Macloras Tablets 1 mg Tablet

RASATRAX TABLETS is indicated for the treatment of idiopathic Parkinson's disease (PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations.

Posology RASATRAX TABLETS is administered orally, at a dose of 1 mg once daily with or without levodopa.

Special populations Elderly: No change in dosage is required. Hepatic impairment: RASATRAX TABLETS use in patients with moderate or severe hepatic impairment is contraindicated (see section 4.3). Caution should be used when initiating treatment with RASATRAX TABLETS in patients with mild hepatic insufficiency. In case patients progress from mild to moderate hepatic impairment RASATRAX TABLETS should be stopped (see section 4.4) Renal impairment: No change in dosage is required. Paediatric population (below 18 years): RASATRAX TABLETS is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy. Method of administration For oral use. May be taken with or without food.

RASATRAX TABLETS is contraindicated:

• in patients with a history of hypersensitivity to the active substance rasagiline or to any of the excipients listed in 6.1.
• Concomitant treatment with other monoamine oxidase (MAO) inhibitors (including medicines and natural products without prescription e.g. St. John's Wort) or pethidine (see section 4.5). At least 14 days must elapse between discontinuation of rasagiline and initiation of treatment with MAO inhibitors or pethidine.
• Moderate to severe hepatic impairment.

Concomitant use of rasagiline with other medicines The concomitant use of RASATRAX TABLETS and fluoxetine or fluvoxamine should be avoided (see section 4.5). At least five weeks should elapse between discontinuation of fluoxetine and initiation of treatment with RASATRAX TABLETS. At least 14 days should elapse between discontinuation of RASATRAX TABLETS and initiation of treatment with fluoxetine or fluvoxamine. The concomitant use of RASATRAX TABLETS and dextromethorphan or sympathomimetics such as those present in nasal and oral decongestants or cold medicine containing ephedrine or pseudoephedrine is not recommended (see section 4.5).

Concomitant use of rasagiline and levodopa Since rasagiline potentiates the effects of levodopa, the adverse reactions of levodopa may be increased and pre-existing dyskinesia exacerbated. Decreasing the dose of levodopa may ameliorate this adverse reaction. There have been reports of hypotensive effects when rasagiline is taken concomitantly with levodopa. Patients with Parkinson's disease are particularly vulnerable to the adverse reactions of hypotension due to existing gait issues.

Dopaminergic effects Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes RASATRAX TABLETS may cause daytime drowsiness, somnolence, and, occasionally, especially if used with other dopaminergic medicines - falling asleep during activities of daily living. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with RASATRAX TABLETS. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see section 4.7).

Impulse control disorders (ICDs) ICDs can occur in patients treated with dopamine agonists and/or dopaminergic treatments. Similar reports of ICDs have also been received post-marketing with rasagiline. Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware of the behavioural symptoms of impulse control disorders that were observed in patients treated with rasagiline, including cases of compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behaviour and compulsive spending or buying.

Melanoma A retrospective cohort study suggested a possibly increased risk of melanoma with the use of rasagiline, especially in patients with longer duration of rasagiline exposure and/or with the higher cumulative dose of rasagiline. Any suspicious skin lesion should be evaluated by a specialist. Patients should therefore be advised to seek medical review if a new or changing skin lesion is identified.

Hepatic impairment Caution should be used when initiating treatment with RASATRAX TABLETS in patients with mild hepatic impairment. RASATRAX TABLETS use in patients with moderate hepatic impairment should be avoided. In case patients progress from mild to moderate hepatic impairment, RASATRAX TABLETS should be stopped (see section 5.2).

MAO Inhibitors RASATRAX TABLETS is contraindicated with other MAO inhibitors (including medicinal and natural products without prescription e.g. St. John's Wort) as there may be a risk of non-selective MAO inhibition that may lead to hypertensive crises (see section 4.3).

Pethidine Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors including another selective MAO-B inhibitor. The concomitant administration of RASATRAX TABLETS and pethidine is contraindicated (see section 4.3).

Sympathomimetics With MAO inhibitors there have been reports of medicine interactions with the concomitant use of sympathomimetic medicines. Therefore, in view of the MAO inhibitory activity of rasagiline, concomitant administration of rasagiline and sympathomimetics such as those present in nasal and oral decongestants or cold medicines, containing ephedrine or pseudoephedrine, is not recommended (see section 4.4).

Dextromethorphan There have been reports of medicine interactions with the concomitant use of dextromethorphan and non-selective MAO inhibitors. Therefore, in view of the MAO inhibitory activity of rasagiline, the concomitant administration of rasagiline and dextromethorphan is not recommended (see section 4.4).

SNRI/SSRI/tri- and tetracyclic antidepressants The concomitant use of RASATRAX TABLETS and fluoxetine or fluvoxamine should be avoided (see section 4.4). For concomitant use of rasagiline with selective serotonin reuptake inhibitors (SSRIs)/selective serotonin-norepinephrine uptake inhibitors (SNRIs) in clinical trials, see section 4.8. Serious adverse reactions have been reported with the concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors. Therefore, in view of the MAO inhibitory activity of rasagiline, antidepressants should be administered with caution.

Medicines that affect CYP1A2 activity In vitro metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of rasagiline. CYP1A2 inhibitors Co-administration of rasagiline and ciprofloxacin (an inhibitor of CYP1A2) increased the AUC of rasagiline by 83%. Co-administration of rasagiline and theophylline (a substrate of CYP1A2) did not affect the pharmacokinetics of either product. Thus, potent CYP1A2 inhibitors may alter rasagiline plasma levels and should be administered with caution.

CYP1A2 inducers There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to induction of the metabolising enzyme CYP1A2. Other cytochrome P450 isoenzymes In vitro studies showed that rasagiline at a concentration of 1 u03bcg/ml (equivalent to a level that is 160 times the average C max ~ 5.9-8.5 ng/ml in Parkinson's disease patients after 1 mg rasagiline multiple dosing), did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline's therapeutic concentrations are unlikely to cause any clinically significant interference with substrates of these enzymes.

Levodopa and other Parkinson's disease medicinal products In Parkinson's disease patients receiving rasagiline as adjunct therapy to chronic levodopa treatment, there was no clinically significant effect of levodopa treatment on rasagiline clearance.

Tyramine/rasagiline interaction Results of four tyramine challenge studies (in volunteers and Parkinson's disease patients), together with results of home monitoring of blood pressure after meals (of 464 patients treated with 0.5 or 1 mg/day of rasagiline or placebo as adjunct therapy to levodopa for six months without tyramine restrictions), and the fact that there were no reports of tyramine/rasagiline interaction in clinical studies conducted without tyramine restriction, indicate that rasagiline can be used safely without dietary tyramine restrictions.

Pregnancy Safety in pregnancy has not been demonstrated.

Breastfeeding Safety during lactation has not been demonstrated.

Fertility No human data on the effect of rasagiline on fertility are available. Non-clinical data indicate that rasagiline has no effect on fertility.

Rasagiline cause somnolence or sudden sleep episodes and it may have major influence on the ability to drive and use machines. Patients should be cautioned about operating hazardous machines, including motor vehicles or working at heights until they are reasonably certain that rasagiline does not affect them.

Summary of the safety profile In clinical studies in Parkinson's disease patients the frequently reported adverse reactions were: headache, depression, vertigo, and flu (influenza and rhinitis) in monotherapy; dyskinesia, orthostatic hypotension, fall, abdominal pain, nausea and vomiting, and dry mouth in adjunct to levodopa therapy; musculoskeletal pain, as back and neck pain, and arthralgia in both regimens. These adverse reactions were not associated with an elevated rate of medicine discontinuation.

Tabulated summary of adverse reactions Monotherapy: System organ class Frequent Less frequent Frequency unknown Infections and infestations Influenza Neoplasms, benign, malignan10,t and unspecified (including cysts and polyps) Skin carcinoma Blood and lymphatic system disorders Leucopenia Immune system disorders Allergy Allergic reaction Metabolism and nutrition disorders Decreased appetite Psychiatric disorders Depression, Hallucinations Impulse control disorders Nervous system disorders Headache Cerebrovascular accident Serotonin syndrome excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes Eye disorders Conjunctivitis Ear and labyrinth disorders Vertigo Cardiac disorders Angina pectoris Myocardial infarction Vascular disorders Hypertension Respiratory, thoracic and mediastinal disorders Rhinitis Gastrointestinal disorders Flatulence, anorexia, dyspepsia Skin and subcutaneous Dermatitis, contact dermatitis, Skin carcinoma Vesiculobullous rash Musculoskeletal connective tissue and bone disorders Musculoskeletal pain, neck pain, arthritis Renal and urinary disorders Urinary urgency General disorders and administration site conditions Fever Malaise Adjunct therapy System organ class Frequent Less frequent Frequency unknown Neoplasms, benign, malignant and unspecified Skin melanoma Metabolism and nutrition disorders Decreased appetite Decreased weight Psychiatric disorders Hallucinations Abnormal dreams Confusion Impulse control disorders Nervous system disorders Dyskinesia Dystonia Carpal tunnel syndrome balance disorder Abnormal dreams, ataxia Cerebrovascular accident Serotonin syndrome excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes Cardiac disorders Angina pectoris Vascular disorders Orthostatic hypotension Hypertension Gastrointestinal disorders Abdominal pain, constipation, nausea and vomiting, dry mouth Skin and subcutaneous tissue disorders Rash Skin melanoma Musculoskeletal connective tissue and bone disorders Arthralgia, neck pain, tenosynovitis Injury, poisoning and procedural complications Fall Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

No cases of overdose have been reported in clinical studies. Overdose can be associated with significant inhibition of MAO. In a single-dose study healthy volunteers received 20 mg/day and in a ten-day study healthy volunteers received 10 mg/day. Adverse reactions were mild or moderate and not related to rasagiline treatment. In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg/day of rasagiline, there were reports of cardiovascular adverse reactions (including hypertension and postural hypotension) which resolved following treatment discontinuation. These symptoms may resemble those observed with non-selective MAO inhibitors.

Management There is no specific antidote. In case of overdose, patients should be monitored and the appropriate symptomatic and supportive therapy instituted.