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 are weakened or become inconsistent and fluctuations in the therapeutic effect (on-off) occur.

Pharmacological effect

Pharmacotherapeutic group: antiparkinsonian drug – dopamine agonist.

ATX code: N04BC05

Pharmacological properties

Pharmacodynamics

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

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

Pramipexole inhibits the synthesis, release and metabolism of dopamine, protecting dopaminergic neurons from degeneration that occurs in response to ischemia or methamphetamine neurotoxicity.

Clinical studies have shown the effectiveness of pramipexole therapy in late stages of Parkinson’s disease, in which there was a significant reduction in the number of motor disorders and a significantly later development of complications compared with levodopa monotherapy.

Pharmacokinetics

Suction. Pramipexole is rapidly and completely absorbed after oral administration, reaching maximum plasma concentrations (Cmax) in approximately 1-3 hours. The absolute bioavailability of pramipexole exceeds 90%. The rate of absorption decreases with food intake, but the total amount of absorption is not affected by food intake. Pramipexole exhibits linear kinetics and relatively little intra-patient variability in concentrations.

Distribution. The distribution volume (Vd) is 400 l. Plasma protein binding 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 feces. The total clearance of pramipexole is about 500 ml/min, renal clearance is about 400 ml/min.

The terminal half-life (T1/2) is 8 hours in young healthy volunteers and about 12 hours in elderly people.

Special instructions

Kidney failure. In patients with renal failure, a dose reduction of Pramipexole-Teva is recommended.

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

Impulse control disorders. Patients and those caring for them should be aware that signs of abnormal behavior (impulsive and compulsive actions), such as overeating, compulsive shopping (pathological shopping), hypersexuality and pathological gambling, may occur in connection with the treatment of patients with dopaminergic drugs. In such cases, a decision should be made to reduce the dose/gradually discontinue treatment.

Mania and delirium. Patients should be monitored regularly for the development of mania or delirium. Patients and their caregivers should be aware that mania and delirium may occur in patients taking pramipexole. If such symptoms develop, the issue of reducing the dose of the drug or discontinuing it should be decided.

Patients with psychotic disorders. In patients with mental disorders, the prescription of dopamine agonists in combination with pramipexole is possible only after a preliminary assessment of the possible risk-benefit. Concomitant use of pramipexole and antipsychotic drugs is not recommended, for example, if a dopamine antagonistic effect is possible.

Ophthalmological monitoring. If visual disturbances occur, regular ophthalmological examinations should be carried out.

Severe cardiovascular diseases. Caution must be exercised if the patient has severe cardiovascular disease. Due to the risk of orthostatic hypotension during dopaminergic therapy, it is recommended to monitor blood pressure, especially at the beginning of treatment.

Dyskinesia. When using pramipexole in combination with levodopa in the later stages of Parkinson’s disease, dyskinesia may develop at the initial stage of dose selection, if which occurs, the dose of levodopa must be reduced.

Sudden falling asleep and drowsiness. Patients should be warned about the possible sedative effects of pramipexole, including drowsiness and sudden sleepiness during daytime activities. Patients should be advised that if excessive sleepiness or episodes of sudden falling asleep during daytime activities (eg, talking, eating), which may occur at any time during treatment, occur, they should not drive or participate in potentially hazardous activities and should consult their physician. Due to the possibility of additive effects, caution should be exercised when taking other sedative medications or alcohol at the same time as pramipexole.

Melanoma. Epidemiological studies have shown that patients with Parkinson’s disease have a high risk (2 to approximately 6 times higher) of developing melanoma than the general population. Whether this increased risk is due to Parkinson’s disease or is related to other factors, such as medications used for Parkinson’s disease, is unknown. For the reasons given above, patients and those caring for them should be informed that they should be alert to the possibility of developing melanoma while taking pramipexole or other dopaminergic drugs.

Neuroleptic malignant syndrome. There are reports that symptoms of neuroleptic malignant syndrome may occur if dopaminergic drug therapy is abruptly discontinued.

Residues of the drug in the feces. Some patients have reported having residue in their feces that resembled whole tablets of the drug. If a patient reports such an event, the physician should reassess the patient’s response to treatment.

Reports in the literature indicate that treatment of restless legs syndrome with dopaminergic drugs may lead to an increase in its severity. This increase represented an earlier onset of symptoms in the evening (or even in the afternoon), worsening of symptoms, and spread of symptoms to other extremities. However, in a 26-week controlled clinical trial specifically dedicated to studying this effect, there was no significant difference in the increase in clinical symptoms between the pramipexole and placebo groups.

Impact on the ability to drive vehicles and machinery
Pramipexole-Teva may have a significant effect on your ability to drive a car or operate technical devices. Due to the possibility of developing drowsiness and hallucinations, in order to avoid episodes of falling asleep, patients taking the drug should refrain from driving and operating machinery that require increased concentration and speed of psychomotor reactions for the duration of treatment or until symptoms of relapse of the disease and signs of drowsiness disappear.

Active ingredient

Pramipexole

Composition

1 tablet contains: active ingredient: pramipexole dihydrochloride monohydrate 0.125 mg/0.25 mg/0.50 mg/1.00 mg; excipients: mannitol 35.185 mg/70.37 mg/140.74 mg/140.24 mg; microcrystalline cellulose type 101 (PH 101) 18.00 mg/36.00 mg/72.00 mg/72.00 mg; sodium carboxymethyl starch (type A) 3.00 mg/6.00 mg/12.00 mg/12.00 mg; povidone-K25 1.80 mg/3.60 mg/7.20 mg/7.20 mg; colloidal silicon dioxide 0.30 mg/0.60 mg/1.20 mg/1.20 mg; magnesium stearate 0.57 mg/1.14 mg/2.28 mg/2.28 mg; sodium stearyl fumarate 1.02 mg/2.04 mg/4.08 mg/4.08 mg.

Pregnancy

Pregnancy

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

The possible effects of pramipexole on reproductive function have been studied in animal experiments. Pramipexole does not show teratogenicity in rats and rabbits, but at doses toxic to pregnant females, it was embryotoxic in rats. The drug should not be prescribed during pregnancy.

Breast-feeding

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

Contraindications

hypersensitivity to pramipexole or any of the components of the drug;
breastfeeding period;
age up to 18 years.

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

Side Effects

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

Table 1. The most common adverse reactions when using pramipexole in patients with Parkinson’s disease

Organ system

Frequency

Adverse reaction

Nervous system disorders

very often

dizziness, dyskinesia, drowsiness

often

headache

infrequently

amnesia, hyperkinesia, sudden onset of drowsiness, fainting

Endocrine system disorders

infrequently

impaired secretion of antidiuretic hormone*

Heart disorders

often

arterial hypotension

infrequently

heart failure1

Gastrointestinal disorders

very often

nausea

often

constipation, vomiting

Mental disorders

often

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

infrequently

overeating1, pathological desire for shopping, pathological desire for gambling, hyperphagia1, mania, hypersexuality; libido disorders (increase or decrease), paranoia, anxiety

Respiratory, thoracic and mediastinal disorders

infrequently

shortness of breath, hiccups

Visual disorders

often

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

Skin and subcutaneous tissue disorders

infrequently

hypersensitivity, itching, rash

Infectious and parasitic diseases

infrequently

pneumonia

General and administration site disorders

often

fatigue, peripheral edema

Violations identified during special studies

often

weight loss, loss of appetite

infrequently

weight gain

1 Adverse reaction during the post-registration period. In 95% of cases, the frequency is not higher than ≥1/1000-<1/100, but may be lower. Establishing an exact frequency is not possible because the adverse reaction was not identified during clinical trials among 2762 patients with Parkinson's disease taking pramipexole.

Drowsiness. The use of pramipexole is often accompanied by drowsiness and infrequently by excessive daytime sleepiness and cases of sudden sleep onset. Motivation control disorders and compulsive behavior. In a cross-sectional retrospective screening and case-control study of 3090 patients with Parkinson’s disease, 13.6% of patients receiving dopaminergic or nondopaminergic therapy reported symptoms of motivational control disorder in the past 6 months, including pathological gambling, compulsive shopping, excessive food cravings, and compulsive sexual behavior. behavior (hypersexuality). Possible independent risk factors for motivational control disorders included dopaminergic therapy, age <65 years, unmarried status, and a family history of self-reported pathological gambling.

Heart failure. In post-marketing clinical studies, heart failure occurred in selected patients receiving pramipexole. In a pharmacoepidemiological study, pramipexole use was associated with an increased risk of heart failure compared with no use (hazard ratio, 1.86; 95% CI, 1.21–2.85).

If any of the adverse reactions indicated in the instructions worsen, or you notice any other adverse reactions not listed in the instructions, tell your doctor.

Table 2. The most common adverse reactions when using pramipexole in patients with restless legs syndrome.

Organ system

Frequency

Side effect

Nervous system disorders

often

dizziness, headache, drowsiness

infrequently

amnesia, dyskinesia, hyperkinesia, sudden sleep onset, fainting

Endocrine system disorders

infrequently

impaired secretion of antidiuretic hormone2

Heart disorders

infrequently

heart failure

Vascular disorders

infrequently

lowering blood pressure

Mental disorders

often

abnormal dreams, insomnia

infrequently

behavioral disorders (symptoms of impulsive and compulsive actions), such as: binge eating, compulsive shopping, delusions, hyperphagia, hypersexuality, confusion, hallucinations, sexual desire disorders, paranoia, anxiety, pathological gambling

Infectious and parasitic diseases

infrequently

pneumonia

Visual disorders

infrequently

visual impairment, including diplopia, decreased visual acuity and clarity of perception

Respiratory, thoracic and mediastinal disorders

infrequently

shortness of breath, hiccups

Gastrointestinal disorders

very often

nausea

often

constipation, vomiting

Skin and subcutaneous tissue disorders

infrequently

itching, rash and other symptoms of hypersensitivity

General violations

often

fatigue

infrequently

peripheral edema

Violations identified during special studies

infrequently

weight loss, loss of appetite, weight gain

2Side effects were observed during post-registration surveillance. With a 95% probability, the frequency category does not exceed “infrequently”, but may be lower.

A precise estimate of the frequency category is not possible because adverse reactions were not recorded in the clinical trials database containing information on 1395 patients with restless legs syndrome treated with pramipexole.

Interaction

Binding to blood proteins. Pramipexole binds to plasma proteins to a small extent (less than 20%) and undergoes biotransformation. Therefore, interactions with other drugs that affect plasma protein binding or elimination due to biotransformation are unlikely. Interactions with anticholinergic drugs and amantadine have not been studied. However, interaction with amantadine is possible, because drugs have a similar mechanism of elimination. Anticholinergic drugs are primarily metabolized and are therefore unlikely to interact with pramipexole.

No pharmacokinetic interaction with seleginine or levodopa was noted.

Inhibitors/competitors of the active pathway of drug excretion by the kidneys. Cimetidine reduces the renal clearance of pramipexole by approximately 34%, probably due to inhibition of the renal tubular cationic secretory transport system. Therefore, drugs that are inhibitors of this metabolic pathway for active renal excretion of the drug or are eliminated by this pathway, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine and procainamide, may interact with pramipexole, which may lead to a decrease in drug clearance. The possibility of reducing the dose of pramipexole should be considered when taking these drugs simultaneously.

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

Antipsychotic drugs. Concomitant use of antipsychotic drugs and pramipexole is not recommended, for example, in the case of using drugs that are dopamine antagonists.

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.

Storage conditions

Store at a temperature not exceeding 25oC in the original packaging (bottle in a cardboard pack) or (blisters in a cardboard pack) to protect from light.
Keep out of the reach of children!

Shelf life

2 years. Do not use after expiration date.

Manufacturer

Teva Canada Limited, Canada