5.1       QT Prolongation

Transient prolongation of the mean QTc interval was noted on the electrocardiographic recordings in dogs [see Nonclinical Toxicology (13.2)]. Monitor ECG in patients with a history of prolongation of the QTc interval or a history of symptoms compatible with a long QT interval or when EGATEN is used in patients who receive drugs that prolong the QT interval.

6.1       Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of triclabendazole was evaluated in 208 adult and pediatric patients 5 years of age and older who participated in 6 clinical trials for the treatment of fascioliasis and received 10 mg/kg or 20 mg/kg of triclabendazole; of these, 6 patients failed the 10 mg/kg dose and were retreated with 20 mg/kg. The 10 mg/kg dosing regimen is not approved [see Dosage and Administration (2)]. In these trials, 186 patients received a single dose of 10 mg/kg and 28 patients received a dose of 20 mg/kg as two divided doses. Pooled data for adverse reactions reported in more than 2% of the patients in these clinical trials for the 10 mg/kg and 20 mg/kg dosing regimens are presented in Table 1.

Adverse reactions reported in less than or equal to 2% of patients who received a total of 10 mg/kg of triclabendazole were constipation, biliary colic, arthralgia, back pain, spinal pain, and chromaturia. Some adverse reactions associated with triclabendazole treatment in fascioliasis, e.g. abdominal pain, biliary colic, and jaundice, could be secondary to the infection and may be more frequent and/or severe in patients with a heavy worm burden.

The safety profile of triclabendazole 20 mg/kg in divided doses in a non-hepatic parasitic infection (N = 104) was generally similar to the safety profile in fascioliasis, except for a lower incidence of post-treatment abdominal pain.

Liver Enzyme Elevations

In clinical studies, up to one third of patients had liver enzyme elevations at baseline, which generally improved post-treatment. Of those with normal liver enzyme values at baseline, 6.8%, 4.5%, 4.2% and 3% of patients had post-treatment elevations in bilirubin, aspartate aminotransferase (AST), alkaline phosphatase (ALP) and alanine aminotransferase (ALT), respectively. Transient increases in liver enzymes and total bilirubin in fascioliasis patients receiving triclabendazole are reported in the literature.

6.2       Postmarketing Experience

Resistance to triclabendazole has been reported outside the United States [see Microbiology (12.4)].

7.1       Effect of EGATEN on 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 [see Clinical Pharmacology (12.3)]. The potential elevation in concentrations of concomitantly used CYP2C19 substrates is expected to be transient based on the short elimination half-life and short treatment duration of triclabendazole.

For those CYP2C19 substrate drugs that require therapeutic monitoring of systemic drug exposures, if the plasma concentrations of the CYP2C19 substrates are elevated during administration of triclabendazole, re-check the plasma concentration of the CYP2C19 substrates after cessation of triclabendazole therapy.

8.1       Pregnancy

Risk Summary

There are no available data on EGATEN use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies in animals (rat and rabbits) have not shown a risk of increased fetal abnormalities with exposure to triclabendazole during organogenesis at doses approximately 0.3 to 1.6 times the maximum recommended human dose (MRHD) of 20 mg/kg based on body surface area comparison (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data

Animal Data

Embryo-fetal developmental toxicity studies revealed no malformations in rats and rabbits at doses up to 200 mg/kg/day and 20 mg/kg/day, respectively (approximately 1.6 times and 0.3 times the MRHD based on body surface area comparison, respectively). The animals were treated orally during organogenesis, starting on Day 6 of the pregnancy until Day 15 in rats and Day 18 in rabbits. Maternal toxicity was noted at doses greater than or equal to 100 mg/kg/day in rats and 10 mg/kg/day in rabbits, which was associated with lower fetus weights and delayed ossification. These findings were considered indicative of delayed physiological growth that was secondary to maternal toxicity. No increase in malformation or other abnormalities was observed at any dose level in either species.

8.2       Lactation

Risk Summary

There are no data on the presence of triclabendazole in human milk, the effects on the breastfed infant, or the effects on milk production. Published animal data indicate that triclabendazole is detected in goat milk when administered as a single dose to one lactating animal. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EGATEN and any potential adverse effects on the breastfed infant from EGATEN or from the underlying maternal condition.

8.4       Pediatric Use

Safety and effectiveness of EGATEN has been established in pediatric patients aged 6 years and older.

Safety and effectiveness of EGATEN in pediatric patients below the age of 6 years have not been established.

8.5       Geriatric Use

Clinical studies of EGATEN did not include sufficient numbers of patients aged 65 and over to determine whether the elderly respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6       Renal Impairment

EGATEN has not been studied in patients with renal impairment.

8.7       Hepatic Impairment

EGATEN has not been studied in patients with hepatic impairment.

12.1       Mechanism of Action

Triclabendazole is an anthelmintic against Fasciola species [see Microbiology (12.4)].

12.2       Pharmacodynamics

Triclabendazole exposure-response relationships and the time course of pharmacodynamics response are unknown.

12.3       Pharmacokinetics

After oral administration of a single dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients with fascioliasis, mean peak plasma concentrations (Cmax) for triclabendazole, the sulfoxide and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively.

Absorption

Following oral administration of a single dose of triclabendazole at 10 mg/kg with a 560-kcal meal to patients with fascioliasis, the median Tmax for the parent compound and the sulfoxide metabolite was 3 to 4 hours.

Effect of Food

Cmax and AUC of triclabendazole and sulfoxide metabolite increased approximately 3-fold and 2-fold respectively when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing a total of approximately 560 kcal (consisting of 2 cups of sweetened white coffee, a roll with cheese, and a roll with butter and jam). In addition, 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 (Vd) of the sulfoxide metabolite in fed patients is approximately 1 L/kg.

Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%, 98.4% and 98.8% respectively.

Elimination

The plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in humans is approximately 8, 14, and 11 hours, respectively.

Metabolism

Based on in vitro studies, triclabendazole is primarily metabolized by CYP1A2 (approximately 64%) into 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 the 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, the drug is largely excreted via the biliary tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is excreted in the urine.

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, in one pharmacokinetic study of 20 patients, 7 children (ages 9 to 15 years) were dosed with triclabendazole 10 mg/kg single dose. AUC values of triclabendazole sulfoxide were 20% lower in these pediatric patients in the fed state than in the 13 patients above 15 years of age, but the difference was not statistically significant.

Drug Interaction Studies:

Clinical drug interaction studies have not been conducted for triclabendazole.

In Vitro Studies

Triclabendazole and its sulfoxide and sulfone metabolites have the potential to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A at clinically relevant plasma concentrations, with the highest potential of inhibition on CYP2C19. No in vitro studies were conducted to assess the ability of triclabendazole and its metabolites to induce CYP enzymes. No in vitro studies were conducted to assess the ability of triclabendazole and its metabolites to induce or inhibit transporters.

12.4       Microbiology

Mechanism of Action

The mechanism by which triclabendazole exhibits its effect against Fasciola species is not fully elucidated. Studies in vitro and/or in infected animals suggest that triclabendazole and its active metabolites (sulfoxide and sulfone) are absorbed by the tegument of the immature and mature worms, leading to a decrease of the resting membrane potential, inhibition of tubulin function as well as protein and enzyme synthesis. These metabolic disturbances are associated with inhibition of motility, disruption of the surface as well as ultrastructure that includes inhibition of spermatogenesis and vitelline cells.

Antimicrobial Activity

Triclabendazole and its metabolites are active against the immature and mature worms of Fasciola hepatica and Fasciola gigantica [see Clinical Studies (14)].

Resistance

Studies in vitro and in vivo as well as case reports suggest a potential for development of resistance to triclabendazole.

The mechanism of resistance may be multifactorial that include changes in drug uptake/efflux mechanisms, the target molecules, and altered drug metabolism. The clinical significance of triclabendazole resistance in humans is not established.

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenesis

No genotoxic potential was noted for triclabendazole tested in a battery of 6 genotoxicity in vitro and in vivo assays which include a bacterial reverse mutation assay, chromosome aberration assays, and a micronucleus assay.

Impairment of Fertility

No drug-related effects on reproductive performance, mating ratios or fertility indices have been noted in a 2-generation reproductive and developmental toxicity study in rats. The animals were treated with up to 75 ppm triclabendazole via diet, amounting to a mean daily intake of 7.3 mg/kg/day (approximately 0.1 times the MRHD based on body surface area comparison) for a period of 110 days, which included a 12-day mating period beginning on Day 62 of dosing and continuing until the offspring were weaned.

13.2       Animal Toxicology and/or Pharmacology

Dietary administration of triclabendazole at a dose of 39 mg/kg/day (1.1-times the MRHD based on body surface area comparison) was associated with a transient increase in the QT and QTc intervals on weeks 5 and 9 in some dogs in a 13-week study resulting in QT (QTc) intervals of 212-227 (318-338) msec in the 39 mg/kg dose group (adjusted) compared to 190-193 (280-297) msec in controls. At Week 13, no statistically significant differences were noted between the treatment and control groups.

Additionally, when dogs were administered triclabendazole at a single dose of 40 or 100 mg/kg (1.1 or 2.7 times the MRHD based on body surface area comparison), increase in QTc intervals was observed resulting in QTc intervals of 217-247 msec compared to a normal (historical control) of 193-231 msec. However, plasma levels of the sulfone metabolite in dogs (which is thought to mediate QTc prolongation) was about 100-500 times the plasma level of the sulfone metabolite measured in human plasma.

In the 13-week study in beagle dogs, slight anemia accompanied by minimal increases in reticulocyte and nucleated red cell counts were observed at 39 mg/kg/day (1.1 times the MRHD based on body surface area comparison) predominantly at week 9 of dosing.