Parlin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARLIN (PARLIN)

Composition:

Active substance: rasagiline;

1 tablet contains rasagiline mesylate equivalent to rasagiline 1 mg;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round, flat tablets with a break line on one side.

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 recognized – type A and type B. MAO-B is the predominant type localized in the human brain.

In ex vivo studies on brain, 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 not fully understood. It is believed to be partly 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 contribute to 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 (C_max) reached approximately within 0.5 hours. The absolute bioavailability of rasagiline after a single oral dose is 36%. Food does not affect the time to reach peak plasma concentration (T_max), but administration with a high-fat meal reduces C_max and the area under the plasma 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 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 in the form of glucuronide conjugates of rasagiline and its metabolites.

Elimination. Following oral administration of ¹⁴C-labeled rasagiline, excretion occurs primarily via urine (62.6%) and to a lesser extent via feces (21.8%). Complete excretion 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. The 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, 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 with end-of-dose fluctuations.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Concomitant therapy with other MAO inhibitors (including medicinal products and herbal preparations, e.g., those containing Hypericum perforatum) or with 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 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 is used 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 used 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 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.

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 therapy with fluoxetine or fluvoxamine.

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 concomitantly with antidepressants.

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

In vitro metabolism studies indicated that the cytochrome P450 isoenzyme CYP1A2 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 plasma levels of rasagiline and should be used with caution.

There is a risk that induction of the CYP1A2 isoenzyme in smokers may reduce plasma concentrations of rasagiline.

In vitro studies have shown that rasagiline at a concentration of 1 µg/mL (equivalent to a concentration exceeding the mean Cmax (5.9–8.5 ng/mL) by 160-fold 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 interaction

Five clinical studies involving healthy volunteers and patients with Parkinson's disease, as well as blood pressure monitoring after meals (in 464 patients receiving 0.5–1 mg/day rasagiline or placebo as add-on therapy to levodopa for 6 months without dietary tyramine restriction), have shown 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"). 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 presence of impulse control disorders. Patients and healthcare providers should be informed about behavioral changes indicating impulse control disorders observed in patients receiving rasagiline, including compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behavior, and pathological spending or shopping.

Rasagiline may potentiate the effects of levodopa, potentially increasing levodopa-related adverse reactions and exacerbating existing dyskinesia. The intensity of these adverse effects 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 observed in 3.1% of patients receiving 1 mg rasagiline in combination with dopamine agonists, compared to 0.6% of patients receiving placebo.

In a study evaluating 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 evaluating concomitant use of rasagiline and dopamine agonists, hallucinations were observed in 1.2% of patients receiving 1 mg rasagiline and in 1.8% of patients receiving placebo. In the group receiving 1 mg rasagiline daily in combination with 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 due to hallucinations.

Concomitant use of rasagiline with dextromethorphan or sympathomimetics, such as those found 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").

During clinical trials, cases of melanoma development have been reported, which may be associated 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 or changing skin lesions.

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 routine 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 affect reaction rate when driving vehicles or operating other machinery").

Use during pregnancy or breastfeeding

There are no clinical data on the use of rasagiline in pregnant women. Animal studies have not shown any direct or indirect harmful effects on pregnancy, fetal development, parturition, or the postnatal period. 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 reaction rate when driving vehicles or operating other machinery

Rasagiline may affect the ability to drive vehicles 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 receiving rasagiline who experience somnolence and/or sudden episodes of sleep should be advised to refrain from driving vehicles 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 assess whether these medications adversely affect their mental and/or motor performance.

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

Patients should not drive vehicles, operate machinery, or perform work at heights during treatment if they previously experienced somnolence and/or sudden sleep attacks without warning prior to starting rasagiline.

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 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 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 severity, rasagiline treatment should be discontinued.

Patients with renal impairment

Dose adjustment is not required for patients with renal impairment.

Children

The use of the drug is not recommended in this patient population.

Overdose

Symptoms of overdose with doses ranging from 3 mg to 100 mg: 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, including adverse reactions not typically associated with rasagiline treatment.

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

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

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

Adverse Reactions

Monotherapy

Below are adverse reactions reported at a higher frequency in placebo-controlled studies in patients treated with rasagiline at a dose of 1 mg per day.

The following classification was used to assess the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (frequency cannot be estimated from available data).

Infections and infestations

Common: influenza.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Common: skin carcinoma.

Blood and lymphatic system disorders

Common: leukopenia.

Immune system disorders

Common: allergy.

Metabolism and nutrition disorders

Uncommon: decreased appetite.

Psychiatric disorders

Common: depression, hallucinations*.

Frequency not known: impulse control disorders*.

Nervous system disorders

Very common: headache.

Uncommon: cerebrovascular disorders.

Frequency not known: serotonin syndrome*, excessive daytime sleepiness and episodes of sudden sleep onset*.

Eye disorders

Common: conjunctivitis.

Ear and labyrinth disorders

Common: dizziness.

Cardiac disorders

Common: angina pectoris.

Uncommon: myocardial infarction.

Vascular disorders

Frequency not known: hypertension*.

Respiratory, thoracic and mediastinal disorders

Common: rhinitis.

Gastrointestinal disorders

Common: flatulence.

Skin and subcutaneous tissue disorders

Common: dermatitis.

Uncommon: vesiculobullous eruptions.

Musculoskeletal and connective tissue disorders

Common: bone and muscle pain, neck pain, arthritis.

Renal and urinary disorders

Common: urinary urgency.

General disorders

Common: fever, fatigue.

* See section "Description of selected adverse reactions".

Adjunctive therapy

Below are adverse reactions reported at a higher frequency in placebo-controlled studies in patients treated with rasagiline at a dose of 1 mg per day.

The following classification was used to assess the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (frequency cannot be estimated from available data).

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Uncommon: skin melanoma*.

Metabolism and nutrition disorders

Common: decreased appetite.

Psychiatric disorders

Common: hallucinations*, pathological dreams.

Uncommon: confusion.

Frequency not known: impulse control disorders*.

Nervous system disorders

Very common: dyskinesia.

Common: dystonia, carpal tunnel syndrome, gait instability.

Uncommon: acute cerebrovascular accident.

Frequency not known: serotonin syndrome*, excessive daytime sleepiness and episodes of sudden sleep onset*.

Cardiac disorders

Uncommon: angina pectoris.

Vascular disorders

Common: orthostatic hypotension*.

Frequency not known: hypertension*.

Gastrointestinal disorders

Common: abdominal pain, constipation, nausea and vomiting, dry mouth.

Skin and subcutaneous tissue disorders

Common: rash.

Musculoskeletal and connective tissue disorders

Common: arthralgia, neck pain.

Investigations

Common: weight decreased.

Injury, poisoning and procedural complications

Common: accidental falls.

* See section "Description of selected adverse reactions".

Description of selected adverse reactions

Orthostatic hypotension

In double-blind, placebo-controlled studies, severe orthostatic hypotension was reported in one subject (0.3%) in the rasagiline group (adjunctive studies), with no cases reported in the placebo group. Clinical trial data also suggest that orthostatic hypotension most commonly occurs during the first two months of treatment with rasagiline and tends to decrease over time.

Hypertension

Rasagiline is a selective MAO-B inhibitor and is not associated with increased sensitivity to tyramine at the recommended dose (1 mg daily). In double-blind, placebo-controlled studies (monotherapy and adjunctive therapy), no cases of severe arterial hypertension were reported in the rasagiline group. During the post-marketing period, cases of increased blood pressure, including isolated cases of hypertensive crisis associated with ingestion of tyramine-rich foods, have been reported in patients taking rasagiline. During the post-marketing period, one case of increased blood pressure was reported in a patient who was taking rasagiline concomitantly with the ophthalmic vasoconstrictor tetrahydrozoline hydrochloride.

Impulse control disorders

One case of hypersexuality was reported in a placebo-controlled study (monotherapy). During the post-marketing period, the following events were reported at an unknown frequency: compulsions, compulsive shopping urges, dermatillomania, dopamine dysregulation syndrome, impulse control disorder, impulsive behavior, kleptomania, theft, obsessive thoughts, obsessive-compulsive disorder, stereotypy, gambling, pathological gambling, increased libido, hypersexuality, psychosexual disorders, inappropriate sexual behavior. Half of the reports of impulse control disorders were considered serious. Recovery was not observed in only isolated cases at the time of reporting.

Excessive daytime sleepiness and episodes of sudden sleep onset

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

Cases of falling asleep during routine daily activities have been reported in patients treated with rasagiline and other dopaminergic agents. Although many patients reported somnolence while taking rasagiline with other dopaminergic agents, some reported no warning signs such as excessive drowsiness. Some of these events occurred more than one year after initiation of treatment.

Hallucinations

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

Serotonin syndrome

Fluoxetine or fluvoxamine were not co-administered with rasagiline in clinical trials; however, other 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 (see section "Interaction with other medicinal products and other forms of interaction").

During post-marketing studies, potentially life-threatening cases of serotonin syndrome, characterized by agitation, confusion, muscle rigidity, hyperthermia, and myoclonic seizures, have been reported in patients taking antidepressants, meperidine, tramadol, methadone, or propoxyphene concomitantly with rasagiline.

Malignant melanoma

In placebo-controlled clinical studies, the incidence of melanoma cases was 2/380 (0.5%) in the rasagiline 1 mg group used as adjunctive therapy with levodopa, compared to 1/388 (0.3%) in the placebo group. Additional cases of malignant melanoma have been reported during the post-marketing period. All such reports were considered serious.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 **°**C in the original packaging.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister, 3 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of operations.

Sankaklar Quarter, Eskisehir Yolu Akcakoca Highway No:299, 81100 Duzce, Turkey.