jueves, 21 de febrero de 2019

Clinical Pharmacology Corner: FDA Approves EGATEN (Triclabendazole)

FDA Approves EGATEN (Triclabendazole) for Fascioliasis in Patients 6 Years of Age or Older

On February 13, 2019, the U.S. Food and Drug Administration (FDA) approved EGATEN (triclabendazole) for the treatment of fascioliasis in patients 6 years of age or older. The approved recommended dosage of EGATEN is 2 doses of 10 mg/kg given 12 hours apart with food. EGATEN tablets can be swallowed whole or divided in half and taken with water or crushed and administered with applesauce. The crushed tablet mixed with applesauce is stable for up to 4 hours. Additional information regarding dosage and administration can be found in the full prescribing information linked below.

Transient prolongation of the mean QTc interval was noted on the electrocardiographic recordings in dogs. Monitor ECG in patients with a history of QT prolongation, with a history of symptoms compatible with a long QT interval, or those taking drugs that prolong the QT interval.

Mechanism of Action (MOA) and Pharmacokinetics (PK)
  • MOA: Triclabendazole is an anthelmintic against Fasciola species. 
  • General PK: Following oral administration of a single dose of triclabendazole 10 mg/kg in fed patients, mean peak Cmax for triclabendazole, its sulfoxide and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively, and AUC were 5.72, 386, and 30.5 μmol∙h/L, respectively.
  • Absorption: Median Tmax for the parent compound and its sulfoxide metabolite was 3 to 4 hours, following oral administration of a single dose of triclabendazole 10 mg/kg in fed patients. Cmax and AUC of triclabendazole and its sulfoxide metabolite increased approximately 3-fold and 2-fold, respectively, following administration of a single dose of triclabendazole 10 mg/kg with a 560-kcal meal. The sulfoxide metabolite Tmax increased from 2 hours in the fasted state to 4 hours in the fed state.
  • Distribution: The apparent volume of distribution of the sulfoxide metabolite in fed patients is approximately 1 L/kg. Protein binding of triclabendazole, its sulfoxide and sulfone metabolites is 96.7%, 98.4%, and 98.8%, respectively.
  • Elimination: The plasma elimination half-life for triclabendazole, its sulfoxide and sulfone metabolites is approximately 8, 14, and 11 hours, respectively.  
  • Metabolism: Triclabendazole is primarily metabolized by CYP1A2 (approximately 64%) to its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO. This sulfoxide metabolite is further metabolized primarily by CYP2C9 to its active sulfone metabolite and to a lesser extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4, in vitro.
  • Excretion: No excretion data is available in humans. However, in animals, triclabendazole and its sulfoxide and sulfone metabolites are excreted 90% in feces and < 10% in urine. 
Drug Interactions

CYP2C19 Substrates

No specific clinical drug interaction studies have been conducted for triclabendazole. However, in vitro data suggest the potential for increased plasma concentrations of CYP2C19 substrates with concomitant use of triclabendazole. The potential elevation in concentrations of concomitant CYP2C19 substrates is expected to be transient based on the short elimination half-life and short treatment duration of triclabendazole. If the plasma concentrations of any CYP2C19 substrates requiring therapeutic drug monitoring are elevated during administration of EGATEN, re-check the plasma concentration of the corresponding CYP2C19 substrates after cessation of EGATEN therapy. 

Use in Specific Populations

The pharmacokinetics of EGATEN were not studied in patients with renal or hepatic impairment. 

Pediatric Patients 

No dedicated pediatric pharmacokinetic studies were conducted. However, there was no clinically significant difference observed with triclabendazole AUC in fed pediatric patients 9 to 15 years old compared to patients above 15 years of age following a single dose of triclabendazole 10 mg/kg in one pharmacokinetic study.

Efficacy and Safety

Efficacy of EGATEN was demonstrated in one open label, randomized trial comparing the approved recommended dosage of triclabendazole to oral artesunate 4 mg/kg once daily for 10 days in patients 9 to 74 years of age with acute symptomatic fascioliasis. In addition, 6 non-randomized, open label studies performed in Cuba, Bolivia, Peru, Chile, and Iran in a total of 245 adult and pediatric patients with stool-confirmed fascioliasis were conducted. Additional information regarding the randomized efficacy trial and the clinical development program for triclabendazole can be found in the full prescribing information linked below.

The most common adverse reactions (> 2%) with triclabendazole 20 mg/kg dose (as two divided doses) are abdominal pain, hyperhidrosis, nausea, decreased appetite, headache, urticaria, diarrhea, vomiting, musculoskeletal chest pain, and pruritus.
Full prescribing information is available at https://go.usa.gov/xEUNy

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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