Azilect

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Azilect (Azilect®)

Composition:

Active substance: rasagiline;

1 tablet contains rasagiline 1 mg (as rasagiline mesylate);

Excipients: maize starch, colloidal anhydrous silicon dioxide, pregelatinized starch, stearic acid, talc, mannitol (E 421).

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat tablets, white or almost white, with a bevel, embossed with "GIL 1" on one side and smooth on the other.

Pharmacotherapeutic group. Anti-parkinson drugs. Inhibitors of monoamine oxidase type B. ATC code N04BD02.

Pharmacological properties.

Pharmacodynamics. Rasagiline is a potent, irreversible, selective inhibitor of monoamine oxidase (MAO). There are two main types of MAO – A and B. MAO-B is the predominant type located in the human brain.

In ex vivo studies on brain cells, liver, and gastrointestinal tissues, rasagiline was shown to be a potent, irreversible, selective inhibitor of monoamine oxidase type B (MAO-B).

The exact mechanism of action of rasagiline is unknown. It is believed to be partly due to its inhibitory activity against MAO-B, thereby increasing extracellular dopamine levels in the striatum. Elevated dopamine levels and, consequently, enhanced dopaminergic activity likely provide the therapeutic efficacy of rasagiline, as demonstrated in models of dopaminergic motor dysfunction.

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

Pharmacokinetics.

Absorption. Rasagiline is rapidly absorbed, with maximum plasma concentration (C_max) reached approximately within 0.5 hours. Absolute bioavailability after a single oral dose of rasagiline is 36%. Food does not affect the time to reach maximum plasma concentration (T_max), but intake with a high-fat meal reduces C_max and area under the concentration-time curve (AUC) by 60% and 20%, respectively. Rasagiline may 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 a single oral 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, producing metabolites including 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 as 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 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 groups.

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 MAO inhibitors (including medicinal products and herbal preparations, e.g. those containing Hypericum perforatum) 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 interactions.

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

Concomitant administration of rasagiline with other MAO inhibitors (including medicinal products and herbal preparations containing Hypericum perforatum) is contraindicated due to the risk of non-selective inhibition, which may lead to hypertensive crisis.

Serious adverse reactions have been reported when pethidine is administered 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 administered concomitantly. Due to the MAO-inhibiting activity of rasagiline, concomitant use with sympathomimetics such as oral or nasal decongestants and cold remedies containing ephedrine or pseudoephedrine is not recommended.

Interactions between dextromethorphan and non-selective MAO inhibitors have been reported when administered concomitantly. Therefore, due to the MAO-inhibiting activity of rasagiline, 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 must elapse between discontinuation of fluoxetine and initiation of rasagiline therapy. A washout period of at least 14 days must elapse between discontinuation of rasagiline and initiation of fluoxetine or fluvoxamine therapy.

Serious adverse reactions have been reported with concomitant use of rasagiline and selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (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 administered 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 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 rasagiline. Therefore, strong CYP1A2 inhibitors may alter plasma levels of rasagiline and should be used with caution.

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

In vitro studies have shown that rasagiline at a concentration of 1 µg/mL (equivalent to a concentration 160 times higher than the mean Cmax (5.9–8.5 ng/mL) after multiple doses 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.

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

Tyramine/rasagiline interactions

Five clinical studies involving healthy volunteers and patients with Parkinson's disease, and 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 tyramine restriction), demonstrated no interaction between rasagiline and tyramine. Therefore, rasagiline can be used without dietary tyramine restriction.

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 may occur in patients treated with dopamine agonists and/or dopaminergic therapy. Cases of impulse control disorders have been reported for rasagiline during the post-marketing period. 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 during rasagiline treatment, including compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behavior, and pathological spending or shopping urges.

Rasagiline may potentiate the effects of levodopa, potentially leading to an increased incidence of levodopa-related adverse reactions and worsening of pre-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 vulnerable to hypotensive adverse reactions due to pre-existing gait disturbances. Orthostatic hypotension was reported in 3.1% of patients receiving 1 mg rasagiline and in 0.6% of those receiving placebo when used concomitantly with dopamine agonists.

In a study evaluating rasagiline as monotherapy, hallucinations were reported in 1.3% of patients receiving 1 mg rasagiline and in 0.7% of those receiving placebo. In a study evaluating concomitant use of rasagiline and dopamine agonists, hallucinations occurred in 1.2% of patients receiving 1 mg rasagiline and in 1.8% of those receiving placebo. In the group receiving concomitant rasagiline 1 mg/day and dopamine agonists, 0.6% of patients discontinued treatment and prematurely withdrew from the study due to hallucinations, whereas no patients in the placebo group discontinued treatment or study participation because of hallucinations.

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 rasagiline use, particularly with long-term treatment 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 skin conditions.

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, rasagiline treatment should be discontinued.

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

Use during pregnancy or breastfeeding.

There are no clinical data on the use of rasagiline in pregnant women. Animal studies have not shown direct or indirect harmful effects on pregnancy, embryo-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 operating machinery.

Rasagiline may affect the ability to drive or operate machinery.

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

Patients receiving rasagiline therapy who experience somnolence and/or sudden episodes of sleep should be advised to refrain from driving or engaging 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 activities (e.g., watching television, riding in a car as a passenger, etc.) at any time during treatment, patients should not drive or participate in potentially hazardous activities.

Patients should not drive or 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 sedative effects when using central nervous system depressants such as alcohol or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants) 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 meals.

elderly patients

Dose adjustment is not required for elderly patients.

Patients with hepatic impairment

Rasagiline should be avoided in patients with moderate hepatic impairment, and therapy 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, Azilect is not recommended for use in this patient population.

Overdose

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

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

Studies have been conducted in healthy volunteers receiving single doses of up to 20 mg per day, as well as a 10-day study in healthy volunteers receiving 10 mg once daily. 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 ongoing levodopa therapy and rasagiline at 10 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.

There are no specific antidotes. In case of overdose, careful monitoring of the patient is required; treatment should be symptomatic and supportive.

Side effects

Monotherapy

Below are the adverse reactions reported with higher frequency during placebo-controlled studies in patients receiving 1 mg/day of rasagiline (number of patients receiving rasagiline – 149, placebo group – 151).

In parentheses, the respective frequencies of adverse reactions (% of patients) in the rasagiline group and the placebo group are indicated.

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 ≥ 1/10,000 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 carcinoma (1.3% / 0.7%).

Blood and lymphatic system disorders

Common: leukopenia (1.3% / 0%).

Immune system disorders

Common: allergy (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 (14.1% / 11.9%).

Uncommon: cerebrovascular disorders (0.7% / 0%).

Eye disorders

Common: conjunctivitis (2.7% / 0.7%).

Ear and labyrinth disorders

Common: dizziness (2.7% / 1.3%).

Cardiac disorders

Common: angina pectoris (1.3% / 0%).

Uncommon: myocardial infarction (0.7% / 0%).

Respiratory, thoracic and mediastinal disorders

Common: rhinitis (3.4% / 0.7%).

Gastrointestinal disorders

Common: flatulence (1.3% / 0%).

Skin and subcutaneous tissue disorders

Common: dermatitis (2% / 0%).

Uncommon: vesiculobullous rash (0.7% / 0%).

Musculoskeletal and connective tissue disorders

Common: bone and muscle pain (6.7% / 2.6%), neck pain (2.7% / 0%), arthritides (1.3% / 0.7%).

Renal and urinary disorders

Common: urinary urgency (1.3% / 0.7%).

General disorders

Common: fever (2.7% / 1.3%), fatigue (2% / 0%).

Adjunctive therapy with levodopa

Below are the adverse reactions reported with higher frequency during placebo-controlled studies in patients receiving 1 mg/day of rasagiline (number of patients receiving rasagiline – 380, placebo group – 388).

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 ≥ 1/10,000 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%), pathological dreams (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%), gait instability (1.6% / 0.3%).

Uncommon: acute cerebrovascular accident (0.5% / 0.3%).

Cardiac disorders

Uncommon: angina pectoris (0.5% / 0%).

Vascular disorders

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%).

Investigations

Common: weight decrease (4.5% / 1.5%).

Injury and complications

Common: accidental falls (4.7% / 3.4%).

Adjunctive therapy with dopamine agonists

The most common adverse reactions, occurring at a frequency > 3% higher in patients treated with Azilect than in the placebo group, include peripheral edema, accidental falls, arthralgia, cough, and insomnia.

Below are the adverse reactions that occurred in > 2% of patients receiving 1 mg/day rasagiline (as adjunctive therapy with dopamine agonists) during a placebo-controlled study. The incidence of these adverse reactions exceeded those in the placebo group (number of patients receiving rasagiline – 162, placebo group – 164).

In parentheses, the respective frequencies of adverse reactions (% of patients) in the rasagiline group and the placebo group are indicated.

Infections and infestations

Upper respiratory tract infections (4% / 2%).

Psychiatric disorders

Insomnia (4% / 1%).

Nervous system disorders

Headache (6% / 4%).

Ear and labyrinth disorders

Dizziness (7% / 6%).

Cardiovascular disorders

Orthostatic hypotension (3% / 1%).

Respiratory, thoracic and mediastinal disorders

Cough (4% / 1%).

Gastrointestinal disorders

Nausea (6% / 4%).

Musculoskeletal and connective tissue disorders

Arthralgia (5% / 2%), back pain (4% / 3%).

General disorders

Peripheral edema (7% / 4%).

Injury and complications

Accidental falls (6% / 1%).

Other adverse events potentially of clinical significance, observed in 1% of patients receiving Azilect (as adjunctive therapy with dopamine agonists), and occurring at least as frequently as in the placebo group (listed in descending order of frequency), include somnolence, fatigue, unusual dreams, gait instability, constipation, urge urinary incontinence, weight gain, bronchitis, chest pain, cognitive disorders, dyskinesia, flatulence, gastroesophageal reflux disease, arterial hypotension, restlessness, oropharyngeal pain, pain, pre-syncope, rapid eye movement (REM) sleep behavior disorder, rash, rhinorrhea, sinusitis, skin papillomas, streptococcal pharyngitis, syncope, viral gastroenteritis, blurred vision.

No significant differences in safety profile based on age or gender were observed.

Parkinson’s disease is associated with the occurrence of hallucinations and confusion. These symptoms have been observed during post-marketing surveillance in patients with Parkinsonism receiving rasagiline.

Serious adverse reactions are known to occur with concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants, and MAO inhibitors. Cases of serotonin syndrome, characterized by agitation, confusion, muscle rigidity, hyperthermia, and myoclonic jerks, have been reported during post-marketing surveillance in patients receiving antidepressants/SNRIs concomitantly with rasagiline.

Fluoxetine or fluvoxamine were not co-administered with rasagiline during clinical trials; however, other antidepressants were used with rasagiline: amitriptyline ≤ 50 mg/day, trazodone ≤ 100 mg/day, citalopram ≤ 20 mg/day, sertraline ≤ 100 mg/day, and paroxetine ≤ 30 mg/day. No cases of serotonin syndrome were reported in a study involving 115 patients receiving rasagiline concomitantly with tricyclic antidepressants and 141 patients receiving rasagiline with SSRIs/SNRIs.

Five clinical studies involving healthy volunteers and patients with Parkinson’s disease, along with 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 tyramine restriction), demonstrated no interaction between rasagiline and tyramine. Therefore, rasagiline can be used without dietary restriction of tyramine intake.

During the post-marketing period, cases of increased blood pressure, including isolated cases of hypertensive crisis associated with consumption of tyramine-rich food, have been reported in patients receiving rasagiline.

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

During the post-marketing period, a case of increased blood pressure was reported in a patient receiving 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, compulsive spending or shopping, binge eating, and compulsive eating may occur.

Similar adverse reactions have been reported during post-marketing use of rasagiline: compulsions, obsessive thoughts, impulsive behavior.

Excessive daytime sleepiness and sudden sleep episodes

Excessive daytime sleepiness (hypersomnia, lethargy, sedation, sleep attacks, somnolence, 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 post-marketing use of rasagiline.

Cases of falling asleep during routine activities have been reported in patients receiving rasagiline and other dopaminergic agents. Although many of these patients reported somnolence while taking rasagiline with other dopaminergic agents, some did not experience any warning signs such as excessive sleepiness. Some of these events occurred more than one year after initiation of treatment.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging. 10 tablets per blister; 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturers. Teva Pharmaceutical Industries Ltd.

PLIVA Hrvatska d.o.o.

Manufacturers' addresses and locations of operations.

18 Hameleche Street, Industrial Zone, Kfar Saba, Israel.

Baruna Filipovića 25, 10000 Zagreb, Croatia.