However if administration of drug it is necessary, feeding by a breast should be stopped.

Children. Safety and efficiency of use of drug are not established to children therefore use of drug of this category of patients is not shown.

Features of use. Patients with Parkinson's disease who have a renal failure should appoint the reduced drug dose (see the section "Route of Administration and Doses").

Hallucinations are the known side effect of treatment by dopamine agonists and a levodopa. Patients should be informed on possibility of hallucinations (preferential visual).

At treatment of the progressing Parkinson's disease dyskinesia can arise a combination with a levodopa during initial titration of drug. When developing dyskinesia it is necessary to lower a levodopa dose.

Pramipeksol was associated with drowsiness and episodes of sudden backfilling, especially at patients with Parkinson's disease. It was infrequently reported about sudden backfilling during daily activity which sometimes arose without understanding of it or without precautionary signs. It is necessary to inform patients on it and to recommend to be careful at control of motor transport and work with mechanisms during treatment pramipeksoly. To patients who tested drowsiness and/or had episodes of sudden backfilling, it is necessary to abstain from control of motor transport and work with mechanisms. Besides, it is necessary to consider expediency of a dose decline or the termination of treatment. Through possible additive effects it is necessary to be careful at use by patients of other sedative medicines or alcohol in a combination with pramipeksoly.

The libido and hyper sexuality at patients, Parkinson's disease at whom treated dopamine agonists, including прамипексол, was reported about cases of pathological thirst for gamblings, increase. Besides, the patients and persons who are looking after patients need to be informed on possibility of symptoms of disturbance of control of impulsive behavior and pathological drafts, such as overeating and pathological thirst for shopping. It is necessary to consider expediency of decrease in a dose / gradual drug withdrawal.

Patients with mental disorders should be treated dopaminovy agonists only in case the potential advantage exceeds possible risk.

It is necessary to avoid simultaneous use of antipsychotic medicines with pramipeksoly.

Ophthalmologic observation is recommended to be made through regular intervals of time or at emergence of vision disorders.

It is necessary to be careful in case of heavy cardiovascular pathology. It is recommended to control arterial pressure, especially in an initiation of treatment, through the general risk of the postural hypotension connected with dopaminergic therapy.

The symptoms reminding an antipsychotic malignant syndrome were noted after sharp cancellation dopaminergic therapies.

Messages in literature indicate that treatment of a syndrome of uneasy legs dopaminergic drugs can cause augmentation. Augmentation is shown as earlier emergence of symptoms in the evening (or even in the afternoon), strengthening of symptoms and distribution of symptoms on upper extremities. Controlled researches of use of a prampeksol by patients with a syndrome of uneasy legs usually were insufficiently long to give an adequate assessment to the augmentation phenomenon. During controlled clinical trials augmentation frequencies after more prolonged use of a pramipeksol and the corresponding treatment of these phenomena did not carry out assessment.

Ability to influence speed of response at control of motor transport or work with other mechanisms. Drug exerts considerable impact on ability to manage motor transport and to work with other mechanisms.

Emergence of hallucinations or drowsiness is possible. Patients who are treated drug and in whom drowsiness and/or episodes of sudden backfilling is observed should be informed on need of abstention from control of motor transport and types of activity at which disturbance of attention can lead to traumatizing itself or other people or to death (for example during the work with mechanisms) until such recurrent episodes or drowsiness do not disappear.

Side effects:

Parkinson's disease. Infections and invasions: pneumonia.

From mentality: abnormal dreams, behavioural symptoms of disturbance of control of impulsive behavior and pathological drafts, confusion of consciousness, hallucination, sleeplessness, concern, pathological thirst for shopping, mania, hyper sexuality, disturbances libido, paranoia, pathological thirst for gamblings, overeating, hyperphagia.

From a nervous system: dizziness, dyskinesia, drowsiness, amnesia, headache, hyperkinesia, episodes of sudden backfilling, syncope.

From organs of sight: a vision disorder, including the obscured sight and decrease in visual acuity.

From cardiovascular system: arterial hypotension.

From respiratory system: asthma.

From a digestive tract: nausea, lock, vomiting.

From skin and hypodermic cellulose: hypersensitivity, itch, rash.

The general disturbances and reactions in an injection site: fatigue, peripheral hypostasis, decrease in body weight, increase in body weight.

Syndrome of uneasy legs. Patients with a syndrome of uneasy legs at treatment pramipeksoly the most frequent side reactions (≥ 5%) had a nausea, a headache, dizziness and fatigue. Nausea and fatigue were more often observed at women in comparison with men at treatment pramipeksoly.

Infections and invasions: pneumonia.

From mentality: sleep disorders, sleeplessness, symptoms of disorder of control over motivation and compulsive behavior, such as an overeating, a morbid attraction to visit of shops, hyper sexuality and a morbid attraction to gamblings, confusion of consciousness, a mania, hallucinations, a hyperphagia, frustration a libido, paranoia, concern.

From a nervous system: dizziness, headache, drowsiness, amnesia, dyskinesia, hyperkinesia, sudden attack of drowsiness, syncope.

From organs of sight: a vision disorder, including a diplopia, an illegibility of sight and deterioration in visual acuity.

From cardiovascular system: heart failure, arterial hypotension.

From respiratory system: asthma, hiccups.

From a digestive tract: nausea, lock, vomiting.

From skin and hypodermic cellulose: hypersensitivity, itch, rashes.

General frustration: fatigue, peripheral hypostases.

Laboratory indicators: a body degrowth, including a loss of appetite, increase in body weight.

Drowsiness. Use of a pramipeksol is often connected with drowsiness and infrequently with excessive drowsiness in the afternoon and episodes of a sudden attack of drowsiness (see the section "Features of Use").

Frustration of a libido. Use of a pramipeksol can be infrequently connected with frustration of a libido (increase or decrease).

Disorders of control over motivation. At treatment by dopamine agonists, including Ramipeks, symptoms of disorder of control over motivation including a morbid attraction to gamblings, strengthening a libido, hyper sexuality, compulsive waste or purchase, a compulsive overeating and the use of food can be observed (see the section "Features of Use").

Heart failure. During the researches heart failure was observed at patients who applied прамипексол. During the pharmakoepidemiologichesky research of use of a pramipeksol it was connected with increase in risk of heart failure in comparison with lack of use (a ratio of risk 1,86, 95% of the SI, 1,21-2,85).

Interaction with other medicines:

Drug at people contacts proteins of plasma in very insignificant degree (less than 20%) and has low biotransformation. Therefore interactions with other medicines influencing linkng with proteins of a blood plasma or elimination by biotransformation are improbable. As anticholinergics are removed preferential by biotransformation, an opportunity for interaction with them is limited though interaction with anticholinergics it was not investigated. Pharmacokinetic interaction of a pramipeksol with selegiliny and a levodopa was not observed.

Cimetidinum reduced renal clearance of a pramipeksol approximately by 34%, it is probable due to oppression of cationic secretory transport system of renal tubules. Medicines which are inhibitors of this active renal way of removal or which are removed this way such as Cimetidinum and амантадин, can interact with pramipeksoly that leads to decrease in clearance of one or both drugs. At simultaneous use of these medicines it is necessary to consider expediency of a dose decline of a pramipeksol.

At use of drug with a levodopa it is recommended to reduce a levodopa dose, and doses of other protivoparkinsonichesky means to leave not changed against the background of increase in a dose of drug.

Through the additive effects are possible it is necessary to be careful at use of other sedatives or alcohol in a combination with pramipeksoly.

It is necessary to avoid simultaneous use of antipsychotic medicines with pramipeksoly, for example, when possible antagonistic effects.

Contraindications:

Hypersensitivity to active ingredient or to any of drug excipients.

Overdose:

Symptoms. Data about considerable overdoses are absent. The expected side effects are connected with a pharmakodinamichesky profile dopamine an agonist and include nausea, vomiting, a hyperkinesia, hallucinations, excitement and arterial hypotension.

Treatment. The antidote at overdose by a dopamine agonist is not established. In case of signs of excitement of the central nervous system neuroleptics can be appointed. Treatment of overdose can demand the general supporting measures, including a gastric lavage, intravenous injections of liquid, use of absorbent carbon and control of the electrocardiogram.

Storage conditions:

Period of validity - 5 years. To store in original packaging at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister, on 3 blisters in a cardboard box.