Azilet, tablets 1 mg 100 pcs

Pharmacotherapeutic group: antiparkinsonian drug – MAOI inhibitor

ATCode: N04BD02

Pharmacological properties

Pharmacodynamics

Razagiline is a selective irreversible inhibitor of monoamine oxidase type B (MAO-B), the enzyme that determines 80% of monoamine oxidase activity in the brain and dopamine metabolism. It is 30-80 times more active against MAO-B than against another type of this enzyme, MAO-A. As a result of the drug’s inhibitory effect on MAO-B in the central nervous system, dopamine levels increase and the formation of toxic free radicals, excessive formation of which is observed in patients with Parkinson’s disease, is reduced. Razagiline also has a neuroprotective effect.

In contrast to non-selective MAO inhibitors, the drug in therapeutic doses does not block metabolism of biogenic amines from food (e.g., tyramine) and therefore does not cause tyramine-dependent hypertensive syndrome (“cheese effect”).

Pharmacokinetics

Rasagiline is rapidly absorbed after oral administration; its maximum plasma concentration (C_max) is reached after 0.5 hours. Absolute bioavailability of the drug after a single administration is about 36%. Food has no effect on the time of reaching maximum blood concentration of Rasagilin, however, when fatty food is consumed, C_max and area under the drug concentration curve (AUC) are reduced by 60% and 20% respectively. Pharmacokinetics of the drug is linear in the dose range of 0.5-2 mg. The binding to plasma proteins varies from 60 to 70%.

Razagiline is almost completely metabolized in the liver. Biotransformation occurs by N-dealkylation and/or hydroxylation to form the main biologically inactive metabolite, 1-aminoindan, and two other metabolites, 3-hydroxy-N-propargyl-1-aminoindan and 3-hydroxy-l-aminoindan. The drug is metabolized with the participation of the CYP1A2 isoform of the cytochrome P450 system.

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

Parameters of pharmacokinetics of rasagiline are practically unchanged in patients with mild and moderate renal insufficiency. In mild hepatic insufficiency there may be increase in AUC and C_max parameters by 80% and 38%, and in patients with moderate hepatic impairment these parameters reach more than 500% and 80%, respectively.

Indications

Parkinson’s disease

Monotherapy or combination therapy for Parkinson’s disease (with levodopa drugs).

Active ingredient

Razagilin

Composition

Tablets white or almost white, round, flat-cylindrical, beveled, with “GIL 1” engraved on one side of the tablet.

1 tablet razagiline mesylate 1.56 mg, which corresponds to the content of razagilin 1 mg

Ancillary substances:

mannitol – 159.24 mg,

silicon dioxide colloid – 1.2 mg,

corn starch – 20 mg,

corn starch pregelatinized – 20 mg,

stearic acid – 4 mg,

talc – 4 mg.

How to take, the dosage

Overly, regardless of meals, in a dose of 1 mg once daily, both for monotherapy and in combination with levodopa.

Elderly patients

Dose adjustment is not required in elderly patients.

Patients with impaired liver function

The use of rasagiline in patients with moderate to severe hepatic impairment is contraindicated.

When using rasagiline in patients with mild hepatic insufficiency, caution should be exercised. If during treatment with Rasagilin progression of hepatic insufficiency to moderate degree is noted, the drug should be discontinued.

Patients with renal failure

Dose adjustment is not required.

Interaction

The concomitant use of rasagiline with other MAO inhibitors, including drugs and food supplements containing St. John’s Wort, is contraindicated, since there is a risk of severe hypertensive crisis due to non-selective MAO inhibition.

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

The interaction of MAO inhibitors and sympathomimetic drugs has been reported with concomitant use. Because of the MAO inhibitory property of rasagiline, concomitant use of rasagiline with sympathomimetics such as decongestants or oral or nasal anti-inflammatory complex drugs containing ephedrine or pseudoephedrine is not recommended.

In concomitant use of dextromethorphan and non-selective MAO inhibitors has been reported. However, due to the property of rasagiline to inhibit MAOIs, concomitant use of rasagiline with dextromethorphan and combination drugs containing it is not recommended.

The concomitant use of Rasagiline with fluoxetine or fluvoxamine should be avoided (see section “Special Precautions”).

Serious adverse reactions have been reported with concomitant use of SSRIs, SSRIs, tricyclic and tetracyclic antidepressants with MAO inhibitors. Due to the property of rasagiline to inhibit MAOIs, caution should be exercised when using it concomitantly with SSRIs, SSRIs, tricyclic and tetracyclic antidepressants.

In patients with Parkinson’s disease receiving rasagiline as adjunctive therapy to long-term levodopa therapy, levodopa had no significant effect on rasagiline clearance.

The 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 AUC of the latter by 83%. Concomitant use of rasagiline and theophylline (substrate of CYP1A2 isoenzyme) had no effect on pharmacokinetics of either of them. Thus, potent CYP1A2 isoenzyme inhibitors may alter the plasma concentration of rasagiline and require cautious concomitant use.

There is a risk that due to induction of CYP1A2 isoenzyme in patients who smoke, plasma concentrations of rasagiline may decrease.

The in vitro studies have shown that rasagiline at a concentration of 1 µg/mL (equivalent to a concentration 160 times the average C_max (5.9-8.5 ng/mL) after repeated administration of 1 mg of rasagiline in patients with Parkinson’s disease) did not inhibit the CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A isoenzymes. This indicates that therapeutic concentrations of rasagiline are likely to be unaffected clinically by substrates of these isoenzymes.

Concomitant use of entacapone with rasagiline increased clearance of the latter by 28%.

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

Special Instructions

Avoid concomitant use of Azilet® and fluoxetine or fluvoxamine (see section “Interaction with other medicinal products”). The interval between withdrawal of fluoxetine and initiation of Azilect^® treatment should be 5 weeks, and 14 days between withdrawal of Azilect^® and initiation of fluoxetine or fluvoxamine.

Cases of impulsive personality disorder have been reported in patients treated with dopamine receptor agonists and/or other dopaminomimetics. The same disorders were observed in the post-registration period in patients treated with Azilect^® (see section “Side effects”). Patients should be monitored due to the possibility of developing impulsive personality disorder. Patients and caregivers should be advised of the possibility of developing behavioral disorders in patients taking Azilect^®, including compulsive behavior, obsessions, gambling addiction, increased libido, hypersexuality, impulsive behavior, and compulsive need to buy or acquire.

The concomitant use of Azilect® with dextromethorphan, sympathomimetics or oral or nasal cold medicines 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 skin cancer, particularly melanoma (see section Side effects). Patients should be advised to consult a physician if any abnormal skin changes occur.

We must be aware that symptoms such as hallucinations and confusion that occur with Azilect® treatment may be considered both as a manifestation of Parkinson’s disease and as an adverse reaction of Azilect® (see “Adverse effects” above).

With caution should be used in patients with mild hepatic impairment. The use of the drug Azilect® is not recommended in patients with moderate hepatic impairment. In case of change in the severity of hepatic impairment from mild to moderate, the use of the drug Azilect^® should be stopped (see section “Pharmacological properties” (“Pharmacokinetics”)).

Excessive daytime sleepiness and episodes of sudden sleep

Rasagiline may cause excessive daytime sleepiness and sometimes, especially when used with dopaminergic drugs, episodes of sudden falling asleep. Patients should be informed about this.

Patients should also be warned about the possible additive effects of sedatives, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) in combination with razagiline or when taking concomitant medications that increase plasma levels of razagiline (e.g., ciprofloxacin).

Influence on driving and operating ability

With regard to the possibility of significant central nervous system side effects during treatment with Azilect

sup>®, patients should be informed about the need for caution when driving vehicles and engaging in potentially dangerous activities requiring high concentration and quick psychomotor reactions. Patients who are drowsy and have experienced sudden falling asleep should not drive or engage in potentially hazardous activities until they are satisfied that the drug has no adverse effect.

Contraindications

Hypersensitivity to Rasagilin or any of the components of the drug;

Concomitant use with other MAO inhibitors (including drugs and food supplements containing St. John’s wort), pethidine. The interval between discontinuation of Rasagilin and initiation of therapy with these drugs should be at least 14 days;

Moderate to severe hepatic insufficiency (Child-Pugh grades B and C);

Phild age under 18 years (no data on effectiveness and safety).

With caution: mild hepatic impairment (Child-Pugh class A); concomitant use with SSRIs (including fluoxetine, fluvoxamine), SSRIs, tricyclic and tetracyclic antidepressants, potent inhibitors of CYP1A2 isoenzyme.

.

Side effects

The following adverse reactions have been most frequently reported in clinical trials: in monotherapy – headache, depression, dizziness, flu, rhinitis; in therapy as adjunctive to levodopa therapy – dyskinesia, orthostatic hypotension, falls, abdominal pain, nausea, vomiting, dry mouth; in both therapy regimens – skeletal muscle pain, back and neck pain, arthralgia.

The list below describes adverse reactions reported with increased frequency in placebo-controlled trials in patients receiving 1 mg/day of Rasagiline.

The incidence of adverse reactions has been defined as follows: very common (≥1/10), common (≥1/100 to < 1/10), infrequent (≥1/1000 to < 1/100), rare (≥1/10000 to < 1/1000), very rare (< 1/10000), unknown – frequency of reactions cannot be determined from available data.

When used as monotherapy

Infectious and parasitic diseases:often flu.

Benign, malignant and unspecified neoplasms (including cysts and polyps): often – skin cancer.

Disorders of the blood and lymphatic system:often – leukopenia.

From the immune system: often – allergy.

From the side of metabolism and nutrition: infrequently – decreased appetite.

Psychiatric disorders: frequent – depression, hallucinations*; unknown – impulsive disorders*.

Nervous system disorders:very frequently – headache; infrequently – impaired cerebral circulation; unknown – excessive daytime sleepiness, episodes of sudden falling asleep, serotonin syndrome*.

Visual side: often – conjunctivitis.

Hearing organ and labyrinth disorders: frequently – vertigo.

Cardiac disorders: frequent – angina pectoris; infrequent – myocardial infarction.

vascular disorders: unknown – hypertension*.

From the gastrointestinal tract:often – bloating.

Respiratory organs: often – rhinitis.

Skin and subcutaneous tissue disorders:often – dermatitis; infrequently – vesicular bullous rash.

Musculoskeletal and connective tissue disorders: frequently – musculoskeletal pain, neck pain, arthritis.

Kidney and urinary tract disorders:often – urge to urinate.

General disorders and disorders at the site of administration: often – fever, malaise.

When used as adjuvant therapy

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

Disorders of metabolism and nutrition: frequently – decreased appetite.

Psychiatric disorders: frequent – hallucinations*, nightmares; infrequent – confusion, impulsive disorders*.

Nervous system disorders: very common – dyskinesia; common – dystonia, carpal tunnel syndrome, balance disorder; infrequent – impaired cerebral circulation; unknown – excessive daytime sleepiness, episodes of sudden falling asleep, serotonin syndrome*.

Cardiac disorders: not infrequently – angina pectoris.

vascular disorders: frequent – orthostatic hypotension*, unknown – hypertension*.

Digestive system disorders: often – abdominal pain, constipation, nausea and vomiting, dry mouth.

Skin and subcutaneous tissue: frequently – rash.

From the musculoskeletal and connective tissue: frequently – arthralgia, pain in the neck;

Results of research: frequently – decreased body weight.

Injuries, poisoning and complications of procedures: frequent – falls.

Parkinson’s disease causes hallucinations and confusion. According to post-registration experience, these symptoms were noted in patients with Parkinson’s disease who received rasagiline.

* – See description of individual adverse reactions.

See also section “Interaction with other medicinal products”.

Description of individual adverse reactions

Ortostatic hypotension

. In blinded placebo-controlled trials, a case of severe orthostatic hypotension was reported in one patient (0.3%) in the rasagiline group (the drug was used as adjuvant therapy); none was reported in the placebo group. Clinical trial data also suggest that orthostatic hypotension occurs most frequently in the first two months of treatment with rasagiline and decreases with time.

Hypertension

An increase in blood pressure (BP) has been reported during the post-treatment period with rasagiline, including rare cases of hypertensive crises in patients using tyramine-rich foods in their diet.

In the post-registration period, a case of BP elevation was reported in a patient who used the ophthalmic vasoconstrictor tetrahydrozoline and was simultaneously treated with rasagiline.

Impulsive personality disorder

. Increased libido, hypersexuality, gambling addiction, compulsive need to buy or acquire, overeating and compulsive overeating, kleptomania, and dermatillomania have been reported in patients treated with dopamine receptor agonists and/or other dopaminomimetics. A similar pattern of impulsive personality disorder was observed in the post-registration period in patients taking Rasagiline, which was characterized by compulsive and impulsive behavior and obsessive compulsions.

Excessive daytime sleepiness and episodes of sudden sleep

Excessive daytime sleepiness may occur in patients taking dopamine agonists and/or other dopaminergic drugs. Cases of such excessive daytime sleepiness have been reported on treatment with rasagiline.

There have also been reported cases of sudden falling asleep while patients perform normal daily activities while using rasagiline with dopaminergic drugs. Some patients had no warning signs before falling asleep, such as excessive sleepiness. In a number of cases, such events were reported more than 1 year after the start of treatment.

Hallucinations

Hallucinations and confusion occur in Parkinson’s disease. According to post-registration experience, these symptoms have been reported in patients with Parkinson’s disease receiving Rasagilin.

Serotonin syndrome

In clinical trials of Rasagiline, its simultaneous use with fluoxetine or fluvoxamine was not allowed. However, the following antidepressants were permitted in the indicated doses: amitriptyline no more than 50 mg/day, trazodone no more than 100 mg/day, citalopram no more than 20 mg/day, sertraline no more than 100 mg/day, and paroxetine no more than 30 mg/day. Serious adverse reactions have been reported, so caution should be exercised when concomitantly using SSRIs, SSRIs, tricyclic/tetracyclic antidepressants and MAOI inhibitors.

Post-registration surveillance has reported cases of potentially life-threatening serotonin syndrome manifested by agitation, confusion, rigidity, fever, and myoclonus in patients receiving antidepressants, meperidine (pethidine), tramadol, methadone, or propoxyphene concurrently with rasagiline.

Melanoma

. The incidence of malignant skin melanoma in placebo-controlled clinical trials was 2/380 (0.5%) in the rasagiline 1 mg group, used as adjunctive therapy to levodopa therapy, versus 1/388 (0.3%) incidence in the placebo group. Cases of melanoma in the post-registration period have also been reported (see also “Special Indications”).

Overdose

Symptoms of drug overdose are similar to those of overdose with non-selective MAO inhibitors (including arterial hypertension, postural hypotension).

Treatment: there is no specific antidote. Gastric lavage, administration of activated charcoal, symptomatic therapy.

Pregnancy use

There are no data on the use of rasagiline in pregnant women. Results of animal studies do not indicate any direct or indirect adverse effects on pregnancy, embryophyte development, labor, and postnatal development. If it is necessary to use rasagiline in pregnant women, it is necessary to balance the expected benefit to the mother and the risk to the fetus.

Rasagiline has been experimentally shown to inhibit prolactin secretion and thus may inhibit lactation. There is no information about the penetration of rasagiline into breast milk.

If it is necessary to use rasagiline during breastfeeding, the expected benefits to the mother and the baby must be weighed.

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