Rasator 0.5/Rasator 1

Rasator 0.5: Rasagiline Mesylate (Rasator 0.5) 500 mcg is a white to off white round shaped flat faced, beveled uncoated tablets debossed with "47" on one side and plain on other side.
Each uncoated tablet contains: Rasagiline Mesilate equivalent to Rasagiline 500 mcg.
Rasator 1: Rasagiline (as mesylate) (Rasator 1) 1 mg is a white to off white round shaped flat faced, beveled uncoated tablets debossed with "46" on one side and plain on other side.
Each uncoated tablet contains: Rasagiline Mesylate equivalent to Rasagiline 1 mg.

Dopaminergic Agent (Monoamine Oxidase Inhibitor).
Pharmacology: Pharmacodynamics: Mechanism of Action: Rasagiline is a selective irreversible inhibitor of MAO type B, the enzyme, 80% defining MAO activity in the brain and dopamine metabolism. Rasagiline is 30-80 times more active with regard to MAO-B, than to another type of this enzyme - MAO-A. As a result of inhibiting MAO-B, Rasagiline may cause an increase in dopamine levels in CNS, reducing formation of toxic free radicals, which are excessive in Parkinson's disease patients. Rasagiline was also shown to have neuroprotective effect. Unlike non-selective MAO inhibitors, Rasagiline at the indicated dose does not block the metabolism of dietary intake of biogenic amines (e.g., tyramine), therefore not causing tyramine-caused hypertensive syndrome ("cheese effect").
Pharmacokinetics: Absorption: After oral administration, Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 0.5 hours. The absolute bioavailability of a single rasagiline dose is about 36%. Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the medicinal product is taken with a high fat meal.
Distribution and Metabolism: Rasagiline pharmacokinetics are linear with dose over the range of 0.5-2 mg. Plasma protein binding is approximately 60 to 70%. Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield: 1-aminoindan, 3-hydroxy-N-propargyl-1 aminoindan and 3-hydroxy-1-aminoindan. Both routes of rasagiline metabolism are dependent on cytochrome P450 system, with CYP1A2 being the major iso-enzyme involved in rasagiline metabolism.
Elimination: Rasagiline elimination occurs primarily via urine (>60%) and secondarily via faeces (>20%). Less than 1% of rasagiline is excreted as unchanged product in urine. Its terminal half-life is 0.6-2 hours.
Special Populations: Renal impairment: Rasagiline's pharmacokinetics characteristics in subjects with mild and moderate renal impairment were similar to healthy subjects.
Hepatic impairment: In subjects with mild hepatic impairment, AUC and Cmax were increased by 80% and 38%, respectively. In subjects with moderate hepatic impairment, AUC and Cmax were increased by 568% and 83%, respectively.
Elderly: Rasagiline can be administered at the recommended dose in the elderly (≥65 years) since age has little influence on rasagiline pharmacokinetics.
Pediatric Population: Use of rasagiline in patients below 18 years of age has not been established.
Gender: The pharmacokinetic profile of rasagiline is similar in men and women.

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

General Dosing Recommendation: Rasator 0.5: The recommended initial dose in patients taking levodopa, with or without other Parkinson's disease drugs (e.g., dopamine agonist, amantadine, anticholinergics) is 500 mcg once daily. If the patient tolerates the daily recommended dose, but a clinical response is not achieved, the dose may be increased to 1 mg daily. When used in combination with levodopa, a reduction of levodopa dose may be considered, based upon individual response. The recommended doses should not exceed because risk of hypertension may occur. May be taken with or without food.
Rasator 1: When prescribed as monotherapy or as an adjunct therapy in patients not taking Levodopa, patients may start at the recommended dose of 1 mg administered orally once daily.
The recommended initial dose in patients taking levodopa, with or without other Parkinson's disease drugs (e.g., dopamine agonist, amantadine, anticholinergics) is 500 mcg once daily. If the patient tolerates the daily recommended dose, but a clinical response is not achieved, the dose may be increased to 1 mg daily. When used in combination with levodopa, a reduction of levodopa dose may be considered, based upon individual response. The recommended doses should not exceed because risk of hypertension may occur. May be taken with or without food.
Patients with Hepatic Impairment: Patients with hepatic impairment should not exceed a dose 500 mcg once daily. Should not be used in patients with moderate to severe hepatic impairment.
Renal impairment: No special precautions are required in patients with renal impairment.
Elderly: No dose adjustment is required for elderly.

Clinical symptoms of overdose start to appear at a dose of 10 mg. Though signs and symptoms do not appear immediately and may only occur in a delay of up to 12 hours after ingestion of drugs. The peak intensity of the syndrome may not be reached until for a day following the overdose. Death has been reported following overdose; therefore, immediate hospitalization with continuous patient observation for at least two days following ingestion is strongly recommended.
Signs and symptoms of monoamine oxidase (MAO) inhibitor overdose may include: drowsiness, faintness, dizziness, hyperactivity, agitation, irritability, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool and clammy skin.
There is no specific antidote. Treatment of overdose is symptomatic and supportive. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance as required. Monitoring of body temperature and intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. For this reason, in cases of overdose, dietary tyramine restriction should be observed for several weeks to reduce risk of hypertensive tyramine reaction.

Rasagiline is contraindicated in patients with hypersensitivity to the active substance or any of the excipients and in patients with severe hepatic impairment. Rasagiline cannot be co-administered with drugs such as meperidine, tramadol, methadone, and propoxyphene because of risk of serotonin syndrome. At least 14 days must elapse between discontinuation of rasagiline and initiation of treatment of these medications. Rasagiline is also contraindicated for use with St. John's Wort and cyclobenzaprine. It is also not recommended for concomitant use with dextromethorphan because of risk of episode of psychosis or bizarre behavior.

Hypertension: Exacerbation of hypertension may occur during treatment with Rasagiline. Dosage adjustment may be necessary if elevation of blood pressure is sustained. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting rasagiline.
Serotonin Syndrome: Concomitant use of rasagiline with meperidine, tramadol, methadone, and propoxyphene, antidepressants, and non-selective MAO inhibitors have been reported to increase risk of developing Serotonin syndrome. The symptoms of serotonin syndrome included behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), and autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, tachycardia, nausea, and diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). Serotonin syndrome may result to death.
Dyskinesia: When used as an adjunct to Levodopa, Rasagiline may potentiate dopaminergic side effects and exacerbate preexisting dyskinesia.
Impulse Control/Compulsive Behavior: Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more medications. Rasagiline increases the central dopaminergic tone that are generally used for the treatment of Parkinson's disease. Consider dose reduction or stopping the medication if a patient develops such urges while taking Rasagiline.
Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.
Somnolence: Cases of patients treated with dopaminergic medications have reported falling asleep or somnolence while engaged in activities of daily living. Patients should be advised of the potential to develop drowsiness.
Skin Cancer: The data collected suggests that use of Rasagiline in 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.
Effects on the Ability to Drive and Use Machines: Cases of mild somnolence has been reported with the use of Rasagiline and other dopaminergic medications. Avoid driving and other potentially dangerous activities.
Rasator 0.5: Hallucinations/Psychotic-like Behavior: Reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with Rasagiline or after starting or increasing the dose.
Rasator 1: Hallucinations/Psychotic-like Behavior: Reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with Rasagiline or after starting or increasing the dose. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. Abnormal thinking and behavior consist of one or more variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Patients with major psychotic disorder should not be treated with Rasagiline because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. Consider dose reduction and or drug discontinuation if patient develops hallucinations or psychotic-like behaviors during treatment.
Hepatic Impairment: Rasagiline plasma concentration may increase in patients with hepatic impairment. Patients with mild hepatic impairment should be given the dose of 0.5 mg once daily. Rasagiline should not be used in patients with moderate to severe hepatic impairment.

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 pregnancy, embryo-fetal development, delivery and postnatal development. Rasagiline Tablets should be used only if the potential benefit justifies the potential risk to the fetus.
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.

One of the most common symptoms of adverse reaction during treatment with rasagiline is hypertension. Serious adverse reactions such as serotonin syndrome, impulse control/compulsive behavior, withdrawal-emergent hyperpyrexia, and confusion may also occur during treatment with rasagiline. Discontinuation of the medication is advised once symptoms occur. Adverse reactions are listed as follows 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 as follows includes adverse reactions which were reported with a higher incidence in placebo-controlled studies, in patients receiving 1 mg/day Rasagiline. (See Table 1.)

Click on icon to see table/diagram/image

Adjunct Therapy: The tabulated list as follows includes adverse reactions which were reported with a higher incidence in placebo-controlled studies in patients receiving 1 mg/day Rasagiline. (See Table 2.)

Click on icon to see table/diagram/image

Monoamine Oxidase (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 crisis.
Pethidine/Meperidine: 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.
Sympathomimetic Medications: Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. Hypertensive crisis has been reported in patients taking the recommended dose of Rasagiline and sympathomimetic medications. Severe hypertension has been reported in patients taking the recommended dose and ophthalmic drops containing sympathomimetic medications. 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.
Dextromethorphan: Co-administration of Rasagiline and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior.
Antidepressants: 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. The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided. At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with fluoxetine or fluvoxamine. At least five weeks should elapse between discontinuation of fluoxetine and initiation of treatment with rasagiline.
Ciprofloxacin or Other CYP1A2 Inhibitors: In Parkinson's disease patients receiving chronic levodopa treatment as adjunct therapy, there was no clinically significant effect of levodopa treatment on rasagiline clearance. Co-administration of rasagiline and ciprofloxacin (an inhibitor of CYP1A2) increased the exposure of Rasagiline. 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. In vitro studies showed that rasagiline at a concentration of 1 μg/mL 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.
Entacapone: Concomitant administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.
Dopaminergic Antagonists: Antipsychotics or metoclopramide could diminish the effectiveness of Rasagiline.
Smoking: There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to induction of the metabolizing enzyme CYP1A2.
Rasator 0.5: Tyramine/Rasagiline interaction: Results of tyramine challenge studies indicate that Rasagiline at recommended dose can be used safely without dietary tyramine restrictions.
Rasator 1: Tyramine/Rasagiline interaction: Results of tyramine challenge studies indicate that Rasagiline at recommended doses can be used safely without dietary tyramine restrictions. However, certain foods may contain very high amounts of tyramine and could potentially cause a hypertensive reaction in patients taking Rasagiline due to increased sensitivity to tyramine. Consumption of foods containing a very large amount of tyramine while taking recommended dose of rasagiline is not advised.

Rasator 0.5: Store below 25°C.
Rasator 1: Store at temperatures not exceeding 30°C.

Antiparkinsonian Drugs

N04BD02 - rasagiline ; Belongs to the class of dopaminergic agents, monoamine oxidase B inhibitors. Used in the management of Parkinson's disease.

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