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

active substance: pramipexole dihydrochloride monohydrate 0.25 mg, 0.5 mg, 1 mg, 1.5 mg (corresponding to pramipexole 0.18 mg, 0.35 mg, 0.7 mg, 1.1 mg);

Excipients: pregelatinized starch 39.90 mg, 79.80 mg, 79.80 mg, 119.70 mg, mannitol 61.00 mg, 121.99 mg, 121.49 mg, 182, 24 mg, povidone (K-29 / 32) 1.17 mg, 2.33 mg, 2.33 mg, 3.50 mg, silicon colloidal dioxide 1.17 mg, 2.33 mg, 2.33 mg, 3.50 mg, magnesium stearate 1.52 mg, 3.05 m, 3.05 mg, 4.57 mg.

Description:

Dosage of 0.25 mg

Oblong flat tablets white or almost white with a narrow risk and engraving "P9AL 0.18 "on one side and a wide risk on the other side.

Dosage 0.5 mg

Oblong flat tablets white or almost white with a narrow risk and engraving "P9AL 0.35 "on one side and a wide risk on the other side.

Dosage 1 mg

Round biconvex tablets white or almost white with engraving "P9AL 0.7 "on one side and risk on each side.

Dosage of 1.5 mg

Round biconvex tablets white or almost white with engraving "P9AL 1.1 "on one side and risk on each side.

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 D₂dopamine receptors, having the most pronounced affinity for D₃dopamine 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 dopaminergic neurons from degeneration arising in response to ischemia or methamphetamine neurotoxicity. Reduces the secretion of prolactin (dose-dependent).

Pharmacokinetics:

Absorption: Pramipexole quickly and completely absorbed after ingestion. The rate of absorption decreases with food intake, but the total intake is not affected by food intake.

Distribution: absolute bioavailability is more than 90%, and the maximum concentration in the blood plasma (C_mOh) is achieved in 1-3 hours.

Pramipexole is characterized by linear kinetics and a relatively small variability in the concentrations between individual patients.

Pramipexole binds very little to plasma proteins (less than 20%) and undergoes biotransformation, but has a large volume of distribution (400 L).

Metabolism and excretion: is metabolized to an insignificant degree. About 90% of the dose is excreted through the kidneys (80% unchanged) and less than 2% is excreted through the intestine. The total clearance of pramipexole is about 500 ml / min, the renal clearance is 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 in adults (monotherapy or in combination with levodopa) in the late stage of the disease, when the effects of levodopa are weakened or become unstable and fluctuations of the therapeutic effect (end-dose fluctuations or "on-off" fluctuations) appear.

Symptomatic treatment of idiopathic syndrome of restless legs.

Contraindications:

Hypersensitivity to pramipexole or to one of the components of the drug.

Age under 18 years (effectiveness and safety not studied).

Carefully:

Renal failure, arterial hypotension, psychotic disorders, visual impairment, severe diseases of the cardiovascular system.

Pregnancy and lactation:

The effect of the drug on pregnancy and lactation in humans has not been investigated.

The effect of pramipexole on reproductive function was studied in animal experiments. Pramipexole did not exert teratogenic effects in experiments on rats and rabbits, but when toxic doses were administered to pregnant rats pramipexole had embryotoxic effect.

A drug Pramipexole should not be used during pregnancy, except in cases of extreme necessity, if the potential benefit to the mother is significantly greater than the potential risk to the fetus.

As pramipexole inhibits the secretion of prolactin in humans, presumably that the drug inhibits lactation.

In animal studies, it was found that pramipexole can penetrate into breast milk.

The drug should not be used during breastfeeding. If necessary, breastfeeding should be discontinued.

Dosing and Administration:

Inside, regardless of food intake, with a small amount of water. The daily dose should be divided into 3 divided doses.

Initial therapy

The dose of the drug should be increased gradually, every 5-7 days, starting with 0.375 mg per day. To reduce the risk of side effects, the dose should be selected gradually until the maximum therapeutic effect is achieved.

Scheme of increasing the dose of Pramipexol
A week	Single dose (mg)	Total daily dose (mg)
1	3 х0,125	0,375
2	3 x 0.25	0,75
3	3 x 0.5	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.

It should be borne in mind that when taking doses over 1.5 mg / day, the incidence of drowsiness increases.

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 is effective, starting with a daily dose of 1.5 mg. Further dose changes should depend on the patient's response to treatment and on the development of unwanted effects.It is not excluded that in some patients, a dose of more than 1.5 mg per day can provide an additional therapeutic effect, especially at a late stage of the disease.

Discontinuation of therapy

A sudden cessation of therapy with dopamine receptor agonists can lead to the development of a malignant neuroleptic syndrome.

Pramipexole should be withdrawn gradually, at 0.75 mg per day until the drug is completely discontinued (see section "Special instructions").

Patients with renal insufficiency

The dose of pramipexole depends on the creatinine clearance (CC).

Initial therapy:

- Patients with QC greater than 50 ml / min: a decrease in the daily dose of the drug is not required;

- Patients with KK 20-50 ml / min: 0,125 mg twice a day (0.25 mg per day);

- Patients with SC less than 20 ml / min: 0.125 mg once a day.

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

Patients with hepatic insufficiency

In patients with hepatic insufficiency, dose adjustment is probably not required, since about 90% of the absorbed active substance is excreted by the kidneys, but the potential effect of liver failure on the pharmacokinetics of pramipexole has not been studied.

Patients receiving concurrent therapy with levodopa

With simultaneous therapy with levodopa is recommended as the dose increases, as well as during maintenance therapy with pramipexole, adjust the dose of levodopa. This is necessary to avoid excessive dopamine stimulation.

Symptomatic treatment of idiopathic syndrome ("restless legs")

Initial therapy

The recommended initial dose of pramipexole is 0.125 mg once a day for 2 to 3 hours before bedtime. If it is necessary to prescribe additional symptomatic therapy, the dose can be increased every 4-7 days, until the maximum dose of 0.75 mg per day is reached (as shown in the table below).

Scheme of increasing doses of Pramipexol
Stages of dosing	The dose (mg), for reception once a day in the evening
1	0,125
2*	0,25
3*	0,50
4*	0,75

* if necessary

The clinical response of the patient should be assessed 3 months after the start of therapy for symptomatology of the syndrome, after considering the need for further therapy. Supportive therapy

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

Discontinuation of therapy

Gradual reduction of dose for the abolition of therapy is not required. However, the renewal of symptoms can not be ruled out. In clinical trials, only 10% patients showed signs of heavier symptomatology after a sharp discontinuation of pramipexole, this effect was manifested at any dose.

Patients with renal insufficiency

The excretion of pramipexole depends on the functioning of the kidneys and 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 on hemodialysis and with severe renal failure has not been studied.

Patients with hepatic insufficiency

Side effects:

When using pramipexole, the following side effects are listed: abnormal dreams, amnesia,impaired behavior (symptoms of impulsive and compulsive actions) - such as compulsive overeating (hyperphagia), obsessive desire to shop (pathological shopping), pathological craving for gambling, hypersexuality; disorders of libido, anxiety, paranoia, hallucinations, delirium, heart failure, confusion, constipation, dizziness, tachycardia, dyskinesia, asthenia, headache, dyspnea, weakness, hyperkinesia, hiccough, lowering blood pressure, insomnia, psychosis, extrapyramidal syndrome, nausea , peripheral edema; pneumonia; bursitis, myasthenia gravis, muscle twitching, itching, rash, dry mouth, impaired secretion of antidiuretic hormone, respiratory and urinary tract infections, frequent urination, drowsiness, sudden falling asleep, fainting; visual impairment including diplopia, reduced acuity and clarity of perception; vomiting, weight loss, loss of appetite.

Based on an analysis of pooled placebo-controlled studies, including 1923 patients taking pramipexole and 1354 patients taking placebo in both groups had side effects on the drug.In 63% of patients in the pramipexole group and in 52% of patients in the placebo group, at least one response to the drug was observed. Tables 1 and 2 show the incidence of adverse events in placebo-controlled studies with patients with Parkinson's disease and restless legs syndrome. The tables provide information on the effects that occurred in 1% or more patients who took pramipexole if the effect was considered clinically significant.

Usually side effects appear at the beginning of the course of therapy and disappear with prolonged use of the drug.

The frequency and manifestations of side effects are both dependent and reversible.

Expected side effects - may be associated with the pharmacodynamic profile of the dopamine antagonist and the applied doses. These include nausea, vomiting, hyperkinesia, hallucinations, arousal and orthostatic hypotension. Reduced blood pressure may be observed in individual patients at the beginning of treatment, especially if doses of pramipexole titrate too quickly.

A sharp reduction in dose or withdrawal of the drug, in patients with Parkinson's disease, can cause the emergence and development of neuroleptic malignant syndrome. Side effect with simultaneous admission with levodopa fixed dyskinesia.The frequency of side effects is dose-dependent.

Drowsiness

Taking pramipexole is often accompanied by drowsiness and infrequently excessive drowsiness.

Sudden falling asleep

Episodes of sudden falling asleep during the daytime activity, including driving. While some patients did not report having anxious signs, such as drowsiness, often observed in patients, when taking pramipexole at doses above 1.5 mg / day, which always lead to sudden falling asleep. A clear connection with the duration of therapy was not observed. At the same time, some patients took other drugs with potentially sedative properties. After reducing the dose or stopping the drug, reports of similar side effects in these patients are not documented.

Disorders of sexual desire

Against the background of taking pramipexole, infrequent libido can occur (increase (0.1%) or decrease (0.4%)).

Symptoms of impulsive and compulsive actions

In patients receiving dopamine agonist therapy, including Pramipexole, there may be a pathological passion for gambling, hypersexuality, pathological shopping, compulsive overeating.

In an intergroup retrospective case-control screening study involving 3090 patients with Parkinson's disease, 13.6% of all patients who received dopaminergic or nedophaminergic therapy had symptoms of impulse control disorders during the past six months. Observable manifestations included a pathological passion for gambling, an irresistible craving 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.

Heart failure

In clinical studies and in the process of post-registration observation, there was an increased risk of primary heart failure associated with pramipexole patients. In two pharmacoepidemiological studies using pramipexole, an increasedrisk of heart failure compared with placebo.

Laboratory indicators: an increase in the activity of creatine phosphokinase (CK), a decrease in the secretion of prolactin.

For the system-organ classes, the following classification (WHO) is used for the incidence of side effects: very often> 1/10, often from> 1/100 to <1/10, infrequently from> 1/1000 to <1/100, rarely from > 1/10000 to <1/1000, very rarely from <1/10000, including individual messages.

Parkinson's disease, the most common side effects

Table 1. Frequency of adverse events in patients with Parkinson's disease

System of organs	frequency	By-effect
Nervous system	Often	dizziness, dyskinesia, drowsiness
Nervous system	infrequently	amnesia, hyperkinesia, sudden falling asleep, fainting
Endocrine system	infrequently	violation of the secretion of antidiuretic hormone *
The cardiovascular system	often	lowering of blood pressure
The cardiovascular system	infrequently	heart failure*
Gastrointestinal tract	Often	nausea
Gastrointestinal tract	often	constipation, vomiting
Mental disorders	often	abnormal dreams, amnesia, impaired behavior (symptoms of impulsive and compulsive actions), confusion, hallucinations, insomnia
Mental disorders	infrequently	compulsive overeating, obsessive desire to shop (pathological shopping), pathological craving for gambling, delirium, hypersexuality; violation of libido, paranoia, anxiety
Respiratory system	infrequently	dyspnoea, hiccough
The organs of sight	often	visual impairment, including diplopia, decreased visual acuity of clarity of perception
Skin and subcutaneous tissue	infrequently	itching, rash
Infections and invasions	infrequently	Pneumonia and other infections of the upper and lower respiratory tract
Common violations	often	fatigability, peripheral edema
Violations revealed in special studies	often	decreased appetite, weight loss
Violations revealed in special studies	infrequently	weight gain

* Side effect recorded in post-registration observations. 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, because the side effect is not fixed in the database of clinical trials containing information on 2762 patients with Parkinson's disease who were taking pramipexole.

Idiopathic restless legs syndrome, the most common side effects

Patients with the syndrome of "restless legs" who receive pramipexole, most often (≥5%), the following side effects are recorded: nausea, headache, dizziness, fatigue. Nausea and fatigue were more often recorded in patients who were taking pramipexole (20.8% and 10.5%, respectively) compared with men (6.7% and 7.3% respectively).

Table 2. Frequency of side effects in patients with restless legs syndrome

System of organs	frequency	by-effect
Nervous system	often	dizziness, headache, drowsiness, fatigue
Nervous system	infrequently	amnesia, dyskinesia, hyperkinesia, sudden falling asleep, fainting
Endocrine system	infrequently	violation of the secretion of antidiuretic hormone *
The cardiovascular system	infrequently	lowering of blood pressure
The cardiovascular system	infrequently	heart failure*
Mental disorders	often	abnormal dreams, insomnia
Mental disorders	infrequently	behavioral disorders (symptoms of impulsive and compulsive actions), such as compulsive overeating, obsessive desire to do shopping, delirium , hyperphagia , hypersexuality, confusion, hallucinations, libido disorders, paranoia , anxiety, pathological craving for gambling , anxiety
Infections and invasions	infrequently	pneumonia and other infections of the upper and lower respiratory tract
The organs of sight	infrequently	visual impairment, including diplopia, decreased visual acuity of clarity of perception
Respiratory system	infrequently	dyspnoea, hiccough
Gastrointestinal tract	Often	nausea
Gastrointestinal tract	often	constipation, vomiting
Skin and subcutaneous tissue	infrequently	itching, rash and other symptoms of hypersensitivity
Common violations	often	fatigue
Common violations	infrequently	peripheral edema
Violations revealed in special studies	infrequently	weight loss, decreased appetite, weight gain

* Side effect recorded in post-registration observations. With a probability of 95%, the frequency category does not exceed "infrequently", but it can be lower.

Overdose:

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

Treatment: there is no specific antidote.

Symptomatic therapy: recommended gastric lavage, reception of activated charcoal and ECG monitoring. Also, an intravenous injection of 0.9% sodium chloride solution is necessary.When there are signs of stimulation of the central nervous system, neuroleptics may be recommended.

The effectiveness of hemodialysis is not established.

Interaction:

Pramipexole in a very small extent (less than 20%) is bound to plasma proteins and undergoes biotransformation. Therefore, interaction with other drugs that affect the binding to plasma proteins or excretion due to biotransformation is unlikely.

Selegiline and levodopa - do not affect the pharmacokinetics of pramipexole. Pramipexole does not affect the total amount of absorption or elimination of levodopa.

With a combination of the drug Pramipexole with levodopa - it is recommended to reduce the dose of levodopa and other antiparkinsonian dose medicaments must be maintained at a constant level by increasing the dose of pramipexole (see "Dosing and Administration", section "Side effect".).

Anticholinergics - interaction with anticholinergic drugs has not been studied. As anticholinergics eliminated predominantly by metabolism in the liver, pharmacokinetic interactions between drugs is unlikely.

Inhibitors / competitors active renal excretory pathway - reduce the renal clearance of pramipexole by approximately 34%, mainly due to the inhibition of the cationic secretory transport system of the renal tubules. Drugs that inhibit this mechanism of excretion through the renal tubules (for example, cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, procainamide), or which are themselves excreted in this way, can interact with pramipexole, which is manifested in a decrease in the clearance of one or both drugs. Increases the concentration of pramipexole in plasma. In case of simultaneous use of such drugs, it is necessary to monitor the appearance of dopamine superstimulation signs and to reduce the dose of pramipexole.

Sedatives and alcohol - it is necessary to use with caution other sedative drugs or alcohol in combination with pramipexole, t. an additive effect is possible (see section "Side effect").

Neuroleptics: simultaneous use of neuroleptics and pramipexole should be avoided (possibly antagonistic action).

Dopamine receptor blockers: derivatives of phenothiazine, butyrophenone, thioxanthene and metoclopramide reduce the effectiveness of treatment.

Special instructions:

In connection with the risk of developing orthostatic hypotension, it is recommended to control blood pressure, especially at the beginning of treatment.

Patients with impaired renal function

When the drug is prescribed Pramipexole patients with Parkinson's disease and impaired renal function are advised to reduce the dose in accordance with the recommendations (see section "Method of administration and dose").

Hallucinations

Patients receiving pramipexole and the persons who care for them, it is necessary to inform about the possibility of hallucinations (in most cases, visual) and confusion of consciousness.

Dyskinesia

When using the drug Pramipexole in combination with levodopa, in the late stages of Parkinson's disease, at the initial stage of dose selection, dyskinesias can develop. When dyskinesia appears, it is necessary to reduce the dose of levodopa.

Drowsiness and sudden onset of sleep

Against the background of the use of pramipexole, there were cases of sudden falling asleep, in particular in patients with Parkinson's disease, during active daytime, while there was no drowsiness.Cases of falling asleep during everyday activities, sometimes without any previous signs, were noted infrequently. Taking pramipexole may be accompanied by drowsiness, sometimes excessive drowsiness.

Because of the possibility of developing an additive effect, it is necessary to take with caution other pills and sedatives or alcohol simultaneously with pramipexole.

Disorders of control over motivation and compulsive behavior

During the treatment of Parkinson's disease, dopamine receptor agonists, including pramipexole, cases of pathological excitement, increased libido and the development of hypersexuality were noted. Patients and caregivers should be informed of possible changes in behavior. In such cases, the question of reducing the dose of the drug or its withdrawal should be decided.

Patients with psychotic disorders

Patients with psychotic disorders can receive therapy with dopamine receptor agonists after a preliminary benefit / risk assessment.

It is necessary to avoid simultaneous use of antipsychotics and pramipexole (see the section "Contraindications").

Ophthalmological monitoring

When developing visual disorders, it is recommended that an ophthalmic examination be performed on a regular basis.

Malignant neuroleptic syndrome

Sharp dose reduction or drug withdrawal Pramipexole in patients with Parkinson's disease, neuroleptic syndrome and its malignant development may be provoked (see section "Dosing and Administration"),

Augmentation in "restless leg syndrome"

Reports in the literature indicate that the treatment of restless legs syndrome with dopaminergic drugs can lead to a worsening of the condition, as to the earlier appearance of symptoms in the evening (or even in the afternoon), the increase in symptoms and their spread with the involvement of the upper limbs.

The analysis of the time to Kaplan-Meier augmentation did not show any significant difference between the pramipexole and placebo groups in the controlled study of pramipexole in patients with restless legs syndrome for 26 weeks.

Severe cardiovascular pathology

In the case of severe cardiovascular pathology, a particularly careful prescription of the drug is necessary.It is recommended to monitor blood pressure, especially at the beginning of treatment, taking into account the overall risk of postural hypotension associated with dopaminergic therapy.

Taking pramipexole may increase the risk of a primary onset of heart failure (see "Side effect").

Laboratory indicators

Against the background of taking pramipexole, there is an increase in the activity of creatine phosphokinase, a decrease in the secretion of prolactin.

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

A drug Pramipexole can have a significant impact on the ability to drive a car or work with technical devices. In connection with the possibility of developing drowsiness and hallucinations, in order to avoid episodes of falling asleep, patients taking the drug should refuse for the period of treatment or until the disappearance of relapsing episodes and signs of drowsiness, from driving and working with technical devices related to the concentration of attention and the speed of psychomotor reactions.

Form release / dosage:

Tablets, 0.25 mg, 0.5 mg, 1 mg and 1.5 mg.

Packaging:

For 7 or 10 tablets in a blister from Al / Al or from OBA-Al-PVC / Al or in the blister of PVC / PE / PVDC: Al.

For 3 blisters for 7 tablets or 10 tablets together with instructions for use in a cardboard pack.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002444

Date of registration:29.04.2014

The owner of the registration certificate:Firm EUROSERVICE, CJSC Firm EUROSERVICE, CJSC Russia

Manufacturer: & nbsp

SYNTHON, B.V. Spain

Information update date: & nbsp26.08.2015

Illustrated instructions

Instructions

Pramipexole (Pramipexole)