Drug Interactions between Kelnor 1/35 and ombitasvir / paritaprevir / ritonavir

CONTRAINDICATED: Coadministration of ethinyl estradiol-, mestranol-, or estetrol-containing products may increase the risk of liver enzyme elevations associated with the use of ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. The proposed mechanism is the inhibition of UDP-glucuronosyltransferase (UGT) by ombitasvir, paritaprevir, and dasabuvir. During clinical trials, approximately 1% of all subjects experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment, with or without ribavirin. However, the incidence increased to 25% (4/16) among women taking a concomitant medication containing ethinyl estradiol. The incidence of clinically relevant ALT elevations among women using estrogens other than mestranol or ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy, was 3% (2/59). In general, ALT elevations were asymptomatic, occurred during the first 4 weeks of treatment (mean 20 days; range 8 to 57 days), and declined within two to eight weeks of onset despite continued therapy. Elevations in ALT were typically not associated with bilirubin elevations, and cirrhosis was not a risk factor. Data are not available for estetrol but the possibility of a similar interaction should be considered.

MANAGEMENT: Ethinyl estradiol-, mestranol-, or estetrol-containing medications must be discontinued prior to starting therapy with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. Alternative contraception such as progestin-only contraceptives or non-hormonal methods are recommended. Ethinyl estradiol-, mestranol-, or estetrol-containing medications can be restarted approximately 2 weeks following completion of the hepatitis C treatment. 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.

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ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with ritonavir may decrease the plasma concentrations of contraceptive hormones. In a pharmacokinetic study, 22 of 23 healthy women who received single doses of an oral contraceptive containing ethinyl estradiol 50 mcg and ethynodiol 1 mg had reduced serum levels of ethinyl estradiol following the addition of ritonavir (500 mg twice a day) for 2 weeks. Specifically, the mean peak serum concentration (Cmax) decreased by 32%, the mean systemic exposure (AUC) decreased by 41%, and the mean terminal elimination rate constant increased by 31%. The exact mechanism of interaction is unknown but may involve ritonavir induction of glucuronosyltransferase and/or CYP450 hydroxylation. Since estrogens and progestins may share common routes of metabolism, the possibility of a similar interaction should be considered in patients receiving contraceptive hormones other than ethinyl estradiol.

MANAGEMENT: Women using hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant therapy with ritonavir. Alternative or additional methods of birth control should be used during and for at least 4 weeks after ritonavir therapy. If a combination oral contraceptive pill is used, a regimen containing at least 50 mcg of ethinyl estradiol per day or equivalent should be selected. Although breakthrough bleeding is not necessarily indicative of low ethinyl estradiol serum levels or increased risk of ovulation, some clinicians suggest that women who experience breakthrough bleeding during enzyme-inducing therapy may be prescribed an increased dose of ethinyl estradiol above 50 mcg daily by combining more than one formulation of contraceptive pill if necessary. For emergency contraception in patients who have used an hepatic enzyme inducer in the past 4 weeks, a non-hormonal emergency contraceptive (e.g., copper intrauterine device) is considered preferable. If this is not possible, some authorities recommend that the usual dose of levonorgestrel (1.5 mg) should be doubled to 3 mg and taken as a single dose as soon as possible (within 72 hours of unprotected sexual intercourse). However, there are no data on efficacy, compliance, or side effects of this regimen. No precautions or recommendations are available for women using hormone-releasing intrauterine systems, but a significant interaction with these systems is thought to be unlikely due to their local action. Injectable progestin-only contraceptives are also thought to be unaffected by enzyme-inducing drugs.

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ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with ritonavir may decrease the plasma concentrations of contraceptive hormones. In a pharmacokinetic study, 22 of 23 healthy women who received single doses of an oral contraceptive containing ethinyl estradiol 50 mcg and ethynodiol 1 mg had reduced serum levels of ethinyl estradiol following the addition of ritonavir (500 mg twice a day) for 2 weeks. Specifically, the mean peak serum concentration (Cmax) decreased by 32%, the mean systemic exposure (AUC) decreased by 41%, and the mean terminal elimination rate constant increased by 31%. The exact mechanism of interaction is unknown but may involve ritonavir induction of glucuronosyltransferase and/or CYP450 hydroxylation. Since estrogens and progestins may share common routes of metabolism, the possibility of a similar interaction should be considered in patients receiving contraceptive hormones other than ethinyl estradiol.

MANAGEMENT: Women using hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant therapy with ritonavir. Alternative or additional methods of birth control should be used during and for at least 4 weeks after ritonavir therapy. If a combination oral contraceptive pill is used, a regimen containing at least 50 mcg of ethinyl estradiol per day or equivalent should be selected. Although breakthrough bleeding is not necessarily indicative of low ethinyl estradiol serum levels or increased risk of ovulation, some clinicians suggest that women who experience breakthrough bleeding during enzyme-inducing therapy may be prescribed an increased dose of ethinyl estradiol above 50 mcg daily by combining more than one formulation of contraceptive pill if necessary. For emergency contraception in patients who have used an hepatic enzyme inducer in the past 4 weeks, a non-hormonal emergency contraceptive (e.g., copper intrauterine device) is considered preferable. If this is not possible, some authorities recommend that the usual dose of levonorgestrel (1.5 mg) should be doubled to 3 mg and taken as a single dose as soon as possible (within 72 hours of unprotected sexual intercourse). However, there are no data on efficacy, compliance, or side effects of this regimen. No precautions or recommendations are available for women using hormone-releasing intrauterine systems, but a significant interaction with these systems is thought to be unlikely due to their local action. Injectable progestin-only contraceptives are also thought to be unaffected by enzyme-inducing drugs.

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