Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium

Name: Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium

Cautions for Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Known hypersensitivity to ritonavir (e.g., toxic epidermal necrolysis [TEN], Stevens-Johnson syndrome).1

  • Moderate or severe hepatic impairment (Child-Pugh class B or C).1 (See Hepatic Impairment under Cautions.)

  • If a regimen of ombitasvir/paritaprevir/ritonavir with dasabuvir and ribavirin is being considered, the contraindications for ribavirin apply.1 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

  • Concomitant use with certain drugs (i.e., drugs highly dependent on CYP3A for clearance, potent or moderate inducers of CYP3A and potent inducers of CYP2C8, potent inhibitors of CYP2C8).1 (See Interactions.)

Warnings/Precautions

Hepatic Effects

Hepatic decompensation and hepatic failure, sometimes requiring liver transplantation or resulting in death, reported during postmarketing experience.1 14 Similar cases reported in patients receiving fixed combination of ombitasvir/paritaprevir/ritonavir without dasabuvir.14 179 Most patients with severe outcomes had evidence of advanced cirrhosis prior to initiation of ombitasvir/paritaprevir/ritonavir with dasabuvir or ombitasvir/paritaprevir/ritonavir;1 14 some cases of hepatic failure occurred in patients for whom these drugs were contraindicated or not recommended.14 Reported cases typically occurred within 1–4 weeks after the drugs were initiated and were characterized by acute onset of increasing serum concentrations of direct bilirubin without increased ALT concentrations in association with clinical signs and symptoms of hepatic decompensation.1 14

Increased ALT concentrations (>5 times ULN) observed in approximately 1% of patients in clinical trials.1 These ALT elevations typically were asymptomatic, occurred during first 4 weeks of treatment (mean 20 days; range 8–57 days), and declined within 2–8 weeks after onset despite continued use of ombitasvir/paritaprevir/ritonavir with dasabuvir (with or without ribavirin).1

ALT elevations during ombitasvir/paritaprevir/ritonavir with dasabuvir treatment occurred more frequently in women receiving ethinyl estradiol-containing preparations (e.g., oral contraceptives, contraceptive patches, contraceptive vaginal rings) than in other patients.1 In a limited number of women receiving estrogens other than ethinyl estradiol (e.g., estradiol, conjugated estrogens), rate of ALT elevations was similar to that reported in those not receiving estrogens.1

Because of increased incidence of elevated ALT concentrations, concomitant use of ethinyl estradiol-containing preparations (including combination oral contraceptives) is contraindicated.1 Ethinyl estradiol-containing preparations must be discontinued prior to initiation of ombitasvir/paritaprevir/ritonavir with dasabuvir.1 Alternative methods of contraception (e.g., progestin-only or nonhormonal contraception) recommended.1 Caution recommended if other estrogens (e.g., estradiol, conjugated estrogens) used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir.1 (See Interactions.)

Evaluate liver function using appropriate laboratory tests, including direct bilirubin concentrations, prior to initiation of ombitasvir/paritaprevir/ritonavir with dasabuvir, during first 4 weeks of treatment, and as clinically indicated thereafter.1 If ALT concentrations increase above baseline levels, repeat laboratory tests and closely monitor;1 consider discontinuing ombitasvir/paritaprevir/ritonavir with dasabuvir if ALT concentrations are persistently >10 times the ULN.1

Discontinue ombitasvir/paritaprevir/ritonavir with dasabuvir if ALT elevations are accompanied by signs or symptoms of liver inflammation or increasing serum concentrations of direct bilirubin or alkaline phosphatase or increasing INR.1 Discontinue the drugs if there is evidence of hepatic decompensation (with or without increased bilirubin or transaminase concentrations).1 14 (See Hepatic Impairment under Cautions.)

Instruct patients to immediately contact a clinician if they experience onset of fatigue, weakness, lack of appetite, nausea, vomiting, jaundice, or discolored feces.1

Sensitivity Reactions

Hypersensitivity reactions, including angioedema, reported during postmarketing experience.1

Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens

Consider cautions, precautions, contraindications, and drug interactions associated with all drugs in the ombitasvir/paritaprevir/ritonavir fixed combination with dasabuvir and all drugs in the multiple-drug regimen.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.1

If ombitasvir/paritaprevir/ritonavir with dasabuvir is used in conjunction with ribavirin, consider that ribavirin may cause fetal toxicity and/or death.349 377 Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen.349 377 Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin;349 377 perform pregnancy tests monthly during and for 6 months after ribavirin treatment is completed.1 Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed.349 377

Interactions

Concomitant use of ombitasvir/paritaprevir/ritonavir with dasabuvir and certain drugs is contraindicated or requires particular caution.1 Concomitant use with some drugs may result in drug interactions leading to loss of therapeutic effect of ombitasvir/paritaprevir/ritonavir with dasabuvir and possible development of resistence.1 Certain drug interactions may result in clinically important adverse effects due to higher exposures of the concomitant drugs or components of ombitasvir/paritaprevir/ritonavir with dasabuvir.1

Consider potential drug interactions prior to initiating ombitasvir/paritaprevir/ritonavir with dasabuvir.1 Review drugs used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir during course of treatment;1 monitor patient for adverse effects associated with these drugs.1

Risk of HIV Protease Inhibitor Drug Resistance in Patients Coinfected with HCV and HIV

Ritonavir is included in the fixed combination of ombitasvir/paritaprevir/ritonavir since it is a potent CYP3A inhibitor and increases paritaprevir plasma concentrations and AUC;1 ritonavir is an HIV protease inhibitor (PI) and can select for HIV PI resistance-associated substitutions.1 HCV-infected patients coinfected with HIV receiving ombitasvir/paritaprevir/ritonavir with dasabuvir for treatment of HCV infection also should be receiving a suppressive antiretroviral drug regimen to reduce risk of HIV PI resistance.1 119

Do not use ombitasvir/paritaprevir/ritonavir with dasabuvir in HIV-infected patients who are not receiving antiretroviral therapy.119

Specific Populations

Pregnancy

Category B.1

Use ombitasvir/paritaprevir/ritonavir with dasabuvir during pregnancy only if clearly needed.1

No adequate and well-controlled studies using ombitasvir/paritaprevir/ritonavir with dasabuvir in pregnant women;1 animal studies have not revealed evidence of teratogenicity with ombitasvir, paritaprevir and ritonavir, or dasabuvir at exposures higher than recommended clinical dosage.1

If ombitasvir/paritaprevir/ritonavir with dasabuvir is used in conjunction with ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women.1 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Antiretroviral Pregnancy Registry at 800-258-4263 to monitor pregnancy outcomes of HIV-infected pregnant patients receiving antiretroviral therapy, including those coinfected with HCV and receiving HCV treatment.1

Lactation

Not known whether components of ombitasvir/paritaprevir/ritonavir with dasabuvir are distributed into human milk.1 In lactating rats, unchanged ombitasvir, paritaprevir and its metabolite (M13), and dasabuvir distributed into milk without apparent effects on nursing pups.1

Consider benefits of breast-feeding and importance of ombitasvir/paritaprevir/ritonavir with dasabuvir to the woman along with the potential adverse effects on the breast-fed child from the drugs or from the underlying maternal condition.1

If ombitasvir/paritaprevir/ritonavir with dasabuvir is used in conjunction with ribavirin, consider potential for adverse reactions to ribavirin in nursing infants;1 decide whether to discontinue nursing or ribavirin, taking into account the importance of the treatment regimen to the woman.349 377

Pediatric Use

Safety and efficacy not established in children and adolescents <18 years of age.1

Geriatric Use

No overall differences in safety and efficacy observed between patients ≥65 years of age and younger adults.1 Greater sensitivity in some older individuals cannot be ruled out.1

Hepatic Impairment

Ombitasvir/paritaprevir/ritonavir with dasabuvir is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1

If used in patients with compensated cirrhosis, closely monitor for clinical signs and symptoms of hepatic decompensation (e.g., ascites, hepatic encephalopathy, variceal hemorrhage).1 14 Evaluate liver function using appropriate laboratory tests, including direct bilirubin concentrations, prior to initiation of ombitasvir/paritaprevir/ritonavir with dasabuvir, during the first 4 weeks of treatment, and as clinically indicated.1 If there is evidence of hepatic decompensation (with or without increased bilirubin or transaminase concentrations), discontinue the drugs.1 14

Renal Impairment

Studies in individuals with mild, moderate, or severe renal impairment (without HCV infection) indicated overall changes in ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures not expected to be clinically important in patients with renal impairment.1

Pharmacokinetic data not available regarding use of ombitasvir/paritaprevir/ritonavir with dasabuvir in individuals with end-stage renal disease (ESRD);1 not studied in patients undergoing dialysis.1

Common Adverse Effects

Ombitasvir/paritaprevir/ritonavir with dasabuvir without ribavirin: Nausea,1 pruritus,1 rash or other skin reactions,1 insomnia.1

Ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin: Fatigue,1 nausea,1 diarrhea,1 pruritus,1 rash or other skin reactions,1 headache,1 insomnia,1 dyspnea,1 cough,1 irritability,1 ocular icterus,1 muscle spasms,1 asthenia.1

Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium Pharmacokinetics

Absorption

Bioavailability

Ombitasvir, paritaprevir, ritonavir, and dasabuvir well absorbed following oral administration;1 peak plasma concentrations of the drugs occur approximately 4–5 hours after a dose.1

Absolute bioavailability of dasabuvir is 70%.1

Food

Ombitasvir: AUC increased by 82 or 76% when administered with moderate- or high-fat meal, respectively, relative to administration in fasting state.1

Paritaprevir: AUC increased by 211 or 180% when administered with moderate- or high-fat meal, respectively, relative to administration in fasting state.1

Ritonavir: AUC increased by 49 or 44% when administered with moderate- or high-fat meal, respectively, relative to administration in fasting state.1

Dasabuvir: AUC increased by 30 or 22% when administered with moderate- or high-fat meal, respectively, relative to administration in fasting state.1

Plasma Concentrations

Ombitasvir: Exposures increase in dose-proportional manner with minimal accumulation.1

Paritaprevir: Exposures increase in more than dose-proportional manner with accumulation of approximately 1.5- to 2-fold.1

Ritonavir: Exposures increase in more than dose-proportional manner with accumulation of approximately 1.5- to 2-fold.1

Dasabuvir: Exposures increase in dose-proportional manner with minimal accumulation.1

Steady-state drug exposures of ombitasvir, paritaprevir, ritonavir, and dasabuvir occur after approximately 12 days.1

Special Populations

Mild hepatic impairment (Child-Pugh class A, score 5–6) without HCV infection: AUCs of ombitasvir, paritaprevir, and ritonavir decreased by 8, 29, and 34%, respectively, and AUC of dasabuvir increased by 17% compared with AUCs in those with normal hepatic function.1

Moderate hepatic impairment (Child-Pugh class B, score 7–9) without HCV infection: AUCs of ombitasvir, paritaprevir, and dasabuvir decreased by 30, 30, and 16%, respectively, and AUC of paritaprevir increased by 62% compared with AUCs in those with normal hepatic function.1

Severe hepatic impairment (Child-Pugh class C, score 10–15) without HCV infection: AUC of ombitasvir decreased by 54% and AUCs of paritaprevir, ritonavir, and dasabuvir increased by 945, 13, and 325%, respectively, compared with AUCs in those with normal hepatic function.1

Mild renal impairment (Clcr 60–89 mL/minute) without HCV infection: AUCs of paritaprevir, ritonavir, and dasabuvir increased by 19, 42, and 21%, respectively, and AUC of ombitasvir unchanged compared with AUCs in those with normal renal function.1

Moderate renal impairment (Clcr 30–59 mL/minute) without HCV infection: AUCs of paritaprevir, ritonavir, and dasabuvir increased by 33, 80, and 37%, respectively, and AUC of ombitasvir unchanged compared with AUCs in those with normal renal function.1

Severe renal impairment (Clcr 15–29 mL/minute) without HCV infection: AUCs of paritaprevir, ritonavir, and dasabuvir increased by 45, 114, and 50%, respectively, and AUC of ombitasvir unchanged compared with AUCs in those with normal renal function.1

Distribution

Plasma Protein Binding

Ombitasvir: Approximately 99.9%.1

Paritaprevir: Approximately 97–98.6%.1

Ritonavir: Approximately 99%.1

Dasabuvir: >99.5%.1

Elimination

Metabolism

Ombitasvir: Principally by amide hydrolysis followed by oxidative metabolism.1

Paritaprevir: Principally by CYP3A4 and, to lesser extent, by CYP3A5.1

Ritonavir: Principally by CYP3A and, to lesser extent, by CYP2D6.1

Dasabuvir: Principally by CYP2C8 and, to lesser extent, by CYP3A.1

Elimination Route

Ombitasvir: Approximately 90% of dose excreted in feces (88% as unchanged drug);1 2% eliminated in urine.1

Paritaprevir: Approximately 88% of dose excreted in feces (1% as unchanged drug);1 8.8% eliminated in urine.1

Ritonavir: Approximately 86% of dose excreted in feces; 11% eliminated in urine.1

Dasabuvir: Approximately 94% of dose excreted in feces (26% as unchanged drug);1 approximately 2% eliminated in urine.1

Half-life

Ombitasvir: Approximately 21–25 hours.1

Paritaprevir: Approximately 5.5 hours.1

Ritonavir: Approximately 4 hours when administered concomitantly with ombitasvir and paritaprevir.1

Dasabuvir: Approximately 5.5–6 hours.1

Stability

Storage

Oral

Tablets

≤30º C.1

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Advise patients to take ombitasvir/paritaprevir/ritonavir once daily (in the morning) with a meal and to take dasabuvir twice daily (morning and evening) with a meal.1

  • If a dose of ombitasvir/paritaprevir/ritonavir is missed, advise patient to take it as soon as remembered, if within 12 hours of originally scheduled time.1 If >12 hours after originally scheduled time, advise patient to omit the missed dose and resume regular dosing schedule with the next dose.1

  • If a dose of dasabuvir is missed, advise patient to take it as soon as remembered, if within 6 hours of originally scheduled time.1 If >6 hours after originally scheduled time, advise patient to omit the missed dose and resume regular dosing schedule with the next dose.1

  • Advise patients to watch for early signs of liver inflammation or failure (e.g., fatigue, weakness, lack of appetite, nausea, vomiting) as well as later signs (e.g., jaundice, onset of confusion, abdominal swelling, discolored feces) and to immediately contact a clinician if such manifestations occur.1 14

  • Inform patients that the effect of HCV treatment on transmission of HCV is unknown;1 take appropriate precautions to prevent transmission of the virus during treatment or in the event of treatment failure.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 If ombitasvir/paritaprevir/ritonavir with dasabuvir is used in conjunction with ribavirin, advise men and women of the importance of avoiding pregnancy during and for 6 months after ribavirin therapy.1 Inform patients that contraceptives containing ethinyl estradiol are contraindicated during treatment with ombitasvir/paritaprevir/ritonavir with dasabuvir.1 (See Hepatic Effects under Cautions.)

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

Ombitasvir 12.5 mg, Paritaprevir 75 mg, and Ritonavir 50 mg film-coated tablets

Dasabuvir Sodium 250 mg (of dasabuvir) film-coated tablets

Viekira Pak

AbbVie

(web3)