cromol/L.
Elimination
The mean terminal elimination half-life of edaravone is 4.5 to 6 hours. The half-lives of its metabolites are 2 to 2.8 hours.
Metabolism
Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A6, UGT1A9, UGT2B7, and UGT2B17) in the liver and kidney. In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases..
Excretion
In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate form (70-90% of the dose). Approximately 5-10% of the dose was recovered in the urine as sulfate conjugate, and only 1% of the dose or less was recovered in the urine as unchanged form. In vitro studies suggest that sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine.
Specific Populations
Geriatric Patients
No age effect on edaravone pharmacokinetics has been found [see USE IN SPECIFIC POPULATIONS (8.5)].
Patients with Renal and Hepatic Impairment
No pharmacokinetic data are available in patients with renal impairment or hepatic impairment [see USE IN SPECIFICPOPULATIONS (8.6,8.7)].
Male and Female Patients
No gender effect on edaravone pharmacokinetics has been found.
Racial or Ethnic Groups
There were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.
Drug Interaction Studies
The pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of CYP enzymes, UGTs, or major transporters.
In vitro studies demonstrated that, at clinical dose, edaravone and its metabolites are not expected to significantly inhibit cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4), UGT1A1, UGT2B7, or transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, CYP2B6, or CYP3A4 at the clinical dose level of RADICAVA.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of edaravone has not been adequately assessed.
Mutagenesis
Edaravone was negative in in vitro (bacterial reverse mutation and Chinese hamster lung chromosomal aberration) and in vivo (mouse micronucleus) assays.
Impairment of Fertility
Intravenous administration of edaravone (0, 3, 20, or 200 mg/kg) prior to and throughout mating in males and females and continuing in females to gestation day 7 had no effect on fertility; however, disruption of the estrus cycle and mating behavior was observed at the highest dose tested. No effects on reproductive function were observed at the lower doses, which are up to 3 times the RHD of 60 mg, on a body surface area (mg/m2) basis.
14 CLINICAL STUDIES
The efficacy of RADICAVA for the treatment of ALS was established in a 6-month, randomized, placebo-controlled, double-blind study conducted in Japanese patients with ALS who were living independently and met the following criteria at screening:
1.Functionality retained most activities of daily living (defined as scores of 2 points or better on each |
