Drug Interactions between chlorotrianisene and Mavyret

MONITOR: Theoretical concerns exist that coadministration of estrogen-containing products may increase the risk of liver enzyme elevations associated with the use of glecaprevir/pibrentasvir. In clinical trials, women using ethinyl estradiol-containing medications such as combined oral contraceptives were significantly more likely to have alanine aminotransferase (ALT) elevations, in some cases greater than 20 times the upper limit of normal. ALT elevations are also associated with glecaprevir, particularly at high exposures, thus an additive risk may occur. Pharmacokinetically, glecaprevir/pibrentasvir may increase the plasma concentrations of ethinyl estradiol, presumably due to mild inhibition of CYP450 3A4-mediated metabolism. In 11 study subjects, once daily coadministration of ethinyl estradiol-norgestimate 35 mcg-250 mcg with glecaprevir/pibrentasvir 300 mg-120 mg increased ethinyl estradiol peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 31%, 28% and 38%, respectively. Likewise, once daily coadministration of ethinyl estradiol-levonorgestrel 20 mcg-100 mcg with glecaprevir/pibrentasvir 300 mg-120 mg to 12 study subjects increased ethinyl estradiol Cmax, AUC and Cmin by 30%, 40% and 56%, respectively. Plasma levels of the progestins were also increased by glecaprevir/pibrentasvir in these studies. No effects were observed in the pharmacokinetics of glecaprevir and pibrentasvir.

MANAGEMENT: Some authorities recommend using caution when coadministering estrogens in patients receiving glecaprevir-pibrentasvir. Liver function tests should be performed on all patients during the first 4 weeks of treatment and as clinically indicated thereafter. If ALT is elevated above baseline at any time during treatment, the test should be repeated and monitored closely. Therapy should be discontinued if ALT levels remain persistently greater than 10 times the ULN, or if ALT elevations are accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

MONITOR: Theoretical concerns exist that coadministration of estrogen-containing products may increase the risk of liver enzyme elevations associated with the use of glecaprevir/pibrentasvir. In clinical trials, women using ethinyl estradiol-containing medications such as combined oral contraceptives were significantly more likely to have alanine aminotransferase (ALT) elevations, in some cases greater than 20 times the upper limit of normal. ALT elevations are also associated with glecaprevir, particularly at high exposures, thus an additive risk may occur. Pharmacokinetically, glecaprevir/pibrentasvir may increase the plasma concentrations of ethinyl estradiol, presumably due to mild inhibition of CYP450 3A4-mediated metabolism. In 11 study subjects, once daily coadministration of ethinyl estradiol-norgestimate 35 mcg-250 mcg with glecaprevir/pibrentasvir 300 mg-120 mg increased ethinyl estradiol peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 31%, 28% and 38%, respectively. Likewise, once daily coadministration of ethinyl estradiol-levonorgestrel 20 mcg-100 mcg with glecaprevir/pibrentasvir 300 mg-120 mg to 12 study subjects increased ethinyl estradiol Cmax, AUC and Cmin by 30%, 40% and 56%, respectively. Plasma levels of the progestins were also increased by glecaprevir/pibrentasvir in these studies. No effects were observed in the pharmacokinetics of glecaprevir and pibrentasvir.

MANAGEMENT: Some authorities recommend using caution when coadministering estrogens in patients receiving glecaprevir-pibrentasvir. Liver function tests should be performed on all patients during the first 4 weeks of treatment and as clinically indicated thereafter. If ALT is elevated above baseline at any time during treatment, the test should be repeated and monitored closely. Therapy should be discontinued if ALT levels remain persistently greater than 10 times the ULN, or if ALT elevations are accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.