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Active ingredients
Razagilin
Release form
Pills
Composition
Tablets, composition (1 tab.): Active substance: rasagiline mesilate - 1.56 mg (corresponding to 1 mg of rasagiline base) 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
Pharmacological effect
antiparkinsonian inhibiting MAO-B
Pharmacokinetics
Rasagiline is rapidly absorbed after oral administration, its Cmax in the blood plasma is reached after 0.5 h. The absolute bioavailability of the drug after a single injection is about 36%. Food does not affect the Tmax of rasagiline in the blood, however, with the consumption of fatty foods, Cmax and AUC are reduced by 60% and 20%, respectively. Pharmacokinetics of the drug is linear in the dose range of 0.5-2 mg. Plasma protein binding ranges from 60 to 70%. Razagilin is almost completely metabolized in the liver. Biotransformation is carried out by N-dealkylation and / or hydroxylation with the formation of the main biologically low metabolite - 1-aminoindane, as well as two other metabolites - 3-hydroxy-N-propargyl-1-aminoindane and 3-hydroxy-1-aminoindane. Metabolism of the drug is carried out with the participation of the CYP1A2 isoenzyme of the cytochrome P450 system. Razagilin is excreted primarily by the kidneys (more than 60%) and to a lesser extent through the intestines (more than 20%). Less than 1% of the administered dose is excreted unchanged. T1 / 2 is 0.6–2 hours. The parameters of rasagiline pharmacokinetics remain virtually unchanged in patients with mild to moderate renal failure. In mild liver failure, the AUC and Cmax values may increase by 80 and 38%, and in patients with moderately impaired liver function, these parameters reach more than 500 and 80%, respectively.
Indications
Monotherapy or combination therapy for Parkinson's disease (with levodopa preparations).
Contraindications
hypersensitivity to rasagiline or any of the components of the drug; simultaneous use with other MAO inhibitors (including drugs and food additives containing St. John's wort), petidine. The interval between the withdrawal of rasagiline and the start of therapy with these drugs should be at least 14days; moderate and severe liver failure (grades B and C on the Child-Pugh scale); children under 18 years of age (no data on efficacy and safety). With caution: mild hepatic insufficiency (Grade A on the Child-Pugh scale) ; simultaneous use with SSRIs (including fluoxetine, fluvoxamine), SSRIs, tricyclic and tetracyclic antidepressants, potent inhibitors of the isoenzyme CYP1A2.
Use during pregnancy and lactation
The simultaneous use of the drug azilect and fluoxetine or fluvoxamine should be avoided (see "Interaction"). The interval between the discontinuation of fluoxetine and the start of treatment with Azilect should be 5 weeks, and between the discontinuation of Azilect and the start of fluoxetine or fluvoxamine 14 days. There were reports of cases of impulsive personality disorder in patients treated with dopamine receptor agonists and / or other dopaminomimetici. The same disorders were observed in the post-registration period in patients taking the Azilect drug (see “Side Effects”). It is necessary to monitor patients, in connection with the possibility of the development of impulsive personality disorder. Patients and caregivers should be informed about the possible development of behavioral disorders in patients taking Azilect, including compulsive behavior, obsessive ideas, gambling, increased libido, hypersexuality, impulsive behavior, and compulsive needs to buy or acquire. Simultaneous use of the drug Azilect with dextromethorphan, sympathomimetics or complex anti-cough drugs for oral or nasal use, containing ephedrine or pseudoephedrine is not recommended (see "Interaction"). There is evidence that Parkinson’s disease, and not the use of any drug, incl. Azilect, is a risk factor for the development of skin cancer, in particular melanoma (see “Side effects”). It is necessary to warn the patient about the need to consult a doctor if any pathological changes in the skin appear. It is necessary to bear in mind that symptoms such as hallucinations and confusion that appear during the treatment with Azilect can be considered as a manifestation of Parkinson's disease and adverse reactions of the drug Azilect (see"Side effects"). It is necessary to carefully use the drug Azilect in patients with mild hepatic insufficiency. The use of the drug Azilect in patients with moderate liver dysfunction is not recommended. In the event of a change in the severity of liver failure from mild to moderate use, Azilect should be discontinued (see Pharmacokinetics). Influence on the ability to drive and work with equipment that requires increased concentration of attention. Studying the effect of rasagiline on driving a car and controlling other mechanisms has not been done. However, taking into account the possibility of significant side effects from the central nervous system, during the period of 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 the speed of psychomotor reactions until they make sure that the drug does not have a negative effect.
Dosage and administration
Inside, regardless of the meal, at a dose of 1 mg 1 time per day, both in monotherapy and in combination with levodopa. Older patients Dose adjustment in elderly patients is not required. Patients with impaired liver function. The use of rasagiline in patients with moderate and severe hepatic insufficiency. contraindicated. When using rasagiline in patients with mild hepatic insufficiency, caution should be exercised. If during the treatment with rasagiline, progression of liver failure to a moderate degree is noted, the use of the drug should be discontinued. Patients with renal insufficiency No dose adjustment is required.
Side effects
Simultaneous use of rasagiline with other MAO inhibitors, incl. with drugs and food supplements containing St. John's wort, is contraindicated, because there is a risk of severe hypertensive crisis due to non-selective inhibition of MAO. There have been reports of the development of serious adverse reactions with the simultaneous use of petidine and MAO inhibitors, including selective MAO-B inhibitors. The simultaneous use of rasagiline and petidine is contraindicated. It was reported on the interaction of MAO inhibitors and sympathomimetic drugs with their simultaneous use.Due to the property of rasagiline to inhibit MAO, simultaneous use of rasagiline with sympathomimetics, such as decongestants or complex anti-cold medicine for oral administration or nasal administration, containing ephedrine or pseudoephedrine, is not recommended. The interaction of dextromethorphan and non-selective MAO inhibitors with their simultaneous use was reported. In connection with the property of rasagiline to inhibit MAO, the simultaneous use of rasagiline with dextromethorphan and the combined drugs containing it is not recommended. The simultaneous use of rasagiline with fluoxetine or fluvoxamine should be avoided. The interval between discontinuation of rasagiline and the start of therapy with these drugs should be at least 14 days. After discontinuation of treatment with fluoxetine or fluvoxamine (long T1 / 2) and the start of treatment with rasagiline, at least 5 weeks should pass. Information on the simultaneous use of SSRIs / SSRIs and rasagiline in clinical studies is presented in the “Side effects” section. It was reported about the development of serious adverse reactions with simultaneous use of SSRIs, SNRIs, tricyclic and tetracyclic antidepressants with MAO inhibitors. In connection with the property of rasagiline to inhibit MAO, caution must be exercised when it is used simultaneously with SSRIs, SSRIs, tricyclic and tetracyclic antidepressants. In patients with Parkinson's disease, receiving long-term levodopa, as an auxiliary therapy, levodopa had no 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. The simultaneous use of ciprofloxacin and razagilin increases the AUC of the latter by 83%. The simultaneous use of rasagiline and theophylline (substrate of the CYP1A2 isoenzyme) did not affect the pharmacokinetics of any of them. Thus, potent inhibitors of the CYP1A2 isoenzyme can alter the plasma concentration of rasagiline and require careful simultaneous use. There is a risk that plasma levels of rasagiline may decrease due to the induction of CYP1A2 isoenzyme in smoking patients. In vitro studies have shown that rasagiline at a concentration of 1 μg / ml (equivalent to a concentration greater than 160 times the average Cmax (5, 9–8.5 ng / ml) after repeated administration of 1 mg of rasagiline by patients with Parkinson’s disease) does not inhibit the isoenzymes of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A.This suggests that therapeutic concentrations of rasagiline are not likely to be clinically significant for the substrates of these isoenzymes. With simultaneous use of entacapone with rasagiline, the clearance of the latter increased by 28%. Clinical studies of the interaction of tyramine and rasagiline in volunteers and patients with Parkinson's (0 , 5–1 mg / day of rasagiline or placebo as an additional therapy to levodopa for 6 months without limiting the use of tyramine) showed that any interaction zagilina and tyramine is absent, and rasagiline can be safely applied without restricting tyramine in the diet.
Overdose
In general, 1361 patients participated in the clinical research program of rasagiline, which amounted to 3076.4 patient-years. In a double-blind, placebo-controlled study, 529 patients took rasagiline at a dose of 1 mg / day, which was 212 patient-years, and 539 patients received a placebo, which was 213 patient-years. Monotherapy The following list describes the adverse reactions reported to increased frequency in placebo-controlled studies in patients who received 1 mg / day rasagiline (rasagiline group - n = 149, placebo group - n = 151). Adverse reactions with differences of more than 2% compared with the placebo group are in italics. The incidence of adverse reactions (% of patients) of rasagiline / placebo is indicated in parentheses. The adverse reactions are distributed according to the following frequency: very often - ≥1 / 10; often - ≥1 / 100 to <1/10; infrequently - ≥1 / 1000 to <1/100; rarely, ≥1 / 10,000 to <1/1000%; very rarely - <1 / 10,000. Infectious and parasitic diseases: often - influenza (4.7 / 0.7%). Benign, malignant and unspecified neoplasms (including cysts and polyps): often - skin cancer (1.3 / 0 , 7%). From the side of blood and lymphatic system: often - leukopenia (1.3 / 0%). From the side of immune system: often - allergy (1.3 / 0.7%). From the side of metabolism and nutrition: Infrequently - loss of appetite (0.7 / 0%). On the part of the psyche: often - depression (5.4 / 2%), hallucinations (1.3 / 0.7%). On the part of the nervous system: very often - headache pain (14.1 / 11.9%); infrequently - cerebrovascular accident (0.7 / 0%). From the organ of vision: often - conjunctivitis (2.7 / 0.7%). From the organ of hearing and labyrinth disorders: often - vertigo (2.7 / 1 , 3%). From the side of the heart: often - angina (1.3 / 0%); infrequently - myocardial infarction(0.7 / 0%). From the gastrointestinal tract: often - abdominal distension (1.3 / 0%). From the respiratory system: often - rhinitis (3.4 / 0.7%). From the skin and subcutaneous tissues: often - dermatitis (2/0%); infrequently - vesicular-bullous rash (0.7 / 0%). From the musculoskeletal and connective tissue: often - musculoskeletal pain (6.7 / 2.6%), neck pain (2.7 / 0 %), arthritis (1.3 / 0.7%). From the kidneys and urinary tract: often - the urge to urinate (1.3 / 0.7%). General disorders and disorders at the injection site: often - fever ( 2.7 / 1.3%), malaise (2/0%). When used as adjuvant therapy, the list below includes adverse reactions that have been reported with increased frequency in placebo-controlled studies in patients receiving 1 mg / day of rasagiline (rasagiline group - n = 380, placebo group - n = 388). The incidence of adverse reactions (% of patients) of rasagiline / placebo is indicated in parentheses. The adverse reactions are distributed according to the following frequency: very often - ≥1 / 10; often - ≥1 / 100 to <1/10; infrequently - ≥1 / 1000 to <1/100; rarely, ≥1 / 10,000 to <1/1000%; very rarely - <1 / 10,000. Benign, malignant and unspecified neoplasms (including cysts and polyps): infrequently - skin melanoma (0.5 / 0.3%). Metabolism and nutrition: often - loss of appetite (2, 4 / 0.8%). From the psyche: often - hallucinations (2.9 / 2.1%), nightmares (2.1 / 0.8%); infrequently - confusion (0.8 / 0.5%). From the nervous system: very often - dyskinesia (10.5 / 6.2%); often - dystonia (2.4 / 0.8%), carpal tunnel syndrome (1.3 / 0%), imbalance (1.6 / 0.3%); infrequently - violation of cerebral circulation (0.5 / 0.3%). From the side of the heart: infrequently - angina (0.5 / 0%). From the side of vessels: often - orthostatic hypotension (3.9 / 0.8%) .In the digestive system: often - abdominal pain (4.2 / 1.3%), constipation (4.2 / 2.1%), nausea and vomiting (8.4 / 6.2%), dryness mouth (3.4 / 1.8%). From the skin and subcutaneous tissues: often - rash (1.1 / 0.3%). From the musculoskeletal and connective tissues: often - arthralgia (2.4 / 2.1%), neck pain (1.3 / 0.5%). Research results: often - weight loss (4.5 / 1.5%). Injuries, poisoning and complications of procedures: often - pad Nia (4.7 / 3.4%). In Parkinson's disease occur hallucinations and confusion. According to post-registration experience, these symptoms were observed in patients with Parkinson's disease who received rasagiline. Serious adverse reactions that occur with simultaneous use of SSRIs, NRIs, tricyclic / tetracyclic antidepressants and MAO inhibitors are well known.In the post-registration period, there were reported cases of serotonin syndrome, manifested in agitation, confusion, rigidity, fever and myoclonia, in patients who were simultaneously taking antidepressants / RIOSN and rasagiline. However, the following antidepressants were allowed 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 The program of clinical studies in which rasagiline was simultaneously used with tricyclic antidepressants (115 patients) and SSRIs / SNRIs (141 patients), cases of serotonin syndrome were not observed. When using rasagiline in the post-registration period, an increase in blood pressure was reported, including rare cases of hypertensive crises, patients using an unspecified amount of foods rich in tyramine in the diet. There are known cases of drug interactions with the simultaneous use of MAO inhibitors with sympatomies In the post-registration period, there was a case of an increase in blood pressure in a patient who used an ophthalmic vasoconstrictor tetrahydrozolin and simultaneously treated with rasagiline. Impulsive personality disorder. Cases of increased libido, hypersexuality, gambling, compulsive need to buy or acquire, overeating and compulsive overeating in patients treated with dopamine receptor agonists and / or other dopaminomimetic have been reported. A similar picture of impulsive personality disorder was observed in the post-registration period in patients taking rasagiline, which was characterized by compulsive and impulsive behavior, obsessive ideas.
Interaction with other drugs
Precautionary measures
special instructions
Symptoms of drug overdose are similar to those in overdose with non-selective MAO inhibitors (including arterial hypertension, postural hypotension). Treatment: There is no specific antidote. Gastric lavage, activated carbon intake, symptomatic therapy.