ラサギリン

Rasagiline has been reported to cause serum enzyme elevations in a small proportion of patients treated long term, although the abnormalities were usually mild and self-limiting. Rasagiline has not been implicated in cases of acute liver injury, but such instances have been reported with other less specific MAO inhibitors.

/SIGNS AND SYMPTOMS/ Hypertensive crisis (i.e., cheese reaction), manifested as marked elevations in systemic blood pressure, may occur at any dose of rasagiline following ingestion of foods containing large amounts of tyramine or drug preparations containing sympathomimetic amines. Hypertensive crisis may be fatal and requires immediate treatment or hospitalization. Patients should be advised to avoid foods containing large amounts of tyramine and drug preparations containing sympathomimetic amines during and for 2 weeks following discontinuance of rasagiline. Patients also should be instructed on how to recognize manifestations of a hypertensive crisis and to immediately notify a clinician if such manifestations occur.

/SIGNS AND SYMPTOMS/ Hypertensive crisis (i.e., cheese reaction), manifested as marked elevations in systemic blood pressure, may occur at any dose of rasagiline following ingestion of foods containing large amounts of tyramine or drug preparations containing sympathomimetic amines. Hypertensive crisis may be fatal and requires immediate treatment or hospitalization. Patients should be advised to avoid foods containing large amounts of tyramine and drug preparations containing sympathomimetic amines during and for 2 weeks following discontinuance of rasagiline. Patients also should be instructed on how to recognize manifestations of a hypertensive crisis and to immediately notify a clinician if such manifestations occur.

/OTHER TOXICOLOGY INFORMATION/ Antidepressant Agents, Selective Serotonin-reuptake Inhibitors (SSRIs): Potential pharmacologic interaction resembling serotonin syndrome (hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes that may progress to extreme agitation, delirium, coma, and death). Concomitant use generally should be avoided. At least 14 days should elapse between discontinuance of rasagiline and initiation of an SSRI.Because both fluoxetine and its principal metabolite have relatively long half-lives, the manufacturer of rasagiline recommends that at least 5 weeks (or longer with high-dose or long-term fluoxetine therapy) elapse between discontinuance of fluoxetine therapy and initiation of rasagiline.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

rasagiline

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ Single dose toxicity studies were conducted by the intravenous route in rats and by the oral route in mice, rats and dogs. Studies were initially conducted with the hydrochloride salt and subsequently with the more stable mesylate salt. Single dose bridging studies were undertaken which established the essentially similar toxicity and kinetics profiles of the hydrochloride and mesylate salts in rats and dogs. Mortalities were induced in rats by intravenous doses greater than or equal to 69 mg/kg/day. Mortalities were induced in mice at oral doses of greater than or equal to 206 mg/kg, in rats at oral doses greater than or equal to 155 mg/kg and in dogs at oral doses of greater than or equal to 84 mg/kg. Death was a result of the functional neuropharmacological changes that can be anticipated when excessive doses of a molecule capable of inhibiting the oxidation of biogenic amines are administered. The maximal non-lethal oral dose for rats and mice was about 100 mg/kg/day and the maximum tolerable dose (MTD) in dogs was 42 mg/kg. These doses represent considerable multiples of the recommended clinically relevant maximum dose of 1 mg/patient/day.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The rat and dog were selected for the conduct of repeat dose toxicity studies, both species having been shown to be pharmacologically responsive to rasagiline-induced inhibition of MAO-B. Repeat dose intravenous toxicity studies of 4-week duration were conducted at maximum doses of 3 mg/kg/day in rats and 5 mg/kg/day in dogs. Repeat dose oral toxicity studies of up to 26 week duration were conducted in rats employing doses spanning the range 0.14 to 17 mg/kg/day and of up to 52 week duration in dogs employing doses spanning 0.28 to 21.0 mg/kg/day. When the multiples of the systemic exposures to rasagiline and aminoindan across the range of doses used for the repeat dose toxicity studies in rats and dogs are compared with the clinically relevant human exposure at the maximum recommended daily dose of 1 mg/day/patient, it is observed that the lowest doses used for the repeat dose toxicity studies afforded at least 7-fold the mean Cmax and AUC last values for PAI (rasagiline) in humans receiving 1 mg/day. The highest doses used for the repeat dose toxicology studies afforded at least 250-fold Cmax and AUC last values for PAI in humans receiving 1 mg/day. After intravenous and oral dosing the principal manifestations of toxicity were related to the loss of selectivity for MAO-B (i.e. reduced food intake and weight gain and hyperactivity and/or aggression in rats). At the higher oral doses these findings were sometimes accompanied by increases in liver weight and changes in hepatocyte morphology in rats. The liver changes were consistent with changes observed in rats treated with hepatic microsomal enzyme inducers, there was however no evidence from studies that measured hepatic microsomal proteins to support this hypothesis. Suspected changes in thyroid and bladder morphology identified in the rat 13-week oral study were not corroborated by findings in either the 4-week or 26-week rat oral studies. The no adverse effect level (NOAEL) defined after 26 weeks treatment of rats and 52 weeks treatment of dogs was 5.1 mg/kg/day (for both rats and dogs). In terms of AUC last values, the animal NOAELs afford multiples of at least 15-fold with respect to exposure to PAI at the clinical dose of 1 mg/patient/day.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Two year carcinogenicity studies were conducted in CD-1 mice at oral (gavage) doses of 1, 15, and 45 mg/kg and in Sprague-Dawley rats at oral (gavage) doses of 0.3, 1, and 3 mg/kg (males) or 0.5, 2, 5, and 17 mg/kg (females). In rats, there was no increase in tumors at any dose tested. Plasma exposures at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, the expected plasma exposures in humans at the maximum recommended dose (MRD) of 1 mg/day.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In the mice study, the doses administered were 1, 15 and 45 mg/kg/day. Increased incidences of combined lung adenomas/adenocarcinomas were observed in both genders, with a lower safety margin (based on human and animal exposure) in males (rasagiline exposure ratios of mice, to humans treated with 1 mg/day (AUC mice/AUC humans) were 6, 213 and 1418 for males and 4, 144 and 419 for females dosed with 1, 15 and 45 mg/kg/day, respectively.). Historical control data showed a wide range of incidences of lung tumors (combined adenoma/carcinoma in males up to 46% and in females up to 28.6%). Although it is recognized that even at 45 mg/kg/day the observed incidence of combined bronchiolar/alveolar adenoma and/or carcinoma was only slightly above the testing laboratory's historical control range for females and was within the historical control range for males CD-1 mice, there was a clear dose-related increase (13/13; 11/12; 23/19; 24/20 respectively in male/female controls, 1, 15 and 45 mg/kg/day dose groups). Furthermore, safety margin at NOEL for males was only 6 (even if it should be noted that there is a 15 fold increase in between the low and intermediate doses).

For more Non-Human Toxicity Excerpts (Complete) data for RASAGILINE (11 total), please visit the HSDB record page.

As with other MAOI's, Azilect is contraindicated in patients with pheochromocytoma. /Rasagiline mesylate/

Following daily administration for 7 days, the area under the plasma concentration-time curve (AUC) or peak plasma concentration of rasagiline was increased by 2- or 1.4-fold, respectively, in patients with mild (Child-Pugh score of 5-6) hepatic impairment and by seven- or twofold, respectively, in patients with moderate (Child-Pugh score of 7-9) hepatic impairment. Dosage adjustment is recommended in patients with mild hepatic impairment. Use is not recommended in patients with moderate or severe (Child-Pugh score of 7 or greater) hepatic impairment.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Rasagiline has a mean steady-state half life of 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B.

Rasagiline's mean steady-state half life is 3 hours ... .

Rasagiline is eliminated with a half life of about 0.6 - 2 hours and ranging from 0.3 to 3.5 hours across the 0.5 to 20 mg dose range examined following oral administration.

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism.

Rasagiline is extensively metabolized in the liver following oral administration. In vitro studies have shown that CYP1A2 is the predominant P450 isoform involved in the metabolic elimination of rasagiline. The primary human plasma metabolite formed following biotransformation of rasagiline is aminoindan. The proposed principal biotransformation pathways of rasagiline in human are N-dealkylation, hydroxylation of the indan ring, along with Phase II N or O-conjugation, including N-glucuronidation of the parent drug and of its metabolites. There was no bioconversion of rasagiline mesylate (R enantiomer) to its S enantiomer within the human body, as determined in plasma samples for healthy volunteers dosed with rasagiline. Rasagiline is not metabolized to amphetamine or methamphetamine.

An extensive first pass metabolism effect is evident, likely due to rasagiline binding to MAO sites in the intestine prior to passing the liver. Metabolism is rapid and extensive, with a similar profile in all tested species. The primary route of biotransformation is via N-dealkylation to form aminoindan and by hydroxylation to form 3-hydroxy-N-propargyl-1-aminoindan. Conjugation by sulfide or glucuronic acid occurs. Microsomal studies indicate CYP1A2 as the primary metabolising isotype, but rasagiline is neither an inducer nor inhibitor of cytochrome p450. The metabolism of rasagiline under inhibition, induction of CYP1A2 or in presence of concomitant substrate to the enzyme has been addressed clinically.

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 (AI), 3-hydroxy-N-propargyl-1 aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway.

003N66TS6T

RASAGILINE

Established Pharmacologic Class [EPC] - Monoamine Oxidase Inhibitor

Mechanisms of Action [MoA] - Monoamine Oxidase Inhibitors

Rasagiline is a Monoamine Oxidase Inhibitor. The mechanism of action of rasagiline is as a Monoamine Oxidase Inhibitor.

RASAGILINE

A chemically heterogeneous group of drugs that have in common the ability to block oxidative deamination of naturally occurring monoamines. (From Gilman, et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p414)

Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.

Rasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%.

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

87 L

After oral administration of (14)C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

Rasagiline is rapidly absorbed; following oral administration, peak plasma concentrations are achieved in approximately 1 hour. The absolute bioavailability of rasagiline is about 36%. Following administration with a high-fat meal, peak plasma rasagiline concentrations and area under the plasma concentration-time curve (AUC) decreased by approximately 60 and 20%, respectively; because AUC is not substantially affected, rasagiline may be administered with or without food. Rasagiline readily crosses the blood-brain barrier. The mean steady-state or terminal half-life of rasagiline is 31 or 1.342 hours, respectively; however, there is no correlation between rasagiline's pharmacokinetic profile and its pharmacologic effects because the drug irreversibly inhibits MAO-B, and restoration of normal enzyme activity depends on the rate of de novo enzyme synthesis. Rasagiline is approximately 88-94% bound to plasma proteins, with 61-63% bound to albumin.

IV studies in rats and dogs show that the volume of distribution (Vd) of rasagiline is several times that of total body water, indicating extensive tissue distribution. Tissue distribution of (14)C-rasagiline was studied in albino and pigmented rats, revealing peaks of tissue radioactivity between 0.25 and 0.5 hours. Distribution to large intestine, urinary bladder and lacrimal glands takes longer, whilst persistence (up to 24 hrs) was seen in eyes, skin and arterial walls of pigmented animals. In-vitro protein binding in plasma of animals is in the range of 70 to 90% and in human plasma in the range of 88 to 94%.