Tormipex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORMIPEX (TORMIPEX)

Composition:

Active substance: pramipexole;

One tablet contains pramipexole dihydrochloride monohydrate 0.25 mg, equivalent to pramipexole 0.18 mg;

Excipients: mannitol (E 421), maize starch, colloidal anhydrous silicon dioxide, pregelatinized starch, povidone (K-30), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: round, flat tablets, white to almost white in color, with bevelled edges, a score line on one side and smooth on the other.

Pharmacotherapeutic group.

Dopaminergic agents. Dopamine agonists. ATC code N04BC05.

Pharmacological Properties

Pharmacodynamics

Pramipexole is a dopamine agonist with high selectivity and specificity for dopamine receptors of the D2 subfamily, among which it has preferential affinity for D3 receptors and full intrinsic activity.

Pramipexole alleviates Parkinsonian motor disturbances by stimulating striatal (corpus striatum) dopamine receptors. Studies in animals have demonstrated that pramipexole inhibits dopamine synthesis, release, and turnover.

The mechanism of action of pramipexole in the treatment of restless legs syndrome is unknown. Neuropharmacological data suggest involvement of the primary dopaminergic system.

In studies conducted in healthy volunteers, a dose-dependent reduction in prolactin levels was observed.

Pharmacokinetics

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%, and maximum plasma concentration is achieved between 1 and 3 hours. The rate of absorption is reduced when taken with food, but the extent of absorption is not affected. Pramipexole exhibits linear kinetics and minimal fluctuations in plasma levels among different patients.

In humans, the protein binding of pramipexole is very low (< 20%), and the volume of distribution is large (400 L). Studies in rats have shown a high concentration of the drug in brain tissue (approximately 8 times higher than in plasma).

Pramipexole undergoes minimal metabolism in humans.

Renal excretion of unchanged pramipexole is the main route of elimination. Approximately 90% of a 14C-labeled dose is excreted by the kidneys, while less than 2% is recovered in feces. Total clearance of pramipexole is approximately 500 mL/min, and renal clearance is approximately 400 mL/min. Elimination half-life ranges from 8 hours in young individuals to 12 hours in elderly individuals.

Clinical characteristics.

Indications.

Treatment of signs and symptoms of idiopathic Parkinson's disease in adults, either as monotherapy (without levodopa) or in combination with levodopa throughout the course of the disease until late stages, when the effect of levodopa decreases or becomes unstable and fluctuations in therapeutic response occur (on-off phenomenon).

Symptomatic treatment of moderate to severe idiopathic restless legs syndrome in adults at doses not exceeding 0.75 mg.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Plasma protein binding.

Pramipexole is minimally bound to plasma proteins (< 20 %) and has low biotransformation. Therefore, interaction with another medicinal product affecting plasma protein binding or elimination via biotransformation is unlikely. Since anticholinergic agents are primarily eliminated via hepatic metabolism, potential interaction is unlikely. Interaction with anticholinergic agents has not been studied. There is no pharmacokinetic interaction between selegiline and levodopa.

Inhibitors/competitors of active renal elimination pathways.

Cimetidine reduces the renal clearance of pramipexole by approximately 34 %, likely by inhibiting the cationic tubular secretion transport system. Medicinal products that inhibit active tubular secretion or are themselves eliminated via this pathway, such as cimetidine, amantadine, mexiletine, zidovudin, cisplatin, quinine, and procainamide, may interact with pramipexole and lead to reduced clearance of pramipexole. When these medicinal products are used concomitantly with pramipexole, dose reduction of pramipexole should be considered.

Combination with levodopa.

During dose escalation of pramipexole in patients with Parkinson's disease, it is recommended to reduce the dose of levodopa, while doses of other antiparkinsonian agents should remain unchanged.

Due to the potential additive effect, caution should be exercised if the patient is using other sedative medicinal products in combination with pramipexole or consuming alcohol (see sections "Special precautions for use", "Ability to influence reaction rate when driving or operating machinery", and "Adverse reactions").

Antipsychotic medicinal products.

Concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section "Special precautions for use") due to possible antagonistic effects.

Special precautions for use.

Dose reduction of pramipexole is recommended for patients with Parkinson's disease and impaired renal function, as described in the section "Dosage and administration".

Hallucinations. Hallucinations are known adverse reactions associated with dopamine agonists and levodopa therapy. Patients should be informed that hallucinations (mostly visual) may occur.

Disorders of impulse control. Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be aware that treatment with dopamine agonists, including pramipexole, may lead to symptoms of impulse control disorders, such as pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating.

If such symptoms develop, dose reduction or discontinuation of the drug should be considered.

Dyskinesia. Dyskinesia may develop during the initial titration of pramipexole in patients with progressive Parkinson's disease receiving concomitant levodopa therapy. In such cases, the levodopa dose should be reduced.

Dystonia.

Axial dystonia, including antecollis, camptocormia, and pleurothotonus (Pisa syndrome), has been reported occasionally in patients with Parkinson's disease after initiation or dose escalation of pramipexole. Although dystonia may be a symptom of Parkinson's disease itself, symptoms in these patients improved after dose reduction or discontinuation of pramipexole.

If dystonia occurs, a reassessment of the dopaminergic treatment regimen and adjustment of the pramipexole dose should be considered.

Sudden sleep attacks and somnolence. Pramipexole has been associated with somnolence and episodes of sudden sleep attacks, particularly in patients with Parkinson's disease. Rare cases of sudden onset of sleep during daily activities, sometimes without awareness or warning signs, have been reported. Therefore, patients should be advised to exercise caution when driving or operating machinery during treatment with pramipexole. Patients who experience somnolence and/or sudden sleep attacks should refrain from driving and operating machinery. Furthermore, dose reduction or shortening of treatment duration should be considered. Caution is advised when pramipexole is used concomitantly with other sedative medicinal products or alcohol due to possible additive effects (see sections "Interaction with other medicinal products and other forms of interaction", "Effect on ability to drive and use machines", and "Adverse reactions").

Mania and delirium. Patients should be closely monitored for the development of mania and delirium. Patients and caregivers should be informed that mania and delirium may occur in patients receiving pramipexole therapy.

If such symptoms occur, dose reduction or discontinuation of the drug should be considered.

Severe cardiovascular disorders. Pramipexole should be administered with particular caution in patients with severe cardiovascular disorders. Blood pressure monitoring is recommended, especially at the beginning of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.

Patients with psychiatric disorders. Dopamine agonists should be used in patients with psychiatric disorders only if the potential benefit outweighs the risks. Concomitant use of antipsychotic medicinal products with pramipexole should be avoided.

Neuroleptic malignant syndrome. Symptoms resembling neuroleptic malignant syndrome have been observed after abrupt withdrawal of dopaminergic therapy.

Ophthalmological examination. Regular ophthalmological examination is recommended in case of visual disturbances.

Dopamine agonist withdrawal syndrome. To discontinue treatment in patients with Parkinson's disease, the dose of pramipexole should be reduced according to the section "Dosage and administration". Non-motor adverse reactions may occur during dose reduction or discontinuation of dopamine agonists (including pramipexole). Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain, and may be severe. Patients should be informed about these symptoms prior to dose reduction, and should be monitored regularly. In case of persistent symptoms, temporary dose increase of pramipexole may be considered (see section "Adverse reactions").

Augmentation (worsening of symptoms). Reports indicate that treatment of restless legs syndrome with dopaminergic agents may lead to augmentation. Augmentation is characterized by earlier onset of symptoms in the evening (or even during the day), worsening of symptoms, and spread of symptoms to the upper limbs.

The risk of augmentation may increase with higher doses. Patients should be informed before starting treatment that augmentation may occur and should be advised to consult their physician if they experience symptoms of augmentation. If augmentation is suspected, consideration should be given to adjusting the dose to the lowest effective dose or discontinuing pramipexole (see sections "Dosage and administration" and "Adverse reactions").

Augmentation was specifically evaluated in a controlled clinical trial over 26 weeks. Augmentation occurred in 11.8% of patients in the pramipexole group and in the placebo group. Kaplan–Meier analysis of time to augmentation showed no significant difference between the pramipexole and placebo groups.

Renal impairment. Tormipex should be used with caution in patients with renal impairment, as pramipexole is primarily excreted via the kidneys.

Rhabdomyolysis. One case of rhabdomyolysis occurred in a 49-year-old man with progressive Parkinson's disease treated with pramipexole. The patient was hospitalized with elevated creatine phosphokinase levels (CPK – 10,631 IU/l). Symptoms resolved after discontinuation of treatment.

Use during pregnancy or breastfeeding.

The effects of pramipexole on pregnancy and lactation in humans are unknown. The drug may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Since pramipexole treatment suppresses prolactin secretion in humans, a reduction in lactation is possible. Data on excretion of pramipexole into human breast milk are not available. The drug is not recommended during breastfeeding. However, if treatment with pramipexole is considered necessary, breastfeeding should be discontinued.

Effect on ability to drive and use machines.

The drug has a marked influence on the ability to drive and operate machinery.

Possible occurrence of hallucinations or somnolence.

Patients being treated with the drug who experience somnolence and/or episodes of sudden sleep should be advised to refrain from driving and from activities where lapses in attention may result in injury to themselves or others, or even death (e.g., operating machinery), until such recurrent episodes or somnolence resolve.

Dosage and Administration

Parkinson's Disease

The tablets should be taken orally, swallowed with water, independent of food intake.

The daily dose should be divided into 3 equal doses taken throughout the day.

Initial treatment: The dose should be gradually increased as shown in Table 1, starting from an initial dose of 0.375 mg salt per day, increasing every 5–7 days. In the absence of intolerable adverse effects, the dose should be titrated until the maximum therapeutic effect is achieved.

Table 1

If further dose increase is required, the daily dose should be increased by 0.75 mg of the salt weekly up to the maximum dose of 4.5 mg of the salt per day.

However, it should be noted that at doses exceeding 1.5 mg of the salt, the frequency of somnolence increases.

Maintenance therapy. The individual dose should range from (0.375 mg) to the maximum dose of 4.5 mg per day. During dose escalation in the three main clinical studies, efficacy was observed starting at a daily dose of 1.5 mg of the salt. Further dose adjustments should be made according to the clinical response and occurrence of adverse effects. In clinical trials, approximately 5% of patients were treated with doses below 1.5 mg. In progressive Parkinson’s disease, doses above 1.5 mg per day may be effective in patients for whom levodopa therapy reduction is planned. It is recommended to reduce the levodopa dose when increasing the dose and during maintenance therapy with the medicinal product, depending on the response of each individual patient.

Discontinuation of treatment. Abrupt discontinuation of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome. Therefore, the dose of pramipexole should be gradually 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.

Renal impairment. The elimination of pramipexole depends on renal function. The following regimen is recommended for initiation of therapy:

• Patients with creatinine clearance above 50 ml/min do not require dose reduction;
• Patients with creatine clearance of 20–50 ml/min should start with a daily dose administered in two separate doses, beginning with 0.125 mg twice daily (0.25 mg per day);
• Patients with creatinine clearance below 20 ml/min should start with a single daily dose of 0.125 mg per day. The maximum daily dose of pramipexole should not exceed 1.5 mg.

When renal function declines during maintenance therapy, the daily dose should be reduced by the same percentage by which creatinine clearance has decreased; for example, if creatinine clearance decreases by 30%, the daily dose should also be reduced by 30%. The daily dose may be administered in two divided doses if creatinine clearance is between 20–50 ml/min, and as a single dose if creatinine clearance is below 20 ml/min.

Hepatic impairment. Dose adjustment is not required in patients with hepatic impairment, as approximately 90% of the absorbed active substance is excreted by the kidneys, although the potential impact of hepatic insufficiency on the pharmacokinetics of pramipexole has not been studied.

Restless legs syndrome.

Tablets should be taken orally, swallowed with water, independent of food intake.

The recommended initial dose is 0.125 mg once daily, taken 2–3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4–7 days up to the maximum dose of 0.75 mg per day (as shown in Table 2). The lowest effective dose should be used (see section "Special precautions for use").

Table 2

Since the long-term efficacy of pramipexole in the treatment of restless legs syndrome has not been sufficiently studied, the patient's response should be evaluated and the need for continuing therapy should be reviewed after 3 months of treatment. If treatment is interrupted for more than a few days, it should be restarted with dose titration as described above.

Discontinuation of treatment. Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg, the drug may be discontinued without gradual dose reduction. However, withdrawal effects (worsening of symptoms after abrupt discontinuation of treatment) should not be ruled out.

Renal impairment. Elimination of pramipexole depends on renal function. Patients with creatinine clearance greater than 20 ml/min do not require dose reduction.

The use of pramipexole in patients undergoing hemodialysis or in patients with severe renal impairment has not been studied.

Hepatic impairment. Dose adjustment is not required in patients with hepatic impairment, since approximately 90% of the absorbed active substance is excreted by the kidneys.

Children.

The safety and efficacy of the drug in children have not been established; therefore, the use of the drug in this patient population is not recommended.

Overdose.

Symptoms. Information on significant overdosage is lacking. Expected adverse effects are related to the pharmacodynamic profile of a dopamine agonist and include nausea, vomiting, hyperkinesia, hallucinations, agitation, and arterial hypotension.

Treatment. There is no specific antidote for overdose with a dopamine agonist. In the event of signs of central nervous system agitation, neuroleptics may be administered. Management of overdose may require general supportive measures, including gastric lavage, intravenous fluid administration, activated charcoal, and electrocardiogram monitoring.

Adverse reactions.

Most adverse reactions usually occur at the beginning of therapy, and a significant proportion of them disappear even if the therapy continues.

Adverse reactions are listed by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 – <1/10), uncommon (≥ 1/1000 – < 1/100), rare (≥1/10000 – < 1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

Parkinson's disease.

In patients with Parkinson's disease, the most common adverse reactions (≥ 5%) observed during treatment with pramipexole compared to placebo were nausea, dyskinesia, arterial hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increased when doses higher than 1.5 mg per day were used (see section "Dosage and administration"). The most common adverse reaction when administered in combination with levodopa was dyskinesia. Arterial hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.

1 This adverse reaction was observed in the post-marketing period. In 95 %, the frequency is no more than uncommon, but it could be lower. Establishing the exact frequency is not possible, as the adverse reaction was not observed during clinical trials in 2762 Parkinson's disease patients treated with pramipexole.

Restless legs syndrome.

In patients with restless legs syndrome treated with pramipexole, the most commonly observed adverse reactions (≥ 5 %) were nausea, headache, dizziness, and increased fatigue. Nausea and increased fatigue were observed more frequently in women (20.8 % and 10.5 %, respectively) compared to men (6.7 % and 7.3 %, respectively) during treatment with pramipexole.

2 This adverse reaction was observed in the post-marketing period. In 95%, the frequency is no higher than uncommon, but it may be lower. Determination of the exact frequency is not possible, as the adverse reaction was not observed during clinical trials in 1395 patients with restless legs syndrome treated with pramipexole.

Somnolence. Pramipexole use is often associated with somnolence and uncommonly with excessive daytime sleepiness and episodes of sudden sleep attacks (see section "Special precautions").

Libido disorders. Pramipexole use may uncommonly be associated with libido disorders (increased or decreased).

Impulse control disorders. When treating with dopamine agonists, including Tormipex, symptoms of impulse control disorders may occur, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating (see section "Special precautions").

Dopamine agonist withdrawal syndrome. Non-motor adverse reactions may occur when reducing the dose or discontinuing dopamine agonists (including pramipexole). Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain (see section "Special precautions").

Heart failure. Heart failure was observed in patients receiving pramipexole during studies. In a pharmacoepidemiological study, the use of pramipexole was associated with an increased risk of heart failure compared to non-use (risk ratio 1.86; 95% CI, 1.21–2.85).

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard pack.

Prescription category. Prescription only.

Manufacturer.

Torrent Pharmaceuticals Ltd.

Manufacturer's location and address of its business site.

Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana Gujarat 382 721, India.