APARKOF

RASAGILINE ARROW is indicated in adults for the treatment of idiopathic Parkinson's disease as monotherapy (without levodopa) or in combination (with levodopa) in patients experiencing end-of-dose motor fluctuations.

Association of rasagiline with other medicinal products

The association of rasagiline and fluoxetine or fluvoxamine must be avoided (see section 4.5). A washout period of at least five weeks must be respected between the discontinuation of fluoxetine and the start of treatment with rasagiline. A washout period of at least 14 days must be respected between the discontinuation of rasagiline and the start of treatment with fluoxetine or fluvoxamine.

The association of rasagiline and dextromethorphan or sympathomimetics, such as those present in certain nasal or oral decongestants or cold treatments containing ephedrine or pseudoephedrine, is not recommended (see section 4.5).

Association of rasagiline and levodopa

Since rasagiline potentiates the effects of levodopa, there is a risk of increased adverse effects of levodopa and exacerbation of pre-existing dyskinesias. A reduction in the dose of levodopa may improve these adverse effects.

Cases of hypotension have been reported when taking rasagiline in association with levodopa. Patients with Parkinson's disease are particularly prone to hypotension due to existing gait disturbances.

Dopaminergic effects

Excessive daytime somnolence and sudden sleep episodes

Rasagiline may cause daytime somnolence and sometimes, particularly when used with other dopaminergic medicines, sleep during daily life activities. Patients must be informed of these effects and must exercise caution when driving vehicles or using machines during their treatment with rasagiline. Patients who have had an episode of somnolence and/or sudden sleep must refrain from driving vehicles or using machines (see section 4.7).

Impulse control disorders

Impulse control disorders may occur in patients treated with dopaminergic agonists and/or dopaminergic treatments. Similar cases of impulse control disorders have also been reported after the marketing of rasagiline. Patients should be monitored regularly for the occurrence of impulse control disorders.

Patients and their entourage must be informed of the behavioral symptoms of impulse control disorders observed in patients treated with rasagiline, including compulsion, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behaviors and compulsive spending or purchasing.

Melanoma

A retrospective cohort study has suggested a possibly increased risk of melanoma during the use of rasagiline, particularly in patients exposed to rasagiline over a longer duration and/or receiving a higher cumulative dose of rasagiline. Any suspicious skin lesion should be subject to evaluation by a specialist. Patients should therefore be advised to consult a doctor in case of the appearance of a new lesion or the evolution of an existing lesion.

Hepatic impairment

Treatment with rasagiline should be initiated with caution in patients with mild hepatic impairment. Its use should be avoided in patients with moderate hepatic impairment. In patients whose hepatic impairment progresses from a mild stage to a moderate stage, rasagiline should be discontinued (see section 5.2).

MAO inhibitors

The combination of rasagiline and other MAO inhibitors (including medicinal products and natural products without prescription, such as St. John's wort) is contraindicated as there is 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 administration of pethidine and MAO inhibitors including another selective MAO-B inhibitor. The combination of rasagiline and pethidine is therefore contraindicated (see section 4.3).

Sympathomimetics

Drug interaction cases have been reported with the concomitant administration of sympathomimetics with MAO inhibitors.

Consequently, given the MAO inhibitory activity of rasagiline, concomitant administration of rasagiline and sympathomimetics, such as those present in nasal or oral decongestants or cold remedies containing ephedrine or pseudoephedrine, is not recommended (see section 4.4).

Dextromethorphan

Drug interaction cases have been reported with the concomitant administration of dextromethorphan and non-selective MAO inhibitors. Consequently, given the MAO inhibitory activity of rasagiline, concomitant administration of rasagiline and dextromethorphan is not recommended (see section 4.4).

SNRIs/SSRIs/tricyclic or tetracyclic antidepressants

Concomitant administration of rasagiline and fluoxetine or fluvoxamine should be avoided (see section 4.4).

For the concomitant use of rasagiline with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in clinical trials, see section 4.8.

Serious adverse reactions have been reported with the concomitant administration of SSRIs, SNRIs, tricyclic or tetracyclic antidepressants and MAO inhibitors. Consequently, given the MAO inhibitory activity of rasagiline, antidepressants should be administered with caution.

Agents affecting CYP1A2 activity

In vitro metabolism studies have shown that cytochrome P450 1A2 (CYP1A2) is the main enzyme responsible for the metabolism of rasagiline.

CYP1A2 isoenzyme inhibitors

Concomitant administration of rasagiline and ciprofloxacin (a CYP1A2 isoenzyme inhibitor) increased the AUC of rasagiline by 83 %. Concomitant administration of rasagiline and theophylline (a CYP1A2 isoenzyme substrate) did not affect the pharmacokinetics of either product. Consequently, potent CYP1A2 isoenzyme inhibitors are likely to alter plasma concentrations of rasagiline and should be administered with caution.

Cytochrome CYP1A2 inducers

Due to enzyme induction of cytochrome CYP1A2 in smokers, plasma levels of rasagiline may be reduced.

Other cytochrome P450 isoenzymes

In vitro studies have shown that rasagiline at a concentration of 1 μg/ml (equivalent to a level 160 times higher than the average C max of ~ 5,9 - 8,5 ng/ml obtained in patients suffering from Parkinson's disease after repeated administration of 1 mg of rasagiline) did not lead to inhibition of the following cytochrome P450 isoenzymes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A.

These results indicate that it is unlikely that therapeutic concentrations of rasagiline will lead to clinically significant interference with the substrates of these enzymes (see section 5.3).

Levodopa and other medicinal products for Parkinson's disease

When rasagiline was administered to patients with Parkinson's disease in combination with long-term levodopa treatment, no clinically significant effect of levodopa on the clearance of rasagiline was observed.

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

Interaction between tyramine and rasagiline

Rasagiline can be used safely without dietary tyramine restriction. This has been shown by the results of five studies on tyramine challenge administration (in volunteers and patients suffering from Parkinson's disease), as well as the results of home blood pressure monitoring after meals (in 464 patients treated with 0,5 or 1 mg/day of rasagiline or placebo in combination with levodopa for 6 months without tyramine restriction), and the fact that no case of drug interaction between tyramine and rasagiline has been reported during clinical studies conducted without tyramine restriction.

Pregnancy

There are no data on the use of rasagiline in pregnant women. Studies in animals have not shown 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.

Breastfeeding

Non-clinical data indicate that rasagiline inhibits prolactin secretion and, therefore, may inhibit lactation. It has not been established whether rasagiline is excreted in human milk. Caution should be exercised when administering rasagiline to a breastfeeding woman.

Fertility

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

In patients presenting with somnolence/episodes of sudden sleep onset, rasagiline may have an important influence on the ability to drive vehicles and use machines.

Patients should be warned about the use of dangerous machines, including motor vehicles, until it is certain that rasagiline does not cause a deleterious effect in them.

Patients treated with rasagiline and presenting with somnolence and/or episodes of sudden sleep onset must be informed that it is preferable for them to refrain from driving vehicles and performing activities during which a decrease in alertness could present, for themselves or for others, a risk of serious injury or death (for example, the use of machines), as long as they have not acquired sufficient experience with rasagiline and other dopaminergic drugs to assess whether their treatment has a deleterious effect or not on their mental and/or motor abilities.

If increased somnolence or new episodes of sudden sleep onset during activities of daily living (for example, watching television, being a passenger in a car, etc.) occur during treatment, patients must neither drive nor participate in potentially dangerous activities.

Patients must neither drive, nor use machines, nor work at heights during their treatment if they have already had episodes of somnolence and/or sudden sleep onset before using rasagiline.

Patients should be warned about the possible additive effects of sedative drugs, alcohol or other central nervous system depressants (for example, benzodiazepines, antipsychotics, antidepressants) used in association with rasagiline or in case of concomitant intake of drugs that increase plasma concentrations of rasagiline (for example, ciproflaxine) (see section 4.4).