Pramitrol

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, or 1,0 mg that is equivalent to 0,7 mg of a pramipeksol.

Excipients: mannitol (Е 421), starch corn, silicon dioxide colloid anhydrous, starch prezhelatinizirovanny, povidone, magnesium stearate.

Pharmacological properties:

Pharmacodynamics. Pramipeksol – an agonist of a dopamine which with high selectivity and specificity contacts dopamine receptors of the D2 subtype also has preferential affinity to D3 receptors, it has total internal activity.

Pramipeksol reduces deficit of a physical activity at Parkinson's disease by stimulation of dopamine receptors in a striate body. Researches on animals showed what прамипексол suppresses synthesis, release and exchange of a dopamine.

The mechanism of action of a pramipeksol as drug for treatment of a syndrome of uneasy legs is unknown. Neuropharmacological signs demonstrate, first of all, influence on dopaminergic system.

At volunteers dozoproportsionalny suppression of prolactin was noted. During clinical trials at healthy volunteers at use of tablets of a pramipeksol of long release which increased a dose quicker than it is recommended (each 3 days) to 4,5 mg of a pramipeksol for days, growth of arterial pressure and heart rate was observed. During the researches with participation of patients of such effect it was not noted.

Clinical trials with participation of patients with Parkinson's disease. Pramipeksol softens signs and symptoms of an idiopathic disease of Parkinson.

Efficiency of a pramipeksol during controlled clinical trials remained within about six months both at early, and at late stages of a disease of Parkinson. During the open researches of the subsequent treatment for more than three years of signs of reduction of efficiency it was not observed.

During controlled, double blind clinical trial lasting 2 years initial treatment pramipeksoly considerably detained the beginning of development of complications of motive functions in comparison with initial treatment by a levodopa. However use of a levodopa provides the bigger improvement of motive functions (measured as average change behind points to the unified scale of assessment of symptoms of a disease of Parkinson). The general frequency of hallucinations and drowsiness was usually higher at a stage of increase in a dose in group of use of a pramipeksol, however during the supporting treatment of a considerable difference was not observed. All these features should be taken into account, appointing прамипексол to patients with Parkinson's disease.

Clinical trials at a syndrome of uneasy legs. Efficiency of a pramipeksol was investigated in four placebos - controlled clinical trials with participation about 1000 patients with an idiopathic syndrome of uneasy legs from moderated to very severe form.

Efficiency was noted at use 0,125 mg of a pramipeksol a day after the first week of treatment.

During placebo - a controlled research using a polisomnografiya within 3 weeks of use of a pramipeksol the number of periodic twitchings of extremities in a dream considerably decreased.

Efficiency during longer period was studied during placebo - controlled clinical trial. After 26 weeks of treatment statistically significant improvement and big frequency of a response in group of a pramipeksol in comparison with group of placebo was observed.

Pharmacokinetics. Pramipeksol is quickly and completely soaked up after oral administration. Absolute bioavailability makes more than 90% and the maximum plasma concentration is reached within 1-3 hours. The accompanying meal does not reduce extent of absorption of a pramipeksol, but slows down its absorption. Pramipeksol shows linear kinetics and small variability of plasma concentration. The person has a linkng of a pramipeksol with proteins very low (less than 20%), and the volume of distribution big (400 l). At rats high concentration in brain tissues is noted (approximately in 8 times more, than in plasma).

Pramipeksol is metabolized at the person only in the insignificant way.

Renal removal of not changed pramipeksol is the main way of excretion. About 90% of a 14C-marked dose are removed by kidneys, and less than 2% – with a stake. The general clearance of a pramipeksol makes about 500 ml/min., renal – about 400 ml/min.

The elimination half-life fluctuates of 8 o'clock at young patients till 12 o'clock at elderly people.

Indications to use:

• Signs and symptoms of an idiopathic disease of Parkinson (as monotherapy, and in a combination with a levodopa).
• A symptomatic treatment of an idiopathic syndrome of uneasy legs at adults.

Route of administration and doses:

Parkinson's disease. A pill needs to be taken orally, washing down with water, both during meal and without it. The daily dose is appointed in 3 receptions equal shares.

Initial treatment. Treatment is begun with 0,375 mg a day, gradually increasing a dose each 5-7 days. If at patients the neperenosimy undesirable phenomena are not observed, the dose is gradually raised to achievement of the maximum therapeutic effect.

Scheme of increase in a dose Pramitrola®:

Week	Dose (salt mg)	General daily dose (salt mg)
1	3 × 0,125	0,375
2	3 × 0,25	0,75
3	3 × 0,5	1,50

If further increase in a dose is necessary, the daily dose is raised on 0,75 mg weekly to maximum - 4,5 mg a day. However it should be noted that at a dose more than 1,5 mg a day the frequency of cases of drowsiness increases.

The supporting treatment. The individual dose of a pramipeksol has to be in range from 0,375 mg up to at most 4,5 mg a day.

During the basic researches during increase in a dose the effect was observed, since a daily dose of 1,5 mg. Further the dose is adjusted depending on clinical reaction and frequency of the undesirable phenomena. During clinical trials about 5% of patients less than 1,5 mg received a dose. At late stages of a disease of Parkinson прамипексол in doses a day the positive therapeutic effect in cases when reduction of doses of a levodopa is planned can give more than 1,5 mg. The dose of a levodopa is recommended to be reduced both during increase in a dose of Pramitrola®, and in the period of a maintenance therapy depending on individual reactions of patients.

Treatment termination. The dose of a pramipeksol should be reduced gradually by 0,75 mg a day before achievement of a daily dose of 0,75 mg. Further the dose should be reduced by 0,375 mg a day. The sudden termination of therapy by dopaminergic means can lead to development of a malignant antipsychotic syndrome.

Patients with a renal failure. A conclusion of a pramipeksol depends on function of kidneys. At the beginning of therapy it is recommended to adhere to the following scheme.

For patients with clearance of creatinine more than 50 mg/min. reduction of a daily dose or frequency of use of drug is not required.

To patients with clearance of creatinine from 20 to 50 mg/min. the initial dose is divided into 2 receptions, since 0,125 mg by 2 times a day (0,25 mg a day). The maximum daily dose should not exceed 2,25 mg of a pramipeksol.

Patients with clearance of creatinine less than 20 ml/min. should apply a daily dose of Pramitrola® at one time, since 0,125 mg a day. The maximum daily dose should not exceed 1,5 mg of a pramipeksol.

If deterioration in renal functions happens against the background of a maintenance therapy of Pramitrolom®, the daily dose should be reduced by the percent equal to percent of decrease in clearance of creatinine that is if the clearance went down for 30%, the daily dose of Pramitrola® also should be reduced by 30%. Patients with clearance of creatinine from 20 to 50 ml/min. can divide a daily dose into 2 receptions, the patient with clearance of creatinine less than 20 ml/min. apply a daily dose at one time.

Patients with an abnormal liver function. Dose adjustment for patients with a liver failure is not required as about 90% of the absorbed active ingredient are removed by kidneys. However potential influence of a liver failure on pharmacokinetics of Pramitrola® it was not investigated.

Children. Safety and efficiency of use of Pramitrola® aged up to 18 years are not established to children therefore it is not necessary to appoint drug for treatment of a disease of Parkinson of this age category.

Syndrome of uneasy legs. The recommended initial dose of Pramitrola® makes 0,125 mg of 1 times a day in 2-3 hours prior to a dream. In case of need additional relief of symptoms it is possible to increase a dose each 4-7 days to the maximum dose of 0,75 mg a day (as shown in the table below).

Scheme of use Pramitrolu®

Titration EEP	Evening single dose (salt mg)
1	0,125
2 *	0,25
3 *	0,50
4 *	0,75

* If necessary

After 3 months of therapy it is necessary to estimate reaction of patients and the need for further treatment. If use of drug is interrupted more than for several days, at its resuming the dose should be titrated again, as shown above.

Treatment termination. As the daily dose for treatment of a syndrome of uneasy legs should not exceed 0,75 mg, use of Pramitrola® can be stopped without gradual reduction of a dose.

Patients with a renal failure. A conclusion of a pramipeksol depends on function of kidneys.

Patients with clearance of creatinine higher than 20 ml/min. do not need to reduce a daily dose.

Use of Pramirola® it was not investigated at the patients who are on a hemodialysis or at patients with a heavy renal failure.

Patients with an abnormal liver function. Dose adjustment for patients with a liver failure is not required as about 90% adsorbed active ingredient are removed by kidneys.

Children. Due to the lack of data on safety and efficiency of Pramitrol® children are not recommended to apply.

Features of use:

Use during pregnancy or feeding by a breast. Pregnancy. Influence on the course of pregnancy and feeding the breast at the person did not investigate. Прамитрол® it is necessary to apply during pregnancy only by unconditional need that is when the potential advantage justifies possible risk for a fruit.

Feeding by a breast. As use of a pramipeksol suppresses release of prolactin at the person, reduction of a lactation is expected. Allocation of a pramipeksol in breast milk at the person was not studied. Прамитрол® it is not necessary to apply during feeding by a breast. However if its reception is necessary, it is necessary to stop feeding by a breast.

Fertility. Researches of influence on fertility at the person were not conducted.

Children. Drug is contraindicated to children.

Features of use. Patients with Parkinson's disease and a renal failure should reduce a dose of Pramitrola® (see the section "Route of Administration and Doses").

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

Dyskinesia. At late stages of a disease of Parkinson at use of drug in a combination with a levodopa at the beginning increase in a dose of Pramitrola® can arise dyskinesia. In that case it is necessary to reduce a levodopa dose.

Sudden backfilling and drowsiness. Use of a pramipeksol was also followed by drowsiness and epidoza of sudden backfilling, in particular at patients with Parkinson's disease. Sudden backfilling during day activity, in certain cases unconsciously and without precautionary symptoms, was noted infrequently. Patients should be warned about a possibility of such phenomena and to recommend to be careful during the driving or work with mechanisms during use of Pramitrola®. Patients who underwent drowsiness and/or episodes of sudden backfilling should refrain from driving and work with mechanisms. Besides, it is possible to consider the possibility of reduction of a dose or the termination of therapy.

Through probability of the additive effect it is necessary to be careful in case of use of other sedative drugs or alcohol intake along with pramipeksoly.

Impulsive frustration and compulsive behavior. At use of agonists of a dopamine, including pramipeksol, for treatment of a disease of Parkinson pathological tendency to gamblings, strengthening a libido and hyper sexuality was noted. Also patients and persons who look after them have to realize a possibility of development of other behavioural symptoms of impulsive frustration and compulsive behavior, such as an overeating, compulsive shopping. In similar cases it is necessary to reduce gradually a dose gradually to stop drug use.

Patients with psychotic frustration. Patients with psychotic frustration should apply agonists of a dopamine, only if the potential advantage exceeds risk. The accompanying use of antipsychotic medicines with pramipeksoly it is necessary to avoid.

Control of organs of sight. It is recommended to check organs of sight through regular intervals or in case of vision disorders.

Serious cardiovascular illness. In case of a serious cardiovascular illness it is necessary to be careful. It is recommended to control arterial pressure, especially in an initiation of treatment, through the general risk of the postural hypotension caused by therapy by dopaminergic means.

Malignant antipsychotic syndrome. At the sudden termination of therapy dopaminergic means noted symptoms, similar a malignant antipsychotic syndrome.

Augmentation. There are messages that treatment of a syndrome of uneasy legs with dopaminergic medicines can lead to augmentation. Augmentation means earlier beginning of symptoms in the evening (or even in the afternoon), strengthening of intensity of symptoms and their distribution on upper extremities. This phenomenon was specially studied during controlled 26 weeks independent clinical trial. Augmentation was observed at 11,8% of patients of group of reception of a pramipeksol (N=152) and 9,4% of patients of group of placebo (N=149). The analysis of time before augmentation by Kaplana-Meyer's method did not reveal a significant difference between groups of use of a pramipeksol and placebo.

Ability to influence speed of response at control of motor transport or work with other mechanisms. Прамитрол® can exert considerable impact on ability to drive the car and to work with mechanisms.

Hallucinations or drowsiness are possible. Patients who apply прамипексол and test drowsiness and/or episodes of sudden backfilling, it is necessary to warn about need to abstain from driving or from other types of activity (for example, work with other mechanisms) when it is worsened attention can lead to threat of a serious injury or death both patients, and people around, so far such repeating episodes and drowsiness will not pass.

Side effects:

The expected undesirable reactions. At use of a pramipeksol the following undesirable reactions are expected: abnormal dreams, amnesia, behavioural symptoms of a syndrome of disorder of control over impulses and compulsive behavior, such as overeating, compulsive shopping, hyper sexuality and pathological tendency to gamblings, confusion of consciousness, obscuring, dizziness, dyskinesia, диспноэ, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, arterial hypotension, sleeplessness, frustration libido, nausea, paranoia, peripheral hypostasis, pneumonia, itch, rash and other reactions of hypersensitivity, uneasiness, drowsiness, sudden backfilling, syncope, vision disorder, including diplopia, blurring of sight, visual acuity reduction, vomiting, body degrowth, including loss of appetite, increase in body weight.

Frequency of undesirable reactions which were observed during placebo - controlled clinical trials at patients with Parkinson's disease and a syndrome of uneasy legs is included below. Undesirable reactions to drug are given noted in 0,1% or more patients of group a pramipeksola and with significantly bigger frequency, than patients have groups of placebo, or are clinically significant phenomena. The majority of reactions to drug were weak or moderate, were noted usually at the beginning of therapy and preferential took place even without therapy interruption.

Undesirable reactions in each of classes of systems of bodies are distributed on the frequency (the number of the patients who underwent such reaction) according to the following categories: very widespread (≥ 1/10), extended (≥ 1/100 to less than 1/10), not widespread (≥ 1/1000 to less than 1/100), seldom widespread (≥ 1/10 000 to less than 1/1000), very seldom widespread (less than 1/10 000), unknown frequency (it is impossible to estimate according to the available data).

The most widespread undesirable reactions noted at patients with Parkinson's disease. (≥ 5%) the undesirable reactions to drug noted at patients with Parkinson's disease who accepted прамипексол nausea, dyskinesia, arterial hypotension, dizziness, drowsiness, sleeplessness, a lock, hallucinations, a headache and fatigue were the most widespread. Frequency of drowsiness increases at doses higher than 1,5 mg of a pramipeksol a day. Dyskinesia was observed more often at use of drug in a combination with a levodopa. In an initiation of treatment arterial hypotension, especially can develop if to raise a dose of a pramipeksol too quickly.

Infections and invasions: not widespread – pneumonia.

Mental disturbances: extended – abnormal dreams, behavioural symptoms of disorder of control over impulses and compulsive the behavior, confusion of consciousness, a hallucination, sleeplessness not widespread – an overeating, compulsive shopping, nonsense, a hyperphagia, hyper sexuality, frustration a libido, paranoia, pathological tendency to gamblings, uneasiness.

From a nervous system: very widespread – the dizziness, dyskinesia, drowsiness extended – a headache, not widespread – amnesia, a hyperkinesia, sudden backfilling, a syncope.

From organs of sight: extended – a vision disorder, including a diplopia, blurring of sight and decrease in visual acuity.

From cardiovascular system: extended – arterial hypotension, not widespread – heart failure.

From respiratory system: not widespread – диспноэ, a hiccups.

From a digestive tract: very widespread – nausea, extended – a lock, vomiting.

From skin and hypodermic cellulose: not widespread – hypersensitivity, an itch, rash.

General frustration and condition of an injection site: extended – fatigue, peripheral hypostasis.

The aberrations revealed as a result of laboratory analyses: extended – a body degrowth, including the loss of appetite not widespread – increase in body weight.

The most widespread undesirable reactions noted at patients with a syndrome of uneasy legs. The most widespread undesirable reactions (5%) noted patients with a syndrome of the uneasy legs accepting прамипексол had a nausea, a headache, dizziness and fatigue. Nausea and fatigue were more often noted at women who accepted прамипексол (20,8% and 10,5% respectively), than at men (6,7% and 7,3% respectively).

Infections and invasions: not widespread – pneumonia.

Mental disturbances: extended – the abnormal dreams, sleeplessness not widespread – behavioural symptoms of disorder of control over impulses and compulsive behavior, such as an overeating, compulsive shopping, hyper sexuality and pathological tendency to gamblings, confusion of consciousness, nonsense, hallucinations, a hyperphagia, frustration a libido, paranoia, uneasiness.

From a nervous system: extended – the dizziness, a headache, drowsiness not widespread – amnesia, dyskinesia, a hyperkinesia, sudden backfilling, a syncope.

From organs of sight: not widespread – vision disorders, including blurring of sight and decrease in visual acuity.

From cardiovascular system: extended – arterial hypotension, not widespread – heart failure.

From respiratory system: not widespread – диспноэ, a hiccups.

From a digestive tract: very widespread – nausea, extended – a lock, vomiting.

From skin and hypodermic cellulose: not widespread – hypersensitivity, an itch, rashes.

General frustration and condition of an injection site: extended – fatigue, not widespread – peripheral hypostasis.

The aberrations established as a result of laboratory analyses: not widespread – decrease in body weight, including a loss of appetite, increase in body weight.

Drowsiness. Use of a pramipeksol often is followed by drowsiness and infrequently – excessive drowsiness in the afternoon and episodes of sudden backfilling.

Frustration of a libido. In rare instances прамипексол can cause frustration of a libido (its strengthening or easing).

Impulsive frustration and compulsive behavior. At patients with Parkinson's disease who applied dopamine agonists including прамипексол, especially in high doses, signs of pathological tendency to gamblings, strengthening of a libido and hyper sexuality were noted that in general disappeared at reduction of a dose or the termination of treatment.

In a krossektsionny research on the case control method with retrospective screening with participation of 3090 patients with Parkinson's disease at 13,6% of patients who received dopaminergic or not dopaminergic drugs symptoms of disorder of control over impulses within the last six months were observed. Manifestations are noted covered pathological tendency to gamblings, compulsive shopping, an overeating and a kompulsivna sexual behavior (hyper sexuality). To possible independent risk factors disturbance an impulse control use of dopaminergic drugs and their highest doses, younger age (≤ 65 years), the unmarried status, existence in the family anamnesis of tendency to gamblings belonged.

Heart failure. During clinical trials and during post-marketing observation at the patients accepting прамипексол it was reported about development of heart failure. In pharmakoepidemiologichesky researches of use of a pramipeksol by patients it was associated with the increased risk of heart failure in comparison with those who did not apply прамипексол (the observed relation of risk 1,86, 95% of DI, 1,21-2,85).

Interaction with other medicines:

Linkng with proteins of plasma. Pramipeksol contacts proteins of plasma very slightly (less than 20%), biotransformation at the person is also very insignificant. Therefore interaction with other medicines influencing linkng with proteins of plasma, or removal by biotransformation is improbable. As anticholinergics are removed preferential by biotransformation, interaction is improbable though interaction researches with such means were not conducted. Drug does not enter in pharmacokinetic interaction with selegiliny and a levodopa.

Inhibitors/competitors for an active renal way of removal. Cimetidinum reduces renal clearance of a pramipeksol approximately by 34%, perhaps, by oppression of cationic secretory transport system of renal tubules. Therefore medicines which inhibit this active way of renal removal or are removed this way, such as Cimetidinum, амантадин, мексилетин, the zidovudine, Cisplatinum, quinine and procaineamide, can interact with pramipeksoly, leading to decrease in its clearance.

In case of the accompanying use of these means with pramipeksoly it is necessary to reduce its dose.

Combination with a levodopa. At use of a pramipeksol in a combination with a levodopa it is recommended to reduce a levodopa dose, and to leave a dose of other antiparkinsonichesky drugs without changes, having increased a dose of a pramipeksol.

Because of a possibility of the additive effect it is necessary to recommend to patients to be careful at use of other sedatives or alcohol intake along with pramipeksoly.

Antipsychotic drugs. The accompanying use of antipsychotic medicines with pramipeksoly it is necessary to avoid, for example, in cases when it is possible to expect effects of antagonism.

Contraindications:

Hypersensitivity to a pramipeksol or to any other component of drug.

Overdose:

There is no clinical experience considerable overdose. To the expected undesirable effects the reactions caused by a pharmakodinamichesky profile of an agonist of a dopamine including nausea, vomiting, a hyperkinesia, hallucinations, agitation and arterial hypotension belong.

There is no known antidote on an overdose case a dopamine agonist. In case of signs of stimulation of the central nervous system use of neuroleptics is possible. At overdose there can be a need for the general supporting actions, including for a gastric lavage, intravenous administration of liquids, purpose of absorbent carbon and control of a condition of the patient by carrying out the electrocardiogram.

Storage conditions:

Period of validity - 2 years. To store in original packaging in the place, unavailable to children, at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

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