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Drug Details

AZILECT 1 mg tablets

• Drug Class Description
  Anti-Parkinson-Drugs, Monoamine oxidase -B inhibitors
• Generic Name
  Rasagiline (as mesilate)
• Presentation
  Tablet White to off-white, round, flat, bevelled tablets, debossed with “GIL” and “1” underneath on one side and plain on the other side.
• Description
  Each tablet contains 1 mg rasagiline (as mesilate).
• Indications
  

  AZILECT 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.

• Adult Dosage
  

  Posology

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

  It may be taken with or without food.

  Elderly: No change in dose is required for elderly patients.

  Paediatric population: AZILECT is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

  Patients with hepatic impairment: Rasagiline use in patients with severe hepatic impairment is contraindicated. Rasagiline use in patients with moderate hepatic impairment should be avoided. Caution should be used when initiating treatment with rasagiline in patients with mild hepatic impairment. If patients progress from mild to moderate hepatic impairment rasagiline should be stopped.

  Patients with renal impairment: No change in dosage is required for renal impairment

• Child Dosage
  

  Children and adolescents (<18 years): Not recommended as the safety and efficacy have not been established in this population.

• Elderly Dosage
  

  No change in dosage is required for elderly patients.

• Contra Indications
  

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

  Concomitant treatment with other monoamine oxidase (MAO) inhibitors or pethidine. At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with MAO inhibitors or pethidine.

  Rasagiline is contraindicated in patients with severe hepatic insufficiency.

• Special Precautions
  

  The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided. 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 medications containing ephedrine or pseudoephedrine is not recommended.

  During the clinical development programme 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 drug in particular, is associated with a higher risk of skin cancer (not exclusively melanoma). Any suspicious skin lesion should be evaluated by a specialist.

  Caution should be used when initiating treatment with rasagiline in patients with mild hepatic insufficiency. 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.

• Interactions
  

  There are a number of known interactions between non-selective MAO inhibitors and other medicinal products.

  Rasagiline should not be administered along with other MAO inhibitors as there may be a risk of non-selective MAO inhibition that may lead to hypertensive crises.

  Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors as well as with another selective MAO-B inhibitor. The concomitant administration of rasagiline and pethidine is contraindicated.

  The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided.

  With MAO inhibitors as well as with another selective MAO-B inhibitor there have been reports of drug 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 medications, containing ephedrine or pseudoephedrine, is not recommended.

  There have been reports of drug 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.

  Serious adverse reactions have been reported with the concomitant use of selective serotonin reuptake inhibitors (SSRIs), tricyclic, tetracylic antidepressants and MAO inhibitors as well as with another selective MAO-B inhibitor. Therefore, in view of the MAO inhibitory activity of rasagiline, antidepressants should be administered with caution.

  In Parkinson's disease patients receiving chronic levodopa treatment as adjunct therapy there was no clinically significant effect of levodopa treatment on rasagiline clearance.

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

  There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to induction of the metabolising enzyme CYP1A2.

  In vitro studies showed that rasagiline at a concentration of 1μg/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.

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

  Tyramine/rasagiline interaction: Results of four tyramine challenge studies (in volunteers and PD 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.

• Adverse Drug Reactions
  

  In the rasagiline clinical programme overall 1361 patients were treated with rasagiline for 3076.4 patient years. In the double-blind placebo-controlled studies 529 patients were treated with rasagiline 1 mg/day for 212 patient years and 539 patients received placebo for 213 patient years.

  Monotherapy

  The list below includes adverse reactions which were reported with a higher incidence in placebo-controlled studies, in patients receiving 1 mg/day rasagiline (rasagiline group n=149, placebo group n=151). Adverse reactions with at least 2% difference over placebo are marked in italics. In parentheses is the adverse reaction incidence (% of patients) in rasagiline vs. placebo, respectively.

  Adverse reactions are ranked under headings of frequency using the following conventions: very common (>1/10) common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000) including isolated reports.

  Body as a Whole: very common: headache (14.1% vs. 11.9%) common: flu syndrome (6.0% vs. 0.7%), malaise (2.0% vs. 0%), neck pain (2.0% vs. 0%), allergic reaction (1.3% vs. 0.7%), fever (2.7% vs. 1.3%)

  Cardiovascular system: common: angina pectoris (1.3% vs. 0%) uncommon: cerebrovascular accident (0.7% vs. 0%), myocardial infarct (0.7% vs. 0%)

  Digestive System: common: dyspepsia (6.7% vs. 4%), anorexia (1.3% vs. 0%)

  Haemic and lymphatic system: common: leucopenia (1.3% vs. 0%)

  Musculoskeletal System: common: arthralgia (7.4% vs. 4%), arthritis (2.0% vs. 0.7%)

  Nervous System: common: depression (5.4% vs. 2%), vertigo (2.0% vs. 0.7%), hallucinations (1.3% vs. 0.7%)

  Respiratory system: common: rhinitis (2.7% vs. 1.3%)

  Special Senses: common: conjunctivitis (2.7% vs. 0.7%)

  Skin and appendages: common: contact dermatitis (1.3% vs. 0%), vesiculobullous rash (1.3% vs. 0%), skin carcinoma (1.3% vs. 0.7%)

  Urogenital system: common: urinary urgency (1.3% vs. 0%).

  Adjunct Therapy

  The list below includes adverse reactions which were reported with a higher incidence in placebo-controlled studies in patients receiving 1 mg/day rasagiline (rasagiline group n=380, placebo group n=388). In parentheses is the adverse reaction incidence (% of patients) in rasagiline vs. placebo, respectively. Adverse reactions with at least 2% difference over placebo are in italics.

  Adverse reactions are ranked under headings of frequency using the following conventions: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000) including isolated reports.

  Body as a Whole: common: abdominal pain (3.9% vs. 1.3%), accidental injury (primarily falls) (8.2% vs. 5.2%), neck pain (1.6% vs. 0.5%)

  Cardiovascular System: common: postural hypotension (4.7% vs. 1.3%) uncommon: angina pectoris (0.5% vs. 0%), cerebrovascular accident (0.5% vs. 0.3%)

  Digestive System: common: constipation (4.2% vs. 2.1%), vomiting (3.4% vs. 1.0%), anorexia (2.1% vs. 0.5%), dry mouth (3.4% vs. 1.8%)

  Musculoskeletal System: common: arthralgia (3.2% vs. 1.3%), tenosynovitis (1.3% vs. 0%)

  Metabolic and Nutritional: common: weight loss (4.2% vs. 1.5%)

  Nervous System: very common: dyskinesia (10.3% vs. 6.4%) common: dystonia (2.4% vs. 0.8%), abnormal dreams (2.1% vs. 0.8%), ataxia (1.3% vs. 0.3%), hallucinations (2.9% vs. 2.1%), uncommon: confusion (0.8% vs. 0.8%)

  Skin and appendages: common: rash (2.6% vs. 1.5%) uncommon: skin melanoma (0.5% vs. 0.3%)

  Other important adverse events that were reported in clinical studies with rasagiline (other dose or in studies without placebo control) occurred in two patients each were rhabdomyolysis (both cases were following fall and prolonged immobilization) and inappropriate antidiuretic hormone (ADH) secretion. The complicated nature of these cases makes it impossible to determine what role, if any, rasagiline played in their pathogenesis.

  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.