Pharmacological properties
Pharmacodynamics. Rasagiline is a potent and irreversible selective MAOI that can cause an increase in extracellular dopamine levels in the brain. In models of dopaminergic motor dysfunction, increased dopamine levels and additional increased dopaminergic activity have been shown, which likely contributes to the therapeutic effects of rasagiline.
1-Aminoindan is the active major metabolite and is not an MAO-B inhibitor.
Pharmacokinetics. Absorption. Rasagiline is rapidly absorbed, C max in blood plasma is reached after 0.5 h. The bioavailability of the drug after a single dose of rasagiline is 36%. Food does not affect the time to reach C max in blood plasma, however, when consuming fatty food, C max and AUC are reduced by 60 and 20%, respectively. Rasagiline can be taken regardless of food intake.
Distribution: The mean volume of distribution after a single intravenous administration of rasagiline is 243 L. Plasma protein binding after a single oral dose of 14 C-labeled rasagiline ranges from 60 to 70%.
Metabolism. Rasagiline is almost completely biotransformed in the liver. Metabolism occurs via 2 main pathways: N-dealkylation and/or hydroxylation to form the metabolites 1-aminoindane, 3-hydroxy-N-propargyl-1-aminoindane and 3-hydroxy-1-aminoindane. In vitro studies have shown that both pathways of rasagiline metabolism are mediated by the cytochrome P450 enzyme CYP 1A2. The main route of elimination of rasagiline is via glucuronic acid conjugates and their metabolites.
Excretion. After administration of 14C-labeled rasagiline, its excretion is mainly in the urine (62.6%) and to a lesser extent in the feces (21.8%), the complete elimination period for 84.4% of the dose is 38 days. Less than 1% of the drug is excreted in the urine unchanged.
Linearity/non-linearity. Rasagiline exhibits linear pharmacokinetics over the 0.5-2 mg dose range. T½ is 0.6-2 hours.
Pharmacokinetics in specific patient groups
Patients with hepatic impairment: In patients with mild hepatic impairment, Cmax and AUC were increased by 80% and 38%, respectively. In patients with moderate hepatic impairment, Cmax and AUC were increased by 568% and 83%, respectively.
Patients with renal impairment: The pharmacokinetic parameters of rasagiline are practically unchanged in patients with mild to moderate renal impairment.
Indication
Monotherapy (without levodopa) in idiopathic parkinsonism or as adjuvant therapy (with levodopa) with final dose fluctuations.
Application
Dosage regimen. Rasagiline is administered orally at a dose of 1 mg once daily with or without levodopa. The drug can be used regardless of meals.
Elderly patients: No dosage adjustment is required for elderly patients.
Patients with hepatic impairment. Rasagiline should be avoided in patients with moderate hepatic impairment and should be initiated with caution in patients with mild hepatic impairment. Rasagiline should be discontinued in patients with mild to moderate hepatic impairment.
Patients with renal impairment: No dose adjustment is required for patients with renal impairment.
Contraindication
Hypersensitivity to the active substance or any other component of the drug.
Concomitant therapy with other MAO inhibitors (including drugs and herbal preparations, for example, containing St. John's wort) or pethidine (the interval between the cancellation of rasagiline and the start of therapy with these drugs should be at least 14 days).
Severe liver failure.
Side effects
Monotherapy: The following adverse reactions were reported with a high frequency in placebo-controlled studies and in patients receiving 1 mg/day of rasagiline (number of patients receiving rasagiline - 149, placebo group - 151).
The frequency of adverse reactions (percentage of patients) in the rasagiline group and the placebo group is indicated in parentheses, respectively.
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 100), rare (≥1/10,000 to 1,000), 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%).
From the side of the blood and lymphatic system: often - leukopenia (1.3% / 0%).
On the part of the immune system: often - allergy (1.3% / 0.7%).
Metabolism and nutrition disorders: infrequently - decreased appetite (0.7% / 0%).
Mental disorders: often - 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%).
On the part of the organ of vision: often - conjunctivitis (2.7% / 1.3%).
From the organs of hearing and balance: often - dizziness (2.7% / 1.3%).
From the cardiovascular system: often - angina pectoris (1.3% / 0%); infrequently - myocardial infarction (0.7% / 0%).
Respiratory, thoracic and mediastinal disorders: common - rhinitis (3.4% / 0.7%).
On the part of the digestive system: often - flatulence (1.3% / 0%).
Skin and subcutaneous tissue disorders: common: dermatitis (2%/0%); uncommon: vesiculobullous rash (0.7%/0%).
Renal and urinary disorders: often - urge to urinate (1.3% / 0.7%).
General disorders: often - fever (2.7% / 1.3%), fatigue (2% / 0%).
adjuvant therapy
The following adverse reactions were reported with a high frequency in placebo-controlled studies and 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 100), rare (≥1/10,000 to 1,000), very rare (<1/10,000).
Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon - cutaneous melanoma (0.5% / 0.3%).
Metabolism and nutrition disorders: often - decreased appetite (2.4% / 0.8%).
Mental disorders: often - hallucinations (2.9% / 2.1%), abnormal dreams (0.8% / 0.5%); infrequently - confusion (2.9% / 2.1%).
From the nervous system: very often - dyskinesia (10.5% / 6.2%); often - dystonia (2.4% / 0.8%), carpal tunnel syndrome (1.3% / 0.8%), cerebral circulation disorders (1.6% / 0.3%); infrequently - cerebrovascular disorders (0.5% / 0.3%).
From the cardiovascular system: infrequently - angina pectoris (0.5% / 0%).
Respiratory, thoracic and mediastinal disorders: common - rhinitis (3.4% / 0.7%).
From the vascular system: often - orthostatic hypotension (3.9% / 0.8%).
From the digestive system: often - 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 loss (4.5% / 1.5%).
Injuries and other complications: often - accidental falls (4.7% / 3.4%).
Parkinson's disease is associated with the occurrence of hallucinations and confusion. During post-marketing studies, these symptoms developed in patients with parkinsonism who received rasagiline.
Serious adverse reactions are known to occur with the concomitant use of selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), tricyclic/tetracyclic antidepressants and MAOIs. In post-marketing experience, cases of serotonin syndrome, which manifests as anxiety, confusion, muscle rigidity, chills and myoclonic seizures, have been reported in patients receiving antidepressants/SNRIs concomitantly with rasagiline.
During clinical trials, fluoxetine or fluvoxamine were not used concomitantly with rasagiline, but antidepressants were used with rasagiline: amitriptyline at a dose of at least 50 mg/day, trazodone at least 50 mg/day, citalopram at least 20 mg/day, sertraline at least 100 mg/day, and paroxetine at least 30 mg/day. No cases of serotonin syndrome were reported in a study involving 115 patients receiving rasagiline and tricyclic antidepressants and 141 patients receiving rasagiline and SSRIs/SNRIs.
In the post-marketing period, cases of increased blood pressure, including isolated cases of hypertensive crisis, associated with the intake of tyramine-rich foods, have been reported in patients receiving rasagiline.
Drug interactions have been reported with the concomitant use of MAO inhibitors and sympathomimetics.
In the post-marketing period, a case of increased blood pressure was reported in a patient who took rasagiline concomitantly with the ophthalmic vasoconstrictor tetrahydrozoline hydrochloride.
Impulse control disorders: Patients taking dopamine agonists and/or other dopaminergic drugs may experience pathological gambling, increased libido, hypersexuality, impulsive buying, overeating, and impulsive eating.
Similar adverse reactions have been observed in the post-marketing period with the use of rasagiline: obsessive states, intrusive thoughts, impulsive behavior.
Excessive daytime sleepiness and sudden sleep onset episodes. Excessive daytime sleepiness (hypersomnia, lethargy, sedation, sleep attacks, somnolence, and sudden sleep onset episodes) may occur in patients receiving dopamine agonists and/or other dopaminergic therapy. Similar cases of excessive daytime sleepiness have been reported in the postmarketing setting with rasagiline.
Cases of falling asleep during activities of daily living have been reported in patients receiving rasagiline and other dopaminergic agents. Although many of these patients reported sleepiness while taking rasagiline with other dopaminergic agents, some of them noted that they had no warning signs, such as excessive sleepiness. Some of these cases were reported more than a year after starting treatment.
Special instructions
Habitual and addictive disorders (ADDs) may occur in patients taking dopamine agonists and/or undergoing dopaminergic therapy. Similar cases of AD have been reported for rasagiline in the post-marketing period. Patients should be monitored for AD. Patients and healthcare professionals should be made aware of changes in behaviour suggestive of AD that have occurred in patients taking rasagiline, including obsessions, compulsions, pathological gambling, increased libido, hypersexuality, impulsive behaviour, and compulsive spending or buying.
Rasagiline may potentiate the effects of levodopa, which may lead to increased adverse reactions to levodopa and exacerbation of existing dyskinesia. These adverse reactions may be reduced by reducing the dose of levodopa.
Hypotension has been reported with concomitant use of rasagiline and levodopa. Patients with Parkinson's disease are particularly vulnerable to adverse reactions of hypotension due to pre-existing gait problems.
The concomitant use of rasagiline and dextromethorphan or sympathomimetics, such as those found in nasal or oral vasoconstrictors or cold preparations containing ephedrine or pseudoephedrine, is not recommended (see Interactions with other medicinal products).
Cases of melanoma have been reported in clinical trials that may be associated with the use of rasagiline. These data suggest that Parkinson's disease and the use of certain medications may be associated with an increased risk of skin cancer (not just melanoma). If any skin abnormality occurs, a dermatologist should be consulted.
Rasagiline therapy should be initiated with caution in patients with mild hepatic impairment. Rasagiline should be avoided in patients with moderate hepatic impairment. Rasagiline should be discontinued in patients with mild to moderate hepatic impairment.
Rasagiline may cause daytime drowsiness and sometimes, especially when used concomitantly with other dopaminergic agents, falling asleep during daily activities. Therefore, patients should be advised to exercise caution when driving or operating machinery during treatment with rasagiline. Patients experiencing drowsiness and/or episodes of sudden onset of drowsiness should refrain from driving or operating machinery (see Effects on ability to drive and use machines).
Use during pregnancy and lactation. There are no clinical data on the use of rasagiline in pregnant women. Animal studies do not indicate direct or indirect harmful effects on pregnancy, fetal development, parturition or the postpartum period. The drug should be prescribed with caution to pregnant women. There is evidence that rasagiline inhibits prolactin secretion and, as a result, inhibits lactation. It is not known whether rasagiline passes into breast milk. Rasagiline should be prescribed with caution during breastfeeding.
Children. Due to insufficient data on the use of the drug in the treatment of children, the drug is not recommended for use in this category of patients.
Ability to influence the reaction speed when driving vehicles or operating other mechanisms. Rasagiline may affect the ability to drive vehicles or operate machinery.
Patients should be cautious when driving or operating machinery until they are certain that rasagiline does not cause any adverse effects.
Patients being treated with rasagiline who experience somnolence and/or sudden sleep onset episodes should be advised to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machinery) until they have had sufficient experience with rasagiline and other dopaminergic agents to assess whether they adversely affect their mental and/or motor performance.
If increased drowsiness or new episodes of sudden sleep onset are observed during daily activities (e.g. watching TV, riding in a car as a passenger, etc.) 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 have previously experienced drowsiness and/or sudden onset of sleep without warning prior to using rasagiline.
Patients should be warned about the possible additive effects of sedatives, alcohol or other CNS depressants (e.g. benzodiazepines, neuroleptics, antidepressants) in combination with rasagiline or when taking concomitant medications that increase rasagiline plasma levels (e.g. ciprofloxacin) (see Precautions).
There are known interactions between non-selective MAO inhibitors and other medicinal products. Rasagiline should not be used concomitantly with other MAO inhibitors (including medicinal products and herbal preparations containing St. John's wort) as there is a risk of non-selective inhibition, which may lead to the development of hypertensive crisis.
Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors, including other selective MAO-B inhibitors. The concomitant use of rasagiline and pethidine is contraindicated.
Interactions have been reported between MAO inhibitors and sympathomimetics when used concomitantly. Since rasagiline is a potent MAO inhibitor, its concomitant use with sympathomimetics, such as oral or nasal vasoconstrictors or cold remedies containing ephedrine or pseudoephedrine, is not recommended.
Interactions have been reported between dextromethorphan and non-selective MAO inhibitors when used concomitantly. Therefore, since rasagiline is a potent MAO inhibitor, its concomitant use with dextromethorphan is not recommended.
The concomitant use of rasagiline with fluoxetine and fluvoxamine should be avoided.
The interval between discontinuation of fluoxetine and initiation of rasagiline therapy should be at least 5 weeks. The interval between discontinuation of rasagiline and initiation of fluoxetine or fluvoxamine therapy should be at least 14 days.
Serious adverse reactions have been reported with concomitant use of rasagiline with SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors. Therefore, since rasagiline is a potent MAO inhibitor, caution should be exercised when rasagiline is used with antidepressants.
Levodopa, when co-administered with rasagiline in patients with Parkinson's disease, had no clinically significant effect on rasagiline clearance.
In vitro metabolism studies have shown that the cytochrome P450 isoenzyme CYP 1A2 is the major enzyme responsible for the metabolism of rasagiline. Concomitant administration of rasagiline and ciprofloxacin (CYP 1A2 inhibitors) increased the AUC of rasagiline by 83%. Concomitant administration of rasagiline and theophylline (CYP 1A2) did not affect the pharmacokinetics of rasagiline. Thus, inhibitors of the enzyme may alter the plasma levels of rasagiline and should be used with caution.
There is a risk that due to induction of the CYP 1A2 enzyme, rasagiline plasma concentrations may decrease in smokers.
In vitro studies have shown that rasagiline at a concentration of 1 μg/ml (equivalent to a concentration exceeding 160 times the mean C max (5.9-8.5 ng/ml) after multiple administration of 1 mg rasagiline to patients with Parkinson's disease) does not inhibit the cytochrome P450 isoenzymes CYP 1A2, CYP 2A6, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1, CYP 3A4 and CYP 4A. This may indicate that rasagiline at therapeutic concentrations may not affect the metabolism of these isoenzymes and have clinically significant effects.
Concomitant oral administration of rasagiline and entacapone increases the clearance of rasagiline by 28%.
Tyramine/rasagiline interaction. 5 clinical studies in volunteers and patients with Parkinson's disease and the results of postprandial blood pressure monitoring (464 patients used 0.5-1 mg/day of rasagiline or placebo as adjunctive therapy to levodopa for 6 months without tyramine restriction) showed that there is no interaction between rasagiline and tyramine, so rasagiline can be used on a diet without tyramine restriction.
Overdose
Symptoms of rasagiline overdose when used in a dose of 3-100 mg: dysphoria, hypomania, hypertensive crisis and serotonin syndrome.
Overdose may be associated with significant inhibition of MAO-A and MAO-B.
A study in healthy volunteers receiving 20 mg once daily and a 10-day study in healthy volunteers receiving 10 mg once daily were conducted. Mild to moderate adverse reactions and adverse reactions not expected to occur with rasagiline were reported.
In a large study of patients receiving continuous levodopa and rasagiline therapy at a dose of 10 mg/day, cardiovascular adverse reactions (including hypertension and postural hypotension) were reported that resolved after treatment discontinuation.
These symptoms are similar to those seen with an overdose of non-selective MAO inhibitors.
Specific treatment is unknown. In case of overdose, patients should be closely monitored and treatment should be symptomatic and supportive.
Storage conditions
At a temperature not exceeding 25 °C.
