DRUG INTERACTIONS 

 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 

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, recheck the plasma concentration of the CYP2C19 substrates after cessation of triclabendazole therapy. 

BRIEF SUMMARY

TRICLABENDAZOLE -(Feb 2019)

Indn-  To treat fascioliasis, a parasitic infestation caused by two species   of flatworms or termatodeses that mainly the affect the liver,  sometimes referred to as ' Liver flukes"

Comp-   Tablets: 250 mg, functionally scored.  The recommended dose  is 2 doses of 10 mg/kg given 12 hours apart in time. Take orally with food. 

ADR-   Most common adverse reactions (greater than 2%) with triclabendazole 20 mg/kg dose are abdominal pain, hyperhidrosis, nausea, decreased appetite, headache, urticaria, diarrhea, vomiting, musculoskeletal chest pain, and prur

CI-  Patients with known hypersensitivity to triclabendazole, other benzimidazole derivatives or any of the excipients 

QT Prolongation Advise patients with a history of prolongation of the QTc interval or a history of symptoms compatible with a long QT interval or when  IT is used in patients who receive drugs that prolong the QT interval that their ECGs will need to be monitored 

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U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No- 3

ADVERSE REACTIONS

 Most common adverse reactions (greater than 2%) with triclabendazole 20 mg/kg dose are abdominal pain, hyperhidrosis, nausea, decreased appetite, headache, urticaria, diarrhea, vomiting, musculoskeletal chest pain, and pruritus. 

 PATIENT COUNSELING INFORMATION

Important Administration Instructions Advise patients that EGATEN should be taken orally with food.

The 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 

QT Prolongation Advise 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 that their ECGs will need to be monitored 

Distributed by:

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 For more information on EGATEN, call 1-888-669-6682.

 CLINICAL PHARMACOLOGY

1. Mechanism of Action Triclabendazole is an anthelmintic against Fasciola species [see Microbiology (12.4)].

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

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 ?mol/L, respectively.

The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 ?mol·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.

 USE IN SPECIFIC POPULATIONS

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 

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.

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.

3. 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.

4. 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.

5. Renal Impairment

EGATEN has not been studied in patients with renal impairment.

6.Hepatic Impairment

EGATEN has not been studied in patients with hepatic impairment.

 OVERDOSAGE

The reported symptom of overdosage following ingestion of approximately 54 mg/kg of EGATEN (approximately 2.7 times the recommended dose) was nausea. The patient recovered following osmotic diuresis.