RASAGILINE MYLAN Tablet Ref.[7501] Active ingredients: Rasagiline

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)

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 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).

MAO Inhibitors

Rasagiline is contraindicated along 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 rasagiline and pethidine is contraindicated (see section 4.3).

Sympathomimetics

With MAO inhibitors there have been reports of medicinal product interactions with the concomitant use of sympathomimetic medicinal products. 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 medicinal products, containing ephedrine or pseudoephedrine, is not recommended (see section 4.4).

Dextromethorphan

There have been reports of medicinal product 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 rasagiline 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 reuptake 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.

Agents 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 μg/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 (see section 5.3).

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.

Concomitant administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.

Tyramine/rasagiline interaction

Results of five 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

There are no data from the use of rasagiline in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of rasagiline during pregnancy.

Breast-feeding

Non-clinical data indicate that rasagiline inhibits prolactin secretion and thus, may inhibit lactation. It is not known whether rasagiline is excreted in human milk. Caution should be exercised when rasagiline is administered to a breast-feeding mother.

Fertility

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

In patients experiencing somnolence/sudden sleep episodes, rasagiline may have major influence on the ability to drive and use machines.

Patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that rasagiline does not affect them adversely.

Patients being treated with rasagiline and presenting with somnolence and/or sudden sleep episodes must be informed 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 machines) until they have gained sufficient experience with rasagiline and other dopaminergic medications to gauge whether or not it affects their mental and/or motor performance adversely.

If increased somnolence or new episodes of falling asleep during activities of daily living (e.g. watching television, passenger in a car, etc.) are experienced at any time during treatment, the patients should not drive or participate in potentially dangerous activities.

Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of rasagiline. Patients should be cautioned about possible additive effects of sedating medicinal products, alcohol, or other central nervous system depressants (e.g. benzodiazepines, antipsychotics, antidepressants) in combination with rasagiline, or when taking concomitant medications that increase plasma levels of rasagiline (e.g. ciprofloxacin) (see section 4.4).

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.

^* See section description of selected adverse reactions

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-threating 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 national reporting system listed in Appendix V.

Not applicable.