Pramipexole-Teva, tablets 1 mg 30 pcs

Pharmacotherapeutic group: antiparkinsonian drug – dopamine agonist.

ATX code: N04BC05

Pharmacological properties

Pharmacodynamics

Pramipexole is a dopamine receptor agonist, binds with high selectivity and specificity to dopamine D₂ receptors and has a strong affinity for dopamine D₃ receptors.

Limits motor deficits in Parkinson’s disease by stimulating dopamine receptors in the striatum.

Pramipexole inhibits dopamine synthesis, release and metabolism and protects dopaminergic neurons from degeneration occurring in response to ischemia or methamphetamine neurotoxicity.

In clinical studies, pramipexole therapy has been shown to be effective in late-stage Parkinson’s disease, with a significant reduction in motor impairment and significantly later development of complications compared to levodopa monotherapy.

Pharmacokinetics

Extraction. Pramipexole is rapidly and completely absorbed after oral administration, reaching maximum plasma concentration (C_max) in approximately 1-3 hours. Absolute bioavailability of pramipexole exceeds 90%. Absorption rate is reduced with food, but total absorption is not affected by food intake. Pramipexole is characterized by linear kinetics and relatively little variability in concentrations between individual patients.

Distribution. The volume of distribution (V_d) is 400 liters. Binding to plasma proteins is less than 20%.

Metabolism and excretion. Slightly metabolized in the body. About 90% of the dose is excreted by the kidneys (80% – unchanged) and less than 2% – in the feces. Total clearance of pramipexole is about 500 ml/min, renal clearance is about 400 ml/min.

The value of the terminal elimination half-life (T_1/2) is 8 hours in young healthy volunteers and about 12 hours in elderly people.

Indications

Symptomatic treatment of Parkinson’s disease as monotherapy or in combination with levodopa drugs in the late stage of the disease, when the effects of levodopa weaken or become intermittent and fluctuations in therapeutic effect (on-off) occur.

Active ingredient

Composition

How to take, the dosage

Ingestion, regardless of meals, with water. The daily dose is evenly divided into 3 doses. Doses are calculated using pramipexole dihydrochloride monohydrate.

Symptomatic treatment of Parkinson’s disease

Primary therapy. As described below, the initial daily dose of 0.375 mg is increased every 5-7 days. To reduce the risk of side effects, the dose should be adjusted gradually until maximum therapeutic effect is achieved.

Week

Dose (mg)

Total daily dose (mg)

1

3×125

0.375

2

3×0.25

0.75

3

3×0.5

1.50

If necessary, add 0.75 mg of pramipexole dihydrochloride per week to a maximum daily dose of 4.5 mg per day.

Maintenance therapy. The individual dose should be between 0.375 mg and 4.5 mg per day. In both the early and late stages of the disease, the drug has been effective starting at a daily dose of 1.5 mg. However, it is possible that doses higher than 1.5 mg daily may have additional therapeutic effect in individual patients, especially in the late stage of disease when a reduction in levodopa dose is indicated.

Cessation of treatment. 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.

Dosages for patients receiving concurrent levodopa therapy

When concurrent therapy with levodopa, it is recommended that as the dose increases, and during supportive therapy with pramipexole, reduce the dose of levodopa to prevent excessive dopaminergic stimulation.

Dosages for patients with renal impairment

For initial therapy: In patients with a creatinine clearance above 50 mL/min, no reduction in the daily dose or frequency of administration is necessary. If creatinine clearance is 20-50 ml/min, the initial daily dose of the drug is administered in two doses, starting with 0.125 mg twice a day (0.25 mg per day). The maximum daily dose of 2.25 mg of pramipexole should not be exceeded. If creatinine clearance is less than 20 ml/min, the daily dose of the drug is administered once a day, starting with 0.125 mg. The maximum daily dose of 1.5 mg of pramipexole should not be exceeded.

If renal function decreases during supportive therapy, the daily dose of the drug is reduced by the same percentage by which creatinine clearance decreases, i.e., if creatinine clearance decreases by 30%, the daily dose of the drug should be reduced by 30%. The daily dose may be divided into two doses if creatinine clearance is between 20-50 mL/min and taken once daily if creatinine clearance is less than 20 mL/min.

Dosages for patients with hepatic impairment

There is no need to reduce the dose in patients with hepatic impairment.

Symptomatic treatment for idiopathic restless legs syndrome

Initial therapy. The recommended initial daily dose is 0.125 mg 2-3 hours before bedtime. If patients require additional symptom reduction, the dose can be increased every 4 to 7 days to a maximum dose of 0.75 mg daily (as shown in the table below).

Pramipexole dose escalation scheme

Dose escalation steps

(if necessary)

Dose to be taken once a day, in the evening (mg)

0.125

2

0.25

3

0.50

4

0.75

Maintenance therapy. Individual dose should be between 0.125 mg and 0.75 mg per day.

Cessation of treatment. Treatment can be discontinued without gradually decreasing the dose.

In clinical studies, only 10% of patients showed evidence of worsening symptoms after abrupt discontinuation of treatment, this effect was seen at any dose.

Doses for patients with renal impairment

The drug excretion depends on renal function and is directly related to creatinine clearance. Based on pharmacokinetic studies in subjects with renal insufficiency, 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 with renal impairment has not been studied.

Dosages for patients with hepatic impairment

The need for dose reduction in patients with hepatic impairment is not considered because approximately 90% of the absorbed drug is excreted by the kidneys.

Dosages for children and adolescents

The safety and effectiveness of pramipexole in children and adolescents under the age of 18 years has not been established.

Interaction

Binding to blood proteins. Pramipexole binds insignificantly (less than 20%) to plasma proteins and is biotransformed. Therefore, interactions with other drugs that affect binding to plasma proteins or excretion by biotransformation are unlikely. Interaction with anticholinergic drugs and amantadine has not been studied. However, interaction with amantadine is possible because the drugs have a similar excretion mechanism. Anticholinergic drugs are mostly metabolized, so interactions with pramipexole are unlikely.

Pharmacokinetic interaction with seleginine or levodopa has not been noted.

Inhibitors/competitors of the active renal excretion pathway of the drug. Cimetidine reduces renal clearance of pramipexole by approximately 34%, probably due to inhibition of the cationic secretory renal tubular transport system. Therefore, drugs that are inhibitors of this metabolic pathway of active drug excretion by the kidneys or excreted by this route, such as: cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine and procainamide may interact with pramipexole, which may lead to reduced clearance of the drug. Consideration should be given to the possibility of reducing the dose of pramipexole if these drugs are taken at the same time.

Combination with levodopa When increasing the dose of the drug in patients with Parkinson’s disease, it is recommended to decrease the dose of levodopa, while keeping the dose of other antiparkinsonian drugs constant. Because of possible additive effects, patients should be advised to exercise caution when taking other sedative medications or ethanol in combination with pramipexole.

Antipsychotic medications. Simultaneous administration of antipsychotic medications and pramipexole is not recommended, such as in the case of drugs that are dopamine antagonists.

Special Instructions

Renal impairment. In patients with renal impairment, reduction of the dose of Pramipexole-Teva is recommended.

Hallucinations. Hallucinations and confusion are common adverse reactions during treatment with dopamine receptor agonists and levodopa. Hallucinations are more frequently observed when pramipexole is treated in combination with levodopa in patients with advanced Parkinson’s disease than when monotherapy is used in patients with early-stage Parkinson’s disease. Patients should be informed that hallucinations (predominantly visual) may develop. Patients should be warned that hallucinations affecting the ability to drive may occur.

Disorders of urge control.

Contraindications

With caution: renal failure; arterial hypotension; cardiovascular disease; simultaneous use with dopamine receptor agonists, sedatives, cimetidine, amantadine, ethanol; pregnancy.

Side effects

In patients with Parkinson’s disease treated with pramipexole, frequent adverse reactions (≥5%) were nausea, dyskinesia, arterial hypotension, dizziness, drowsiness, insomnia, constipation, hallucinations, headache and fatigue. The incidence of drowsiness increased with doses of 1.5 mg per day. A frequent adverse reaction when taking the drug in combination with levodopa was dyskinesia. Arterial hypotension may occur at the beginning of treatment, especially if pramipexole dosage is titrated too quickly.

An organ system

Frequency

Unwanted reaction

Nervous system disorders

very often

dizziness, dyskinesia, drowsiness

often

headache

infrequent

amnesia, hyperkinesia, sudden onset of sleepiness, syncope

Endocrine system disorders

infrequent

disruption of antidiuretic hormone secretion*

Cardiac disorders

often

arterial hypotension

infrequently

heart failure

sup>1

Gastrointestinal disturbances

Gastrointestinal disturbances

very often

nausea

often

constipation, vomiting

Mental disorders

often

sleep disturbances, symptoms of motivational control disorder and compulsive behavior, confusion, hallucinations, insomnia

infrequent

overeating1, pathological cravings for shopping, pathological cravings for gambling, hyperphagia1, mania, hypersexuality; libido disorders (increased or decreased), paranoia, anxiety

Respiratory, thoracic and mediastinal disorders

infrequent

shortness of breath, hiccup

Visual disturbances

often

visual disturbances, including diplopia, blurred vision, and decreased visual acuity

Skin and subcutaneous tissue disorders

infrequent

hypersensitivity, itching, rash

Infectious and parasitic diseases

infrequent

pneumonia

general disorders and disorders at the site of administration

often

fatigue, peripheral edema

Disorders found in special studies

often

decreased body weight, decreased appetite

infrequent

increase in body weight

frequent/table>

1Unwanted reaction in the post-registration period. In 95% of cases, the frequency is no higher than ≥1/1000- < 1/100, but may be lower. It is not possible to establish an exact frequency because no adverse reactions were detected during clinical trials among 2762 patients with Parkinson’s disease who were taking pramipexole.

Sleepiness. The use of pramipexole is often accompanied by somnolence and, infrequently, by excessive daytime sleepiness and instances of sudden onset of sleep.

Overdose

Symptoms: nausea, vomiting, hyperkinesia, hallucinations, agitation and decreased blood pressure (BP).

Treatment: gastric lavage, symptomatic therapy. There is no specific antidote. The effectiveness of hemodialysis has not been established.

Pregnancy use

Pregnancy

The effect on pregnancy and lactation in humans has not been studied.

Possible effects of pramipexole on fertility have been studied in animal experiments. Pramipexole does not exhibit teratogenicity in rats and rabbits, but was embryotoxic in rats at doses toxic to pregnant females. The drug should not be administered in pregnancy.

Breastfeeding

The excretion of pramipexole with breast milk has not been studied. Because pramipexole inhibits prolactin secretion, it is possible that it also suppresses lactation. Therefore, the drug should not be taken while breastfeeding.

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