Gazalia

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GAZALIA (Gazalia)

Composition:

Active substance: rasagiline;

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

Excipients: microcrystalline cellulose, maize starch, colloidal anhydrous silicon dioxide, anhydrous citric acid, pregelatinized starch, talc, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: tablets from white to creamy in color, round, with flat bevelled edges, embossed with "C13" on one side and smooth on the other.

Pharmacotherapeutic group. Anti-parkinson drugs. Monoamine oxidase type B inhibitors. ATC code N04BD02.

Pharmacological properties.

Pharmacodynamics. Rasagiline is a potent, irreversible, selective inhibitor of monoamine oxidase (MAO). Two main types of MAO are identified — type A and type B. MAO-B is the predominant type localized in the human brain.

Ex vivo studies in brain, liver, and gastrointestinal tissues have demonstrated that rasagiline is 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 partially due to its inhibitory activity against MAO-B, thereby increasing extracellular dopamine levels in the striatum. The 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 the active primary metabolite and is not an inhibitor of MAO-B.

Pharmacokinetics.

Absorption. Rasagiline is rapidly absorbed, with peak plasma concentration (Cmax) reached approximately within 0.5 hours. Absolute bioavailability after a single dose is 36%. Food does not affect the time to reach peak plasma concentration (Tmax); however, administration with a high-fat meal reduces Cmax and the 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 following 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, resulting in the formation of metabolites — 1-aminoindan, 3-hydroxy-N-propargyl-1-aminoindan, and 3-hydroxy-1-aminoindan. In vitro studies have shown that both metabolic pathways of rasagiline involve the CYP1A2 isoenzyme of the cytochrome P450 system. Rasagiline is excreted as glucuronide conjugates and metabolites.

Elimination. After oral administration of 14C-labeled rasagiline, elimination occurs predominantly 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 populations.

Patients with hepatic impairment.

In patients with mild hepatic impairment, Cmax and AUC values increased by 80% and 38%, respectively. In patients with moderate hepatic impairment, Cmax 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. The medicinal product should be used for:

• monotherapy in idiopathic Parkinson's disease;
• adjunctive therapy with dopamine agonists;
• adjunctive therapy with levodopa in the presence of end-of-dose motor fluctuations.

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Concomitant therapy with 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 between discontinuation of rasagiline and initiation of therapy with these agents is required).

Severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

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

Concomitant use 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 and MAO inhibitors, including other selective MAO-B inhibitors, are used concomitantly. Concomitant administration of rasagiline and pethidine is contraindicated.

Interactions between MAO inhibitors and sympathomimetics have been reported when used concomitantly. Due to the MAO-inhibiting activity of rasagiline, concomitant use with sympathomimetics such as oral or nasal vasoconstrictors and cold remedies containing ephedrine or pseudoephedrine is not recommended.

Interactions between dextromethorphan and non-selective MAO inhibitors have been reported when used 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.

The washout period between discontinuation of fluoxetine and initiation of rasagiline therapy should be at least 5 weeks. The washout period 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 and selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic/tetracyclic antidepressants, and MAO inhibitors. Therefore, since rasagiline is an active MAO inhibitor, caution should be exercised when using rasagiline with antidepressants.

Levodopa, when co-administered with rasagiline in patients with Parkinson's disease, did not show any clinically significant effect on the clearance of rasagiline.

In vitro metabolism studies indicated 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 inhibitors of CYP1A2 may alter rasagiline plasma levels 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 showed that rasagiline at a concentration of 1 mcg/mL (equivalent to a concentration 160 times higher than the mean Cmax (5.9–8.5 ng/mL) after multiple 1 mg doses of 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%.

Five clinical studies involving 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 restriction of tyramine intake.

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"). 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.

Impulse control disorders may occur in patients treated with dopamine agonists and/or undergoing dopaminergic therapy. Reports of such impulse control disorders have been received during post-marketing use of rasagiline. Patients should be regularly monitored for the presence of impulse control disorders. Patients and healthcare professionals should be informed about behavioral changes indicating impulse control disorders observed in patients during treatment with rasagiline, including compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behavior, and pathological spending or shopping behavior.

Rasagiline may enhance the effects of levodopa, potentially increasing levodopa-related adverse reactions and exacerbating 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 susceptible to hypotensive adverse reactions due to pre-existing gait disturbances. Orthostatic hypotension was observed in 3.1% of patients receiving 1 mg rasagiline and in 0.6% of patients receiving placebo when used concomitantly with dopamine agonists.

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

Cases of melanoma development have been reported during clinical trials, which may be associated with the use of rasagiline. Available data suggest that Parkinson's disease itself and the use of certain medicinal products may predispose to a higher risk of skin cancer (not only melanoma). Any skin abnormalities should prompt consultation with a dermatologist.

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, treatment with rasagiline should be discontinued.

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

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, 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 not known whether rasagiline is excreted in human breast milk. Rasagiline should be used with caution during breastfeeding.

Ability to influence reaction speed when driving or using machines.

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 them.

Patients with a history of somnolence and/or sudden sleep episodes should refrain from driving or engaging in other activities where they may place themselves or others at risk (e.g., operating machinery) until they can assess whether treatment with rasagiline and other dopaminergic agents affects their mental or motor performance.

If increased somnolence or new episodes of sudden sleep occur during routine activities (e.g., watching television, riding as a passenger in a car, etc.) at any time during treatment, patients should not drive or engage in potentially dangerous activities.

Patients should be warned about possible additive effects of sedatives, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) when used in combination with rasagiline, or when concomitant medications that increase plasma levels of rasagiline (e.g., ciprofloxacin) are used (see section "Special precautions for use").

Dosage and Administration

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 medicinal product can be administered independently of food intake.

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, treatment with rasagiline 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 rasagiline in children, the medicinal product is not recommended for use in this patient population.

Overdose

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

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

Studies have been conducted on single-dose administration in healthy volunteers receiving up to 20 mg per day, and a 10-day study in healthy volunteers receiving 10 mg once daily. Adverse reactions of mild or moderate severity were reported, as well as adverse reactions not typically associated with rasagiline treatment.

In a study using high doses of rasagiline in patients receiving concomitant levodopa therapy, adverse cardiovascular reactions (including arterial hypertension and postural hypotension) were observed at a dose of 10 mg/day, which resolved after discontinuation of treatment.

These symptoms are similar to those observed with overdose of non-selective MAO inhibitors.

Specific antidotes are not known. In case of overdose, careful monitoring of patients is required; treatment should be symptomatic and supportive.

Adverse Reactions

Monotherapy

Below are the adverse reactions observed with higher frequency in placebo-controlled studies among patients receiving 1 mg/day of rasagiline (number of patients receiving rasagiline — 149; placebo group — 151).

In parentheses, the frequency of adverse reactions (% of patients) is indicated for the rasagiline group and the placebo group, respectively.

For assessment of the frequency of adverse reactions, the following classification was used: very common (≥ 1/10), common (≥ 1/100 — < 1/10), uncommon (≥ 1/1000 — < 1/100), rare (≥ 1/10000 — < 1/1000), very rare (< 1/10000).

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 observed with higher frequency in placebo-controlled studies among patients receiving 1 mg/day of rasagiline (number of patients receiving rasagiline — 380; placebo group — 388).

For assessment of the frequency of adverse reactions, the following classification was used: very common (≥ 1/10), common (≥ 1/100 — < 1/10), uncommon (≥ 1/1000 — < 1/100), rare (≥ 1/10000 — < 1/1000), very rare (< 1/10000).

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 decreased (4.5% / 1.5%).

Injury and complications

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

Adjunctive therapy with dopamine agonists

Among the most common adverse reactions, with a frequency > 3% higher in patients treated with rasagiline than in the placebo group, are peripheral edema, accidental falls, arthralgia, cough, and insomnia.

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

In parentheses, the frequency of adverse reactions (% of patients) is indicated for the rasagiline group and the placebo group, respectively.

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 rasagiline (as adjunctive therapy with dopamine agonists) and with at least the same frequency as in the placebo group (listed in order of decreasing frequency) include: somnolence, fatigue, unusual dreams, gait instability, constipation, urinary urgency, weight increased, bronchitis, chest pain, cognitive disorders, dyskinesia, flatulence, gastroesophageal reflux disease, arterial hypotension, restlessness, oropharyngeal pain, pain, presyncope, 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. During post-marketing surveillance, these symptoms were observed 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 in post-marketing studies in patients receiving antidepressants/SNRIs concomitantly with rasagiline.

Fluoxetine or fluvoxamine were not used concomitantly with rasagiline in clinical trials; however, the following antidepressants were used concomitantly 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, and blood pressure monitoring after meals (464 patients receiving 0.5–1 mg/day rasagiline or placebo as add-on therapy to levodopa for 6 months without tyramine intake restrictions), showed no interaction between rasagiline and tyramine; therefore, rasagiline can be used without dietary restrictions on 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 taking 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 taking 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 observed during the post-marketing period with rasagiline: compulsions, obsessive thoughts, impulsive behavior.

Excessive daytime sleepiness and sudden sleep episodes

Excessive daytime sleepiness (hypersomnia, lethargy, sedation, sleep attacks, drowsiness, and sudden sleep episodes) may occur in patients treated with dopamine agonists and/or other dopaminergic therapies. Cases of excessive daytime sleepiness have been reported during the post-marketing use of rasagiline.

Cases of falling asleep during daily 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 reported no warning signs such as excessive sleepiness. Some of these events occurred more than one year after initiation of treatment.

Shelf life. 4 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging. Keep out of the reach of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard package.

Prescription category. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and location of business operations.

Village Theda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.