Azilect^® (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Contact Information

TEVA (Israel)

ATC Code

N04BD02 (Rasagiline)

Active Substance

Rasagiline (Rec.INN registered by WHO)

Dosage Form

Azilect®

Tablets 1 mg: 10, 30, or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are white or almost white, round, flat-cylindrical, with a bevel, engraved with “GIL” on top and “1” below on one side and flat on the other side.

Excipients: mannitol – 159.24 mg, colloidal silicon dioxide – 1.2 mg, corn starch – 20 mg, pregelatinized corn starch – 20 mg, stearic acid – 4 mg, talc – 4 mg.

10 pcs. – blisters (1) – cardboard packs^×.
10 pcs. – blisters (3) – cardboard packs^×.
10 pcs. – blisters (10) – cardboard packs^×.

^× protective stickers may additionally be applied.

Clinical-Pharmacological Group

Antiparkinsonian drug – selective MAO type B inhibitor

Pharmacotherapeutic Group

Antiparkinsonian agent – MAO inhibitor

Pharmacological Action

Antiparkinsonian drug. Azilect^® is a selective irreversible inhibitor of MAO type B, an enzyme that accounts for 80% of MAO activity in the brain and dopamine metabolism. Rasagiline is 30-80 times more active against MAO type B compared to MAO type A.

As a result of the inhibitory effect of the drug on MAO type B in the CNS, dopamine levels increase, and the formation of toxic free radicals, the excessive formation of which is observed in Parkinson’s disease, decreases. Rasagiline also has a neuroprotective effect.

Unlike non-selective MAO inhibitors, the drug in therapeutic doses does not block the metabolism of dietary biogenic amines (e.g., tyramine), and therefore does not cause tyramine-induced hypertensive syndrome (“cheese” effect).

Pharmacokinetics

Absorption

Rasagiline is rapidly absorbed after oral administration, C_max in plasma is reached within 0.5 hours. The absolute bioavailability of the drug after a single dose is about 36%. Food does not affect the time to reach C_max of rasagiline in the blood, but when consuming fatty food, C_max and AUC decrease by 60% and 20%, respectively.

The pharmacokinetics of the drug is linear in the dose range of 0.5-2 mg.

Distribution

Binding to plasma proteins ranges from 60% to 70%.

Metabolism

Rasagiline is almost completely metabolized in the liver. Biotransformation occurs through N-dealkylation and/or hydroxylation to form the main biologically low-active metabolite – 1-aminoindan, as well as two other metabolites – 3-hydroxy-N-propargyl-1-aminoindan and 3-hydroxy-1-aminoindan. Drug metabolism occurs with the participation of the CYP1A2 isoenzyme.

Excretion

Rasagiline is excreted mainly by the kidneys (more than 60%) and to a lesser extent through the intestines (more than 20%). Less than 1% of the administered dose of the drug is excreted unchanged. T_1/2 is 0.6-2 hours.

Pharmacokinetics in special clinical cases

The pharmacokinetic parameters of rasagiline practically do not change in patients with mild to moderate renal failure.

In mild hepatic impairment, an increase in AUC and C_max values by 80% and 38% may be observed, and in patients with moderate hepatic impairment, these parameters reach more than 500% and 80%, respectively.

Indications

• Treatment of Parkinson’s disease (as monotherapy or combination therapy with levodopa preparations).

ICD codes

Dosage Regimen

Administer a 1 mg tablet once daily.

Use this dosage for both monotherapy and adjunctive therapy with levodopa.

Continue treatment long-term as directed.

Take tablets orally, with or without food.

Do not exceed the recommended 1 mg daily dose.

For patients with mild hepatic impairment, use with caution.

Discontinue use if hepatic impairment progresses to moderate or severe.

No dosage adjustment is required for patients with mild to moderate renal impairment.

Adverse Reactions

In total, 1361 patients participated in the rasagiline clinical trial program, which amounted to 3076.4 patient-years. In double-blind placebo-controlled studies, 529 patients took Rasagiline at a dose of 1 mg/day, which amounted to 212 patient-years, and 539 patients received placebo, which amounted to 213 patient-years.

Monotherapy

The list below describes adverse reactions that were reported with increased frequency in placebo-controlled studies in patients receiving Rasagiline at a dose of 1 mg/day (rasagiline group – n=149, placebo group – n=151).

Adverse reactions with differences of more than 2% compared to the placebo group are highlighted in italics.

The frequency of adverse reactions (% of patients) is indicated in parentheses: Rasagiline/placebo.

Adverse reactions are distributed according to the following frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

Infections and infestations common – influenza (4.7%/0.7%).

Benign, malignant and unspecified neoplasms (including cysts and polyps) common – skin cancer (1.3%/0.7%).

Blood and lymphatic system disorders common – leukopenia (1.3%/0%).

Immune system disorders common – allergic reactions (1.3%/0.7%).

Metabolism and nutrition disorders uncommon – decreased appetite (0.7%/0%).

Psychiatric disorders common – depression (5.4%/2%), hallucinations (1.3%/ 0.7%).

Nervous system disorders very common – headache (4.1%/11.9%); uncommon – cerebrovascular accident (0.7%/0%).

Eye disorders common – conjunctivitis (2.7%/0.7%).

Ear and labyrinth disorders common – vertigo (2.7%/1.3%).

Cardiac disorders common – angina pectoris (1.3%/0%); uncommon – myocardial infarction (0.7%/0%).

Gastrointestinal disorders abdominal distension (1.3%/0%).

Respiratory, thoracic and mediastinal disorders common – rhinitis (3.4%/0.7%).

Skin and subcutaneous tissue disorders common – dermatitis (2%/0%); uncommon – vesiculobullous rash (0.7%/0%).

Musculoskeletal and connective tissue disorders common – musculoskeletal pain (6.7%/2.6%), neck pain (2.7%/0%), arthritis (1.3%/0.7%).

Renal and urinary disorders common – urinary urgency (1.3%/0.7 %).

General disorders and administration site conditions common – fever (2.7%/1.3%), malaise (2%/0%).

When used as adjunctive therapy

The list below includes adverse reactions that were reported with increased frequency in placebo-controlled studies in patients receiving Rasagiline at a dose of 1 mg/day (rasagiline group – n=380, placebo group – n=388). The frequency of adverse reactions (% of patients) is indicated in parentheses: Rasagiline/placebo.

Adverse reactions with differences of more than 2% compared to the placebo group are highlighted in italics.

The frequency of adverse reactions (% of patients) is indicated in parentheses: Rasagiline/placebo.

Adverse reactions are distributed according to the following frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon – skin melanoma (0.5%/ 0.3%).

Metabolism and nutrition disorders common – decreased appetite (2.4%/0.8%).

Psychiatric disorders common – hallucinations (2.9%/2.1%), nightmares (2.1%/0.8%); uncommon – confusion (0.8%/0.5%).

Nervous system disorders very common – dyskinesia (10.5%/6.2%), common – dystonia (2.4%/0.8%), carpal tunnel syndrome (1.3%/0%), balance disorder (1.6%/0.3%); uncommon – cerebrovascular accident (0.5%/0.3%).

Cardiac disorders uncommon – angina pectoris (0.5%/0%); common – orthostatic hypotension (3.9%/0.8%).

Gastrointestinal disorders common – abdominal pain (4.2%/1.3%), constipation (4.2%/2.1%), nausea and vomiting (8.4%/6.2%), dry mouth (3.4%/1.8%).

Skin and subcutaneous tissue disorders common – rash (1.1%/0.3%).

Musculoskeletal and connective tissue disorders common – arthralgia (2.4%/2.1%), neck pain (1.3%/0.5%).

General disorders and administration site conditions common – weight loss (4.5%/1.5%), falls (4.7%/3.4%).

Hallucinations and confusion occur in Parkinson’s disease. According to post-registration experience, these symptoms were noted in patients with Parkinson’s disease receiving Rasagiline.

Serious adverse reactions occurring with the concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors are well known. In the post-registration period, cases of serotonin syndrome, manifested by agitation, confusion, rigidity, fever and myoclonus, have been reported in patients simultaneously taking antidepressants/SNRIs and Rasagiline.

In rasagiline clinical trials, concomitant use with fluoxetine or fluvoxamine was not allowed. However, the following antidepressants in the specified doses were allowed: amitriptyline not more than 50 mg/day, trazodone not more than 100 mg/day, citalopram not more than 20 mg/day, sertraline not more than 100 mg/day and paroxetine not more than 30 mg/day. In the clinical trial program, in which Rasagiline was used concomitantly with tricyclic antidepressants (115 patients) and SSRIs/SNRIs (141 patients), no cases of serotonin syndrome were noted.

During the post-registration period of rasagiline use, increased blood pressure, including rare cases of hypertensive crises, has been reported in patients using an undetermined amount of tyramine-rich foods in their diet.

Cases of drug interaction with the concomitant use of MAO inhibitors with sympathomimetic drugs are known.

In the post-registration period, a case of increased blood pressure was reported in a patient using the ophthalmic vasoconstrictor tetrahydrozoline and simultaneously receiving rasagiline treatment.

Impulse control disorder

Cases of increased libido, hypersexuality, pathological gambling, compulsive need to buy or acquire, binge eating and compulsive overeating have been reported in patients treated with dopamine receptor agonists and/or other dopaminergics. A similar pattern of impulse control disorder was observed in the post-registration period in patients taking Rasagiline and was characterized by compulsive and impulsive behavior, obsessions.

Contraindications

• Hypersensitivity to rasagiline or any component of the drug;
• Concomitant use with other MAO inhibitors (including drugs and dietary supplements containing St. John’s wort), pethidine. The interval between discontinuation of rasagiline and initiation of therapy with these drugs should be at least 14 days;
• Moderate and severe hepatic impairment (Child-Pugh classes B and C);
• Children and adolescents under 18 years of age (no data on efficacy and safety).

With caution

• Mild hepatic impairment (Child-Pugh class A);
• Concomitant use with selective serotonin reuptake inhibitors (SSRIs) (including fluoxetine, fluvoxamine), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants, potent inhibitors of the CYP1A2 isoenzyme.

Use in Pregnancy and Lactation

There are no data on the use of rasagiline in pregnant women. Results from animal studies do not indicate a direct or indirect adverse effect on pregnancy, embryofetal development, childbirth and postnatal development. If it is necessary to use rasagiline in pregnant women, the expected benefit for the mother and the risk to the fetus should be weighed.

According to experimental data, Rasagiline inhibits prolactin secretion and thus may suppress lactation. Data on the penetration of rasagiline into breast milk are not available. If it is necessary to use rasagiline during breastfeeding, the expected benefit for the mother and child should be weighed.

Use in Hepatic Impairment

Contraindicated in moderate or severe hepatic impairment (Child-Pugh class B and C).

Use in Renal Impairment

The pharmacokinetic parameters of rasagiline practically do not change in patients with mild to moderate renal failure.

Pediatric Use

Contraindicated: children and adolescents under 18 years of age.

Special Precautions

Concomitant use of Azilect^® and fluoxetine or fluvoxamine should be avoided. The interval between discontinuation of fluoxetine and initiation of treatment with Azilect^® should be 5 weeks, and between discontinuation of Azilect^® and initiation of fluoxetine or fluvoxamine 14 days.

Cases of impulse control disorder have been reported in patients treated with dopamine receptor agonists and/or other dopaminergics. The same disorders were observed in the post-registration period in patients taking Azilect^®. Patients should be monitored due to the possibility of developing impulse control disorder. Patients and caregivers should be informed about the possibility of behavioral disturbances in patients taking Azilect^®, including compulsive behavior, obsessions, pathological gambling, increased libido, hypersexuality, impulsive behavior and compulsive needs to buy or acquire.

Concomitant use of Azilect^® with dextromethorphan, with sympathomimetics or complex oral or nasal cold preparations containing ephedrine or pseudoephedrine is not recommended.

There is evidence that Parkinson’s disease, and not the use of any drug, including Azilect^®, is a risk factor for the development of skin cancer, in particular melanoma. The patient should be warned about the need to consult a doctor if any pathological skin changes appear.

It should be borne in mind that symptoms such as hallucinations and confusion that appear during treatment with Azilect^® can be considered both as a manifestation of Parkinson’s disease and as adverse reactions of Azilect^®.

Azilect^® should be used with caution in patients with mild hepatic impairment. The use of Azilect^® in patients with moderate hepatic impairment is not recommended. If the degree of hepatic impairment changes from mild to moderate, the use of Azilect^® should be discontinued.

Effect on ability to drive vehicles and operate machinery

The effect of rasagiline on the ability to drive vehicles and operate machinery has not been studied. However, given the possibility of significant side effects from the CNS, during treatment with Azilect^®, patients should be informed about the need to exercise caution when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions until they are sure that the drug does not have a negative effect.

Overdose

Symptoms of Azilect^® overdose are similar to those of an overdose of non-selective MAO inhibitors (including arterial hypertension, postural hypotension).

Treatment gastric lavage, intake of activated charcoal, symptomatic therapy. There is no specific antidote.

Drug Interactions

Concomitant use of rasagiline with other MAO inhibitors, including drugs and dietary supplements containing St. John’s wort, is contraindicated, because there is a risk of developing a severe hypertensive crisis due to non-selective inhibition of MAO.

Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors, including selective MAO-B inhibitors. Concomitant use of rasagiline and pethidine is contraindicated.

Interaction of MAO inhibitors and sympathomimetic drugs with their concomitant use has been reported. Due to the property of rasagiline to inhibit MAO, concomitant use of rasagiline with sympathomimetics, such as decongestants or complex oral or nasal cold preparations containing ephedrine or pseudoephedrine, is not recommended.

Interaction of dextromethorphan and non-selective MAO inhibitors with their concomitant use has been reported. Due to the property of rasagiline to inhibit MAO, concomitant use of rasagiline with dextromethorphan and combined drugs containing it is not recommended.

Concomitant use of rasagiline with fluoxetine or fluvoxamine should be avoided. The interval between discontinuation of rasagiline and initiation of therapy with these drugs should be at least 14 days. After stopping treatment with fluoxetine or fluvoxamine (long half-life) and starting treatment with rasagiline, at least 5 weeks should pass.

Information on the concomitant use of SSRIs/SNRIs and rasagiline in clinical trials is presented in the “Adverse Reactions” section.

Serious adverse reactions have been reported with the concomitant use of SSRIs, SNRIs, tricyclic and tetracyclic antidepressants with MAO inhibitors.

Due to the property of rasagiline to inhibit MAO, caution is necessary when using it concomitantly with SSRIs, SNRIs, tricyclic, and tetracyclic antidepressants.

In patients with Parkinson’s disease receiving long-term levodopa as adjunctive therapy, levodopa did not have a significant effect on the clearance of rasagiline.

In vitro studies have shown that the main enzyme involved in the metabolism of rasagiline is the CYP1A2 isoenzyme. Concomitant use of ciprofloxacin and rasagiline increases the AUC of the latter by 83%.

Concomitant use of rasagiline and theophylline (a substrate of the CYP1A2 isoenzyme) did not affect the pharmacokinetics of either. Thus, potent inhibitors of the CYP1A2 isoenzyme may alter the plasma concentration of rasagiline and require cautious concomitant use.

There is a risk that due to the induction of the CYP1A2 isoenzyme in smoking patients, the plasma concentration of rasagiline may decrease.

In vitro studies have shown that Rasagiline at a concentration of 1 µg/ml (which is equivalent to a concentration exceeding the average C_max(5.9-8.5 ng/ml) after multiple doses of 1 mg rasagiline in patients with Parkinson’s disease by 160 times) does not inhibit the CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A isoenzymes. This indicates that therapeutic concentrations of rasagiline are unlikely to be subject to clinically significant influence from substrates of the specified isoenzymes.

With the concomitant use of entacapone with rasagiline, the clearance of the latter increased by 28%.

Clinical studies of the interaction between tyramine and rasagiline in volunteers and patients with Parkinson’s disease (0.5-1 mg/day rasagiline or placebo as adjunctive therapy to levodopa for 6 months without tyramine intake restrictions) showed that there is no interaction between rasagiline and tyramine, and Rasagiline can be safely used without dietary tyramine restrictions.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

AZIL-RU-NP-00001-DOC-PHARM-19082016

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.