Ralago

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

Composition:

Active substance: rasagiline;

1 tablet contains 1 mg rasagiline as rasagiline hemitartrate;

Excipients: microcrystalline cellulose, pregelatinized corn starch, colloidal anhydrous silicon dioxide, talc, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, slightly biconvex tablets with bevelled edges, white to almost white in color, with possible darker specks.

Pharmacotherapeutic group. Anti-Parkinson drugs. Monoamine oxidase type B inhibitors. ATC code N04BD02.

Pharmacological properties.

Pharmacodynamics. Rasagiline is a potent, irreversible, selective inhibitor of monoamine oxidase B (MAO-B), which may lead to increased extracellular levels of dopamine in the brain. In models of dopaminergic motor dysfunction, elevated dopamine levels and enhanced dopaminergic activity have been demonstrated, which likely contribute to the therapeutic effects of rasagiline.

1-Aminoindan is an active primary metabolite and is not an MAO-B inhibitor.

Pharmacokinetics.

Absorption. Rasagiline is rapidly absorbed, with peak plasma concentration (C_max) reached approximately within 0.5 hours. The absolute bioavailability after a single dose is 36%. Food does not affect the time to reach peak plasma concentration (T_max), but administration with a high-fat meal reduces C_max and area under the concentration-time curve (AUC) by 60% and 20%, respectively. Rasagiline can be administered independently of food intake.

Distribution. The mean volume of distribution after a single intravenous dose of rasagiline is 243 L. Plasma protein binding after oral administration of a single dose of 14C-labeled rasagiline ranges from 60% to 70%.

Metabolism. Rasagiline is almost completely metabolized in the liver. Metabolism occurs via two main pathways: N-dealkylation and/or hydroxylation, resulting in the formation of the following metabolites: 1-aminoindan, 3-hydroxy-N-propargyl-1-aminoindan, and 3-hydroxy-1-aminoindan. In vitro studies have shown that both metabolic pathways of rasagiline are mediated by the CYP1A2 isoenzyme of the cytochrome P450 system. Conjugation of rasagiline and its metabolites to form glucuronides has also been identified as one of the major elimination pathways.

Elimination. After oral administration of 14C-labeled rasagiline, the drug is primarily excreted in urine (62.6%) and to a lesser extent in feces (21.8%). Complete excretion of 84.4% of the dose takes 38 days. Less than 1% of the drug is excreted unchanged in urine.

Linearity/Non-linearity. Rasagiline exhibits linear pharmacokinetics within the dose range of 0.5–2 mg. Elimination half-life ranges from 0.6 to 2 hours.

Pharmacokinetics in specific patient populations.

Patients with hepatic impairment.

In patients with mild hepatic impairment, C_max and AUC values increased by 80% and 38%, respectively. In patients with moderate hepatic impairment, C_max and AUC values increased by 568% and 83%, respectively.

Patients with renal impairment. Pharmacokinetic parameters of rasagiline are practically unchanged in patients with mild to moderate renal impairment.

Clinical characteristics.

Indications.

Monotherapy (without levodopa) in idiopathic Parkinson's disease or adjunctive therapy (with levodopa) in end-of-dose fluctuations.

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Concomitant therapy with other MAO inhibitors (including medicinal products and herbal preparations, e.g., those containing Hypericum perforatum [St. John's wort]) or with pethidine (a washout period of at least 14 days must elapse between discontinuation of rasagiline and initiation of therapy with these agents).

Severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Interactions between non-selective MAO inhibitors and other medicinal products are known.

Rasagiline should not be used concomitantly with other MAO inhibitors (including medicinal products and herbal preparations containing Hypericum perforatum), as there is a risk of non-selective inhibition, which may lead to hypertensive crisis.

Serious adverse reactions have been reported when pethidine is used concomitantly with MAO inhibitors, including other selective MAO-B inhibitors. Concomitant use of rasagiline and pethidine is contraindicated.

Interactions between MAO inhibitors and sympathomimetics have been reported when used concomitantly. Since rasagiline is a potent MAO inhibitor, its concomitant use with sympathomimetics, such as oral or nasal vasoconstrictors, or cold remedies containing ephedrine or pseudoephedrine, is not recommended.

Interactions between dextromethorphan and non-selective MAO inhibitors have been reported when used concomitantly. Therefore, since rasagiline is a potent MAO inhibitor, its concomitant use with dextromethorphan is not recommended.

Concomitant use of rasagiline with fluoxetine and fluvoxamine should be avoided.

A washout period of at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of rasagiline therapy. A washout period of at least 14 days should elapse between discontinuation of rasagiline and initiation of therapy with fluoxetine or fluvoxamine.

Serious adverse reactions have been reported when rasagiline is used concomitantly with SSRIs, SNRIs, tricyclic/tetracyclic antidepressants, and MAO inhibitors. Therefore, since rasagiline is a potent MAO inhibitor, caution should be exercised when using rasagiline with antidepressants.

Levodopa, when used concomitantly with rasagiline in patients with Parkinson's disease, did not show any clinically significant effect on the clearance of rasagiline.

In vitro metabolism studies have shown that CYP1A2 isoenzyme of cytochrome P450 is the main enzyme responsible for rasagiline metabolism. Concomitant use of rasagiline and ciprofloxacin (an inhibitor of CYP1A2 isoenzyme) increases the AUC of rasagiline by 83%. Concomitant use of rasagiline and theophylline (a CYP1A2 substrate) does not affect the pharmacokinetics of rasagiline. Therefore, inhibitors of this isoenzyme may alter rasagiline plasma levels and should be used with caution.

There is a risk that due to induction of CYP1A2 in smokers, plasma concentrations of rasagiline may be reduced.

In vitro studies have shown that rasagiline at a concentration of 1 µg/mL (which is equivalent to a concentration exceeding the mean Cmax (5.9–8.5 ng/mL) by 160 times after multiple 1 mg doses of rasagiline in patients with Parkinson's disease) does not inhibit the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A. This suggests that rasagiline at therapeutic concentrations is unlikely to affect the metabolism of these isoenzymes or produce clinically significant effects.

Concomitant oral administration of rasagiline and entacapone increases the clearance of rasagiline by 28%.

Five clinical studies involving volunteers and patients with Parkinson's disease, as well as blood pressure monitoring after meals (464 patients received 0.5–1 mg/day rasagiline or placebo as add-on therapy to levodopa for 6 months without dietary restrictions on tyramine intake), showed no interaction between rasagiline and tyramine; therefore, rasagiline can be used without dietary restrictions on tyramine intake.

Special precautions for use

Concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). A washout period of at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of rasagiline therapy. A washout period of at least 14 days should elapse between discontinuation of rasagiline and initiation of fluoxetine or fluvoxamine therapy.

Impulse control disorders (ICDs) may occur in patients receiving dopamine agonists and/or dopaminergic therapy. Cases of ICDs have been reported during post-marketing use of rasagiline. Patients should be regularly monitored for the development of impulse control disorders. Patients and healthcare providers should be informed about behavioral changes indicative of impulse control disorders observed in patients during treatment with rasagiline, including obsessive states, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behavior, and pathological spending or shopping urges.

Rasagiline may enhance the effect of levodopa, potentially increasing adverse reactions associated with levodopa use and possibly worsening pre-existing dyskinesia. The intensity of these adverse reactions may be reduced by decreasing the dose of levodopa.

Cases of hypotension have been reported during concomitant use of rasagiline and levodopa. Patients with Parkinson's disease are particularly susceptible to this adverse reaction due to pre-existing gait disturbances.

Concomitant use of rasagiline with dextromethorphan or sympathomimetics, such as those contained in nasal or oral decongestants or cold remedies containing ephedrine or pseudoephedrine, is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

According to data from a retrospective cohort study, there may be an increased risk of melanoma development with the use of rasagiline, particularly with long-term use and/or high cumulative doses of rasagiline. Any suspicious skin lesions should be evaluated by a specialist. Patients should be advised to consult a dermatologist if they notice any new skin lesions or changes in existing ones.

Caution should be exercised when initiating rasagiline therapy in patients with mild hepatic impairment. Rasagiline should be avoided in patients with moderate hepatic impairment. If hepatic impairment progresses from mild to moderate, treatment with rasagiline should be discontinued.

Excessive daytime sleepiness and sudden sleep episodes

Rasagiline may cause daytime somnolence and, occasionally, especially when used concomitantly with other dopaminergic agents, sudden onset of sleep during routine daily activities. Therefore, patients should be advised to exercise caution when driving or operating machinery during treatment with rasagiline. Patients experiencing somnolence and/or sudden sleep episodes should refrain from driving and operating machinery (see section "Ability to affect driving and use of machines").

Use during pregnancy or breastfeeding

There are no clinical data on the use of rasagiline in pregnant women. Animal studies have not shown any direct or indirect harmful effects on pregnancy, fetal development, parturition, or postnatal development. Rasagiline should be used during pregnancy only if clearly needed and with caution. Data indicate that rasagiline inhibits prolactin secretion and, consequently, suppresses lactation. It is unknown whether rasagiline is excreted in human breast milk. Rasagiline should be used with caution during breastfeeding.

Ability to affect driving and use of machines

Rasagiline may significantly impair the ability to drive or operate machinery in patients experiencing somnolence or sudden sleep episodes.

Patients should exercise caution when driving or operating complex machinery until they are certain that Ralago does not adversely affect them.

Patients receiving rasagiline therapy who experience somnolence and/or sudden sleep episodes should be advised to refrain from driving or participating in activities where reduced alertness may place themselves or others at risk of serious injury or death (e.g., operating machinery), until they have gained sufficient experience with rasagiline and other dopaminergic agents to determine whether these medications adversely affect their mental and/or motor performance.

If increased somnolence or new episodes of sudden sleep onset occur during routine daily activities (e.g., watching television, riding in a car as a passenger, etc.) at any time during treatment, patients should not drive or engage in potentially dangerous activities.

Patients should not drive, operate machinery, or perform work at heights during treatment if they have previously experienced somnolence and/or sudden sleep attacks without warning prior to using rasagiline.

Patients should be warned about the possible additive effects of sedatives, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) when used concomitantly with rasagiline, or when taking concomitant medications that increase plasma levels of rasagiline (e.g., ciprofloxacin) (see section "Special precautions for use").

Dosage and Administration

Dosing Regimen

Rasagiline is administered orally at a dose of 1 mg once daily, with or without levodopa.

The drug may be taken regardless of food intake.

Elderly patients

Dose adjustment is not required for elderly patients.

Patients with hepatic impairment

Rasagiline should be avoided in patients with moderate hepatic impairment. Rasagiline should be initiated with caution in patients with mild hepatic impairment. If hepatic impairment progresses from mild to moderate severity, rasagiline treatment should be discontinued.

Patients with renal impairment

Dose adjustment is not required for patients with renal impairment.

Children

Due to insufficient data on the use of the drug in children, Ralago is not recommended for use in this patient population.

Overdose

Symptoms of Ralago overdose at doses ranging from 3 mg to 100 mg include hypomania, hypertensive crisis, and serotonin syndrome.

Overdose may be associated with significant inhibition of MAO-A and MAO-B.

Studies were conducted in healthy volunteers receiving 20 mg once daily and in a 10-day study in healthy volunteers receiving 10 mg once daily. Adverse reactions of mild or moderate severity were reported, including adverse reactions not typically associated with rasagiline treatment.

During an open-label study in patients receiving concomitant levodopa and rasagiline at a dose of 0.1 mg/day, adverse cardiovascular reactions (including arterial hypertension and postural hypotension) were reported, which resolved after discontinuation of treatment.

These symptoms are similar to those observed with overdose of non-selective MAO inhibitors.

Specific antidotes are not known. In case of overdose, careful patient monitoring is required; treatment should be symptomatic and supportive.

Adverse Reactions

Monotherapy

The following classification was used to assess the frequency of adverse reactions: very common ≥ 1/10, common ≥ 1/100 to < 1/10, uncommon ≥ 1/1000 to < 1/100, rare ≥ 1/10000 to < 1/1000, very rare < 1/10000.

Infections and infestations

Common: influenza.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Common: skin carcinoma.

Blood and lymphatic system disorders

Common: leukopenia.

Immune system disorders

Common: allergy.

Metabolism and nutrition disorders

Uncommon: decreased appetite.

Psychiatric disorders

Common: depression, hallucinations.

Nervous system disorders

Very common: headache.

Uncommon: cerebrovascular disorders.

Eye disorders

Common: conjunctivitis.

Ear and labyrinth disorders

Common: dizziness.

Cardiac disorders

Common: angina pectoris.

Uncommon: myocardial infarction.

Respiratory, thoracic and mediastinal disorders

Common: rhinitis.

Gastrointestinal disorders

Common: flatulence.

Skin and subcutaneous tissue disorders

Common: dermatitis.

Uncommon: vesiculobullous rash.

Musculoskeletal and connective tissue disorders

Common: bone and muscle pain, neck pain, arthritis.

Renal and urinary disorders

Common: urinary urgency.

General disorders

Common: fever, fatigue.

Adjunctive therapy

The following classification was used to assess the frequency of adverse reactions: very common ≥ 1/10, common ≥ 1/100 to < 1/10, uncommon ≥ 1/1000 to < 1/100, rare ≥ 1/10000 to < 1/1000, very rare < 1/10000.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Uncommon: skin melanoma.

Metabolism and nutrition disorders

Common: decreased appetite.

Psychiatric disorders

Common: hallucinations, pathological dreams.

Uncommon: confusion.

Nervous system disorders

Very common: dyskinesia.

Common: dystonia, carpal tunnel syndrome, impaired balance.

Uncommon: acute cerebrovascular accident.

Cardiac disorders

Uncommon: angina pectoris.

Respiratory, thoracic and mediastinal disorders

Common: rhinitis.

Vascular disorders

Common: orthostatic hypotension.

Gastrointestinal disorders

Common: abdominal pain, constipation, nausea and vomiting, dry mouth.

Skin and subcutaneous tissue disorders

Common: rash.

Musculoskeletal and connective tissue disorders

Common: arthralgia, neck pain.

Investigations

Common: weight decreased.

Injury, poisoning and procedural complications

Common: accidental falls.

Parkinson's disease is associated with the occurrence of hallucinations and confusion. During post-marketing studies of rasagiline use, these symptoms were observed in patients with Parkinson's disease who were receiving rasagiline.

It is known that serious adverse reactions may occur with concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants, and MAO inhibitors. During post-marketing surveillance of rasagiline use, cases of serotonin syndrome—manifested by anxiety, confusion, muscle rigidity, shivering, and myoclonic jerks—have been reported in patients who received antidepressants/SNRIs concomitantly with rasagiline.

Studies have been reported in which fluoxetine or fluvoxamine were not co-administered with rasagiline; however, other antidepressants were used with rasagiline: amitriptyline at doses of at least 50 mg per day, trazodone at doses of at least 50 mg per day, citalopram at doses of at least 20 mg per day, sertraline at doses of at least 100 mg per day, and paroxetine at doses of at least 30 mg per day. No cases of serotonin syndrome were reported during these studies.

During the post-marketing use of rasagiline, cases of increased blood pressure, including rare cases of hypertensive crisis associated with ingestion of tyramine-rich food, have been reported in patients taking rasagiline.

Drug interactions have been reported with concomitant use of MAO inhibitors and sympathomimetics.

During the post-marketing use of rasagiline, a case of increased blood pressure was reported in a patient who received rasagiline concomitantly with the ophthalmic vasoconstrictor tetrahydrozoline hydrochloride.

Impulse control disorders: In patients treated with dopamine agonists and/or other dopaminergic agents, pathological gambling, increased libido, hypersexuality, impulsive shopping, binge eating, and impulsive eating may occur.

Such adverse reactions were observed during the post-marketing period of rasagiline use: obsessive states, obsessive thoughts, impulsive behavior.

Excessive daytime sleepiness and episodes of sudden sleep

Excessive daytime sleepiness (hypersomnia, lethargy, sedation, sleep attacks, drowsiness, and sudden sleep episodes) may occur in patients receiving dopamine agonists and/or other dopaminergic therapies. Cases of excessive daytime sleepiness have been reported during the post-marketing use of rasagiline.

Cases of falling asleep during normal daily activities have been reported in patients receiving rasagiline and other dopaminergic agents. Although many of these patients reported drowsiness while taking rasagiline with other dopaminergic agents, some reported no prior warning signs such as excessive sleepiness. Some of these events occurred more than one year after initiation of treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging. 10 tablets in a blister; 3 or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's location and address of place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.