RASAGILINE TORRENT 1 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Rasagiline Torrent 1 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1 mg rasagiline (as rasagiline tartrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

4   CLINICAL PARTICULARS

4.2 Posology and method of administration

4.3 Contraindications

4.4 Special warnings and precautions for use

Concomitant use of rasagiline with other medicinal products

The concomitant use of rasagiline 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 rasagiline. At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with fluoxetine or fluvoxamine.

The concomitant use of rasagiline and dextromethorphan or sympathomimetics such as those present in nasal and oral decongestants or cold medicinal product 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 Rasagiline may cause daytime drowsiness, somnolence, and, occasionally, especially if used with other dopaminergic medicinal products – 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 rasagiline. 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)

ICD s can occur in patients treated with dopamine agonists and/or dopaminergic treatments. Similar reports of ICDs have also been received postmarketing 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

During the clinical development program, the occurrence of cases of melanoma prompted the consideration of a possible association with rasagiline. The data collected suggests that Parkinson’s di­sease, and not any medicinal products in particular, is associated with a higher risk of skin cancer (not exclusively melanoma). Any suspicious skin lesion should be evaluated by a specialist.

Hepatic impairment

Caution should be used when initiating treatment with rasagiline in patients with

mild hepatic impairment. Rasagiline use in patients with moderate hepatic impairment should be avoided. In case patients progress from mild to moderate hepatic impairment, rasagiline should be stopped (see section 5.2).

4.5 Interaction with other medicinal products and other forms of interaction

4   CLINICAL PARTICULARS

4.6 Fertility, pregnancy and lactation

4 CLINICAL PARTICULARS

4.7 Effects on ability to drive and use machines

4 CLINICAL PARTICULARS

4.8 Undesirable effects

Summary of the safety profile

In clinical studies in Parkinson's disease patients the most commonly 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 drug discontinuation.

Tabulated list of adverse reactions

Adverse reactions are listed below in Tables 1 and 2 by system organ class and frequency using the following conventions: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) not known (cannot be estimated from the available data).

Monotherapy

The tabulated list below includes adverse reactions which were reported with a higher incidence in placebo-controlled studies, in patients receiving 1 mg/day rasagiline.

Adjunct Therapy

The tabulated list below includes adverse reactions which were reported with a higher incidence in placebo-controlled studies in patients receiving 1 mg/day rasagiline.

*See section description of selected adverse reactions

Description of selected adverse reactions

Orthostatic hypotension

In blinded placebo-controlled studies, severe orthostatic hypotension was reported in one subject (0.3%) in the rasagiline arm (adjunct studies), none in the placebo arm. Clinical trial data further suggest that orthostatic hypotension occurs most frequently in the first two months of rasagiline treatment and tends to decrease over time.

Hypertension

Rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at the indicated dose (1 mg/day). In blinded placebo-controlled studies (monotherapy and adjunct) severe hypertension was not reported in any subjects in the rasagiline arm. In the post-marketing period, cases of elevated blood pressure, including rare serious cases of hypertensive crisis associated with ingestion of unknown amounts of tyramine-rich foods, have been reported in patients taking rasagiline. In post-marketing period, there was one case of elevated blood pressure in a patient using the ophthalmic vasoconstrictor tetrahydrozoline hydrochloride while taking rasagiline.

Impulse control disorders

One case of hypersexuality was reported in monotherapy placebo-controlled study. The following were reported during post-marketing exposure with unknown frequency: compulsions, compulsive shopping, dermatillomania, dopamine dysregulation syndrome, impulse-control disorder, impulsive behaviour, kleptomania, theft, obsessive thoughts, obsessive-compulsive disorder, stereotypy, gambling, pathological gambling, libido increased, hypersexuality, psychosexual disorder, sexually inappropriate behaviour. Half of the reported ICD cases were assessed as serious. Only single cases of reported cases had not recovered at the time they were reported.

Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes Excessive daily sleepiness (hypersomnia, lethargy, sedation, sleep attacks, somnolence, sudden onset of sleep) can occur in patients treated with dopamine agonists and/or other dopaminergic treatments. A similar pattern of excessive daily sleepiness has been reported post-marketing with rasagiline. Cases of patients, treated with rasagiline and other dopaminergic medicinal products, falling asleep while engaged in activities of daily living have been reported. Although many of these patients reported somnolence while on rasagiline with other dopaminergic medicinal products, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1-year after initiation of treatment.

Hallucinations

Parkinson's disease is associated with symptoms of hallucinations and confusion. In post marketing experience, these symptoms have also been observed in Parkinson's disease patients treated with rasagiline.

Serotonin syndrome

Rasagiline clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with rasagiline, but the following antidepressants and doses were allowed in the rasagiline trials: amitriptyline < 50 mg/daily, trazodone < 100 mg/daily, citalopram < 20 mg/daily, sertraline < 100 mg/daily, and paroxetine < 30 mg/daily (see section 4.5).

In the post-marketing period, cases of potentially life-threatening serotonin syndrome associated with agitation, confusion, rigidity, pyrexia and myoclonus have been reported by patients treated with antidepressants, meperidine, tramadol, methadone, or propoxyphene concomitantly with rasagiline.

Malignant melanoma

Incidence of skin melanoma in placebo-controlled clinical studies was 2/380 (0.5%) in rasagiline 1 mg as adjacent to levodopa therapy group vs. 1/388 (0.3%) incidence in placebo group. Additional cases of malignant melanoma were reported during post-marketing period. These cases were considered serious in all reports.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9   Overdose

5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

5 PHARMACOLOGICAL PROPERTIES

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on the standard studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, reproduction and development.

Rasagiline did not present genotoxic potential in vivo and in several in vitro systems using bacteria or hepatocytes. In the presence of metabolite activation rasagiline induced an increase of chromosomal aberrations at concentrations with excessive cytotoxicity which are unattainable at the clinical conditions of use.

Rasagiline was not carcinogenic in rats at systemic exposure, 84 – 339 times the expected plasma exposures in humans at 1 mg/day. In mice, increased incidences of combined bronchiolar/al­veolar adenoma and/or carcinoma were observed at systemic exposures, 144 – 213 times the expected plasma exposure in humans at 1 mg/day.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose, Microcrystalline

Maize starch

Starch, Pregalatinised (from maize)

Talc

Sodium Stearyl Fumarate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Aluminium-Aluminium blisters, Clear PVC/PE/PVdC-aluminium blister

Pack sizes of 7, 10, 14, 20, 28, 30, 40, 42, 50, 56, 60, 70, 80, 84, 90, 98, 100, 112 tablets

HDPE tablet container with PP child resistant screw cap containing desiccant (silicia gel)

Pack sizes of 30, 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements.

7 MARKETING AUTHORISATION HOLDER

Torrent Pharma (UK) Ltd.

3rd Floor, Nexus Building,

4 Gatwick Road,

Crawley,

West Sussex,

RH10 9BG,

United Kingdom