Azagiline® asino

INSTRUCTIONS for medical use of the medicinal product Azahilin Acino® (Azahilin Acino)

Composition:

Active substance: rasagiline;

1 tablet contains 1.438 mg of rasagiline hemitartrate, equivalent to 1 mg of rasagiline;

Excipients: microcrystalline cellulose; pregelatinized corn starch (partially); colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat tablets of white or almost white color with beveled edges and engraved "1" on one side.

Pharmacotherapeutic group.

Antiparkinson agents. Monoamine oxidase type B inhibitors. ATC code N04BD02.

Pharmacological Properties.

Pharmacodynamics.

There are two main types of monoamine oxidase (MAO) – type A and type B. MAO type B is predominantly localized in the human brain.

Rasagiline is a potent, irreversible, selective inhibitor of MAO type B, as demonstrated in ex vivo studies on brain, liver, and gastrointestinal tissues.

The precise mechanism of action of rasagiline is unknown. It is believed to be partly due to its ability to inhibit MAO-B, thereby increasing extracellular dopamine levels in the striatum. Elevated dopamine levels and, consequently, enhanced dopaminergic activity, likely underlie the therapeutic efficacy of rasagiline, as demonstrated in models of dopaminergic motor dysfunction. 1-Aminoindan is the main active metabolite of rasagiline and is not an inhibitor of MAO-B.

Pharmacokinetics.

Absorption. Rasagiline is rapidly absorbed, with peak plasma concentration (C_max) reached within approximately 0.5 hours. The absolute bioavailability of the drug after a single oral dose of rasagiline is 36%. Food does not affect the time to reach peak plasma concentration (T_max), but consumption of a high-fat meal reduces C_max and the area under the concentration-time curve (AUC) by 60% and 20%, respectively. Rasagiline may be administered with or without food.

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

Metabolism. Rasagiline undergoes almost complete hepatic biotransformation. Metabolism occurs via two main pathways: N-dealkylation and/or hydroxylation, resulting in the formation of 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. Elimination of rasagiline occurs in the form of glucuronide conjugates and its metabolites.

Elimination. After oral administration of 14C-labeled rasagiline, elimination occurs primarily via urine (62.6%) and to a lesser extent via feces (21.8%). Complete elimination of 84.4% of the administered 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. The 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 in idiopathic Parkinson's disease;
• adjunctive therapy with dopamine agonists;
• adjunctive therapy with levodopa in patients experiencing end-of-dose fluctuations.

Contraindications.

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

Concomitant use of other monoamine oxidase inhibitors (MAOIs) (including medicinal products and herbal preparations, e.g. those containing Hypericum perforatum – St. John’s wort) or 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.

MAO inhibitors

Concomitant administration of rasagiline with other MAO inhibitors (including medicinal products and herbal preparations containing Hypericum perforatum) is contraindicated, as non-selective MAO inhibition may lead to accumulation of noradrenaline, potentially resulting in hypertensive crisis (see section "Contraindications").

Pethidine

Serious adverse reactions have been reported with concomitant use of pethidine and MAO inhibitors, including other selective MAO-B inhibitors. Concomitant use of rasagiline and pethidine is contraindicated (see section "Contraindications").

Sympathomimetics

Interactions between MAO inhibitors and sympathomimetics have been observed when used concomitantly. Due to the MAO-inhibiting activity of rasagiline, concomitant use with vasoconstrictive sympathomimetics administered orally or intranasally, and with cold remedies containing ephedrine or pseudoephedrine, is not recommended (see section "Special precautions for use").

Dextromethorphan

Interactions between dextromethorphan and non-selective MAO inhibitors have been reported when used concomitantly. Therefore, due to the MAO-inhibiting activity of rasagiline, concomitant use with dextromethorphan is not recommended (see section "Special precautions for use").

Selective serotonin reuptake inhibitors (SSRIs)/serotonin-noradrenaline reuptake inhibitors (SNRIs)/tricyclic and tetracyclic antidepressants

Concomitant use of rasagiline with fluoxetine and fluvoxamine should be avoided (see section "Special precautions for use").

For information on concomitant use of rasagiline with SSRIs/SNRIs in clinical trials, see section "Adverse reactions".

Serious adverse reactions have been reported with concomitant use of rasagiline and SSRIs, SNRIs, tricyclic/tetracyclic antidepressants, and MAO inhibitors. Therefore, due to the potent MAO-inhibiting activity of rasagiline, caution should be exercised when using rasagiline concomitantly with antidepressants.

Medicinal products affecting CYP1A2 activity

In vitro metabolism studies have shown that cytochrome P450 1A2 (CYP1A2) is the main enzyme responsible for rasagiline metabolism.

Inhibitors of CYP1A2

Concomitant administration of rasagiline and ciprofloxacin (an inhibitor of CYP1A2 isoenzyme) increases the AUC of rasagiline by 83%. Concomitant administration of rasagiline and theophylline (a CYP1A2 substrate) does not affect the pharmacokinetics of either drug. Therefore, strong CYP1A2 inhibitors may alter plasma levels of rasagiline, and concomitant use should be undertaken with caution.

Inducers of CYP1A2

There is a risk that CYP1A2 induction in smokers may reduce plasma concentrations of rasagiline.

Other cytochrome P450 isoenzymes

In vitro studies have shown that rasagiline at a concentration of 1 µg/mL (which exceeds by 160 times the mean Cmax (5.9–8.5 ng/mL) observed after multiple dosing of 1 mg 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.

Levodopa and other medicinal products for the treatment of Parkinson’s disease

Levodopa, when co-administered with rasagiline in patients with Parkinson’s disease, had no clinically significant effect on the clearance of rasagiline.

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

Interaction between rasagiline and tyramine

In five clinical studies involving healthy volunteers and patients with Parkinson’s disease (464 patients received 0.5–1 mg daily rasagiline or placebo as add-on therapy to levodopa for 6 months without dietary tyramine restriction), blood pressure monitoring after meals showed no interaction between rasagiline and tyramine. Therefore, rasagiline can be used without dietary restriction of tyramine intake.

Special precautions for use.

Concomitant use of rasagiline with other medicinal products

Concomitant use of rasagiline with 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 is required between discontinuation of fluoxetine and initiation of rasagiline therapy. A washout period of at least 14 days is required between discontinuation of rasagiline and initiation of therapy with fluoxetine or fluvoxamine.

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

Concomitant use of rasagiline and levodopa

Rasagiline may enhance the effects of levodopa, potentially increasing levodopa-related adverse reactions and worsening existing dyskinesia. The intensity of these adverse reactions may be reduced by decreasing the dose of levodopa.

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

Dopaminergic effects

Excessive daytime sleepiness (EDS) and sudden onset sleep episodes (SOSE)

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

Impulse control disorders

Impulse control disorders may occur in patients receiving dopamine agonists and/or undergoing dopaminergic therapy. Cases of such impulse control disorders have been reported for rasagiline in the post-marketing period. Patients should be regularly monitored for signs of impulse control disorders. Patients and caregivers should be informed about behavioural changes indicating impulse control disorders observed in patients during treatment with rasagiline, including compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behaviour, and pathological spending or shopping.

Melanoma

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 or changing skin lesions.

Hepatic impairment

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no clinical data on the use of rasagiline in pregnant women. Animal studies have not shown direct or indirect harmful effects on reproductive toxicity. As a precautionary measure, it is advisable to avoid the use of rasagiline during pregnancy.

Period of breastfeeding

Preclinical data indicate that rasagiline inhibits prolactin secretion and consequently suppresses lactation. It is unknown whether rasagiline is excreted in human milk. Rasagiline should be used with caution during breastfeeding.

Fertility

There are no data on the effect of rasagiline on fertility in humans. Preclinical data suggest that rasagiline does not affect fertility.

Ability to affect reaction speed when driving or operating machinery.

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

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

Patients treated with rasagiline 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 assess whether these medications adversely affect their mental and/or motor performance.

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

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

Patients should be warned about 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").

Method of Administration and Dosage

Dosage Regimen

Monotherapy

Rasagiline is administered orally at a dose of 1 mg once daily.

Adjunctive therapy with dopamine agonists

Rasagiline is administered orally at a dose of 1 mg once daily.

Adjunctive therapy with levodopa

Rasagiline is administered orally at a dose of 1 mg once daily.

The drug may be administered independently of food intake.

Geriatric patients

Dosage adjustment is not required for elderly patients.

Patients with hepatic impairment

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

Patients with renal impairment

Dosage adjustment is not required for patients with renal impairment.

Children

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

Overdose

Symptoms

Symptoms of rasagiline overdose following doses 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 of single-dose administration in healthy volunteers receiving up to 20 mg per day, and a 10-day study in healthy volunteers receiving 10 mg once daily, have been conducted. Adverse reactions of mild or moderate severity were reported, including reactions not typically associated with rasagiline treatment.

In a high-dose rasagiline study in patients receiving concomitant levodopa therapy, adverse reactions related to the cardiovascular system (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.

Treatment

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

Side effects.

Summary of safety profile

In clinical trials in patients with Parkinson's disease, the most commonly reported adverse reactions were headache, depression, dizziness, and influenza-like symptoms (influenza and rhinitis) during monotherapy; dyskinesia, orthostatic hypotension, falls, abdominal pain, nausea, vomiting, and dry mouth when used as an adjunct to levodopa therapy; musculoskeletal pain such as back and neck pain, and arthralgia in both treatment regimens. These adverse reactions were not associated with an increased rate of treatment discontinuation.

The following classification was used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Monotherapy

The adverse reactions listed below were reported at a higher frequency during placebo-controlled studies in patients treated with rasagiline 1 mg once daily.

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; frequency not known – serotonin syndrome*, excessive daytime sleepiness and sudden onset of sleep episodes*.

Eye disorders: common – conjunctivitis.

Ear and labyrinth disorders: common – dizziness.

Cardiac disorders: common – angina pectoris; uncommon – myocardial infarction.

Vascular disorders: frequency not known – arterial hypertension*.

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 – musculoskeletal pain, neck pain, arthritis.

Renal and urinary disorders: common – urinary urgency.

General disorders and administration site conditions: common – pyrexia, fatigue.

* See section on description of selected adverse reactions.

Adjunctive therapy

The adverse reactions listed below were reported at a higher frequency during placebo-controlled studies in patients treated with rasagiline 1 mg once daily.

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon – skin melanoma*.

Metabolism and nutrition disorders: common – decreased appetite.

Psychiatric disorders: common – hallucinations*, abnormal dreams; uncommon – confusion; frequency not known – impulse control disorders*.

Nervous system disorders: very common – dyskinesia; common – dystonia, carpal tunnel syndrome, gait disturbance; uncommon – acute cerebrovascular accident; frequency not known – serotonin syndrome*, excessive daytime sleepiness and sudden onset of sleep episodes*.

Cardiac disorders: uncommon – angina pectoris.

Vascular disorders: common – orthostatic hypotension*; frequency not known – arterial hypertension*.

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 – falls.

* See section on description of selected adverse reactions.

Description of selected adverse reactions

Orthostatic hypotension

In double-blind, placebo-controlled studies, severe orthostatic hypotension was reported in one patient (0.3%) in the rasagiline group (adjunctive studies), and in none of the patients in the placebo group. Clinical trial data also indicate that orthostatic hypotension occurs most frequently during the first two months of rasagiline treatment and tends to decrease over time.

Arterial hypertension

Rasagiline is a selective MAO-B inhibitor and is not associated with increased sensitivity to tyramine at the recommended dose (1 mg daily). In double-blind, placebo-controlled studies (monotherapy and adjunctive therapy), no cases of severe arterial hypertension were reported in patients receiving rasagiline. During the post-marketing period, cases of increased blood pressure, including isolated cases of hypertensive crisis associated with consumption of tyramine-rich foods, have been reported in patients taking rasagiline. During the post-marketing period, a case of increased blood pressure was reported in a patient who used rasagiline concomitantly with the ophthalmic vasoconstrictor tetrahydrozoline hydrochloride.

Impulse control disorders

One case of hypersexuality was reported in a placebo-controlled monotherapy study. During post-marketing surveillance, the following events have been reported at an unknown frequency: compulsions, compulsive urge to shop, dermatillomania, dopamine dysregulation syndrome, impulse control disorders, impulsive behaviour, kleptomania, stealing, obsessive thoughts, obsessive-compulsive disorder, stereotypy, pathological gambling, pathological gambling, increased libido, hypersexuality, psychosexual disorders, sexually inappropriate behaviour.

Approximately half of the reported cases of impulse control disorders were considered serious. Only isolated cases reported did not resolve at the time of reporting.

Excessive daytime sleepiness and sudden onset of sleep episodes

Excessive daytime sleepiness (hypersomnia, somnolence, sedation, sleep attacks, drowsiness, and sudden sleep episodes) may occur in patients treated with dopamine agonists and/or other dopaminergic therapies. Similar 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 feeling sleepy while taking rasagiline with other dopaminergic agents, some reported no warning signs such as excessive drowsiness and believed they were fully alert immediately before the event. Some of these events occurred more than one year after initiation of treatment.

Hallucinations

Parkinson's disease is associated with the occurrence of hallucinations and confusion. These symptoms have been observed in patients with Parkinsonism during post-marketing studies while taking rasagiline.

Serotonin syndrome

Fluoxetine or fluvoxamine were not co-administered with rasagiline in clinical trials; however, other antidepressants were used concomitantly with rasagiline: amitriptyline ≤ 50 mg daily, trazodone ≤ 100 mg daily, citalopram ≤ 20 mg daily, sertraline ≤ 100 mg daily, and paroxetine ≤ 30 mg daily (see section "Interaction with other medicinal products and other forms of interaction"). During post-marketing surveillance, cases of serotonin syndrome characterized by agitation, confusion, muscle rigidity, hyperthermia, and myoclonic jerks have been reported in patients receiving antidepressants, meperidine, tramadol, methadone, or propoxyphene concomitantly with rasagiline.

Malignant melanoma

The incidence of skin melanoma in placebo-controlled clinical trials was 2/380 (0.5%) in the group receiving rasagiline 1 mg in combination with levodopa therapy, compared to 1/388 (0.3%) in the placebo group. Additional cases of malignant melanoma have been reported during the post-marketing period. All such reports were considered serious.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

In case of adverse effects or questions regarding the safety of this medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children and in the original packaging to protect from light. No special temperature requirements for storage.

Packaging. 15 tablets in a blister; 2 blisters in a cardboard pack.

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

Prescription status. Prescription only.

Manufacturer. Generics S.A.

Manufacturer's address and place of business.
18th km Marathonos Ave, Pallini Attiki, 15351, Greece.