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Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium

Class: HCV Replication Complex Inhibitors
Chemical Name: 2,2′ - [[(2S,5S) - 1 - [4 - (1,1 - dimethylethyl)phenyl] - 2,5 - pyrrolidinediyl]di - 4,1 - phenylene]bis[N - (methoxycarbonyl) - l - valyl - l - prolinamide
Molecular Formula: C50H67N7O8C40H43N7O7SC37H48N6O5S2C26H27N3O5S
CAS Number: 1258226-87-7
Brands: Viekira Pak

Warning(s)

Special Alerts:

[Posted 10/04/2016]

AUDIENCE: Infectious Disease, Gastroenterology, Patient

ISSUE: The FDA is warning about the risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with certain direct-acting antiviral (DAA) medicines for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death. HBV reactivation usually occurred within 4-8 weeks.

As a result, FDA is requiring a Boxed Warning, our most prominent warning, about the risk of HBV reactivation to be added to the drug labels of these DAAs directing health care professionals to screen and monitor for HBV in all patients receiving DAA treatment. This warning will also be included in the patient information leaflet or Medication Guides for these medicines.

BACKGROUND: Direct-acting antiviral medicines are used to treat chronic hepatitis C virus (HCV) infection, an infection that can last a lifetime. These medicines reduce the amount of HCV in the body by preventing HCV from multiplying, and in most cases, they cure HCV. Without treatment, HCV can lead to serious liver problems including cirrhosis, liver cancer, and death (see List of Direct-Acting Antivirals in the FDA Drug Safety Communication, available at: ).

FDA identified 24 cases of HBV reactivation reported to FDA and from the published literature in HCV/HBV co-infected patients treated with DAAs during the 31 months from November 22, 2013 to July 18, 2016. This number includes only cases submitted to FDA, so there are likely additional cases about which FDA is unaware. Of the cases reported, two patients died and one required a liver transplant. HBV reactivation was not reported as an adverse event in the clinical trials submitted for the DAA approvals because patients with HBV co-infection were excluded from the trials. See the data summary section in the Drug Safety Communication, available at: , for more detailed information.

RECOMMENDATION: Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with DAAs, and monitor patients using blood tests for HBV flare-ups or reactivation during treatment and post-treatment follow-up.

Patients should tell your health care professional if you have a history of hepatitis B infection or other liver problems before being treated for hepatitis C. Do not stop taking your DAA medicine without first talking to your health care professional. Stopping treatment early could result in your virus becoming less responsive to certain hepatitis C medicines. Read the patient information leaflet or Medication Guide that comes with each new prescription because the information may have changed. Contact your health care professional immediately if you develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, as these may be signs of serious liver problems.

For more information visit the FDA website at: and .

Introduction

Antiviral; multiple-drug regimen containing fixed combination of ombitasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]), paritaprevir (HCV NS3/4A protease inhibitor), and ritonavir (CYP3A inhibitor) copackaged with dasabuvir (HCV NS5B polymerase inhibitor).1 9 10 11 12 13 Ritonavir increases paritaprevir exposures and is not active against HCV.1

Uses for Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium

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.

Chronic HCV Infection

Treatment of chronic HCV genotype 1 infection in adults with compensated liver disease (including compensated cirrhosis) who are treatment-naive (previously untreated) or in whom previous treatment with an interferon-based regimen (e.g., peginterferon alfa in conjunction with ribavirin) failed, including liver transplant recipients and those with HIV coinfection.1 119

Fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) is commercially available copackaged with dasabuvir (Viekira Pak) for use when a multiple-drug regimen of ombitasvir/paritaprevir/ritonavir with dasabuvir indicated.1 Fixed combination of ombitasvir/paritaprevir/ritonavir also is commercially available alone (Technivie) for use in HCV treatment regimens that do not include dasabuvir.179

Efficacy and safety ombitasvir/paritaprevir/ritonavir with dasabuvir not established for treatment of chronic HCV infection caused by genotypes other than genotype 1.1

Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 (See Hepatic Impairment under Cautions.)

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium Dosage and Administration

General

  • Prior to and during treatment, perform appropriate laboratory tests and clinical evaluation to assess for evidence of hepatic decompensation.1 (See Hepatic Effects under Cautions.)

Administration

Oral Administration

Ombitasvir/paritaprevir/ritonavir commercially available copackaged with dasabuvir (Viekira Pak) for use when multiple-drug regimen of ombitasvir/paritaprevir/ritonavir with dasabuvir indicated.1

Administer ombitasvir/paritaprevir/ritonavir orally once daily (in the morning) with a meal;1 administer dasabuvir orally twice daily (morning and evening) with a meal.1

If a dose of ombitasvir/paritaprevir/ritonavir is missed and remembered within 12 hours of scheduled time, take dose as soon as possible.1 If a missed dose of ombitasvir/paritaprevir/ritonavir is remembered >12 hours after originally scheduled time, skip missed dose and resume regular dosing schedule.1

If a dose of dasabuvir is missed and remembered within 6 hours of scheduled time, take dose as soon as possible.1 If a missed dose of dasabuvir is remembered >6 hours after originally scheduled time, skip missed dose and resume regular dosing schedule.1

Dosage

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.

Each fixed-combination tablet of ombitasvir/paritaprevir/ritonavir contains ombitasvir 12.5 mg, paritaprevir 75 mg, and ritonavir 50 mg.1

Each tablet of dasabuvir sodium contains 250 mg of dasabuvir.1

Adults

Treatment of Chronic HCV Infection
HCV Genotype 1 Infection
Oral

2 tablets of ombitasvir/paritaprevir/ritonavir once daily in the morning (total of 25 mg of ombitasvir, 150 mg of paritaprevir, and 100 mg of ritonavir) and 1 tablet of dasabuvir (250 mg) twice daily (morning and evening).1

Duration of treatment is 12 or 24 weeks depending patient type.1 For certain patients, ribavirin also included in treatment regimen.1 (See Table 1.)

Manufacturer states a treatment duration of 12 weeks can be considered for some patients based on prior treatment history.1

Table 1. Recommended Treatment Regimen and Duration of Ombitasvir/Paritaprevir/Ritonavir with Dasabuvir1119

Patient Type

Treatment Regimen

Duration of Treatment

HCV genotype 1a infection without cirrhosis

Ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin

12 weeks

HCV genotype 1a infection with compensated cirrhosis

Ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin

24 weeks

HCV genotype 1b infection without cirrhosis

Ombitasvir/paritaprevir/ritonavir with dasabuvir

12 weeks

HCV genotype 1b infection with compensated cirrhosis

Ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin

12 weeks

Adults with unknown genotype 1 subtype or mixed genotype 1 subtypes: Follow treatment recommendations for HCV genotype 1a infection.1 (See Table 1.)

HCV Genotype 1 Infection in Individuals Coinfected with HIV
Oral

Use same ombitasvir/paritaprevir/ritonavir with dasabuvir dosage and same HCV genotype-specific multiple-drug regimen and treatment duration recommended for patients without HIV infection.1 (See Table 1.)

HCV Genotype 1 Infection in Liver Transplant Recipients
Oral

HCV genotype 1a or 1b infection in liver transplant recipients with normal hepatic function and Metavir score ≤2: Use ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin for 24 weeks.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.1

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

Renal Impairment

Mild, moderate, or severe renal impairment: Dosage adjustments not needed.1

Geriatric Patients

Dosage adjustments not needed based solely on age.1 (See Geriatric Use under Cautions.)

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

Interactions for Ombitasvir, Paritaprevir, and Ritonavir with Dasabuvir Sodium

Paritaprevir and ritonavir metabolized principally by CYP3A;1 dasabuvir metabolized principally by CYP2C8.1 Ritonavir inhibits CYP3A4.1

Ombitasvir, paritaprevir, and dasabuvir inhibit UGT1A1.1

Ombitasvir, paritaprevir, dasabuvir, and ritonavir are substrates of P-glycoprotein (P-gp) transport.1

Paritaprevir, ritonavir, and dasabuvir inhibit breast cancer resistance protein (BCRP);1 ombitasvir, paritaprevir, and dasabuvir are substrates of BCRP.1

Paritaprevir is a substrate and inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3.1

Ombitasvir, paritaprevir, ritonavir, and dasabuvir do not inhibit organic anion transporter (OAT) 1 and not expected to inhibit OAT3, organic cation transporter (OCT) 2, or multidrug and toxin extrusion protein (MATE) 1 or MATE2K at clinically important concentrations.1

The following interactions are based on studies using ombitasvir/paritaprevir/ritonavir with dasabuvir or studies using the individual components alone.1 Consider interactions associated with each drug in the multiple-drug regimen.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased paritaprevir and ritonavir concentrations).1

CYP3A4 substrates: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased concentrations of CYP3A4 substrate).1

CYP2C8 inhibitors: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased dasabuvir concentrations).1

Drugs Affecting or Metabolized by UGT1A1

UGT1A1 substrates: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased concentrations of UGT1A1 substrate).1

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp inhibitors: Possible pharmacokinetic interactions (increased concentrations of various components of ombitasvir/paritaprevir/ritonavir with dasabuvir).1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased concentrations of BCRP substrate).1

BCRP inhibitors: Possible pharmacokinetic interactions (increased concentrations of various components of ombitasvir/paritaprevir/ritonavir with dasabuvir).1

Drugs Affecting or Affected by Organic Anion Transport Polypeptides

OATP1B1 or OATP1B3 inhibitors: Possible pharmacokinetic interactions (increased concentrations of various components of ombitasvir/paritaprevir/ritonavir with dasabuvir).1

OATP1B1 or OATP1B3 substrates: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased concentrations of OATP1B1 or OATP1B3 substrate).1

Specific Drugs

Drug

Interaction

Comments

Alfuzosin

Increased alfuzosin concentrations may occur and result in hypotension1

Concomitant use contraindicated1

Angiotensin II receptor antagonists (candesartan, losartan, valsartan)

Increased concentrations of the angiotensin II receptor antagonist1

Reduce dosage of the angiotensin II receptor antagonist and monitor for signs and symptoms of hypotension and/or worsening renal function;1 if such events occur, reduce dosage further or consider use of an alternative to the angiotensin II receptor antagonist1

Antiarrhythmic agents (amiodarone, bepridil, disopyramide, flecainide, lidocaine [systemic], mexiletine, propafenone, quinidine)

Increased concentrations of the antiarrhythmic agent1

Use concomitantly with caution;1 therapeutic drug monitoring of antiarrhythmic agent recommended, if available1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Carbamazepine, phenobarbital, phenytoin: Decreased ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures;1 may lead to loss of therapeutic effect of the HCV treatment regimen1

Carbamazepine, phenobarbital, phenytoin: Concomitant use contraindicated1

Antifungals, azoles

Ketoconazole: Increased ketoconazole AUC1

Voriconazole: Decreased voriconazole concentrations1

Ketoconazole: If used concomitantly, do not exceed ketoconazole dosage of 200 mg daily1

Voriconazole: Concomitant use not recommended unless benefits justify risks1

Antimycobacterial agents (rifampin)

Rifampin: Possible decreased ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures; may lead to loss of therapeutic effect of the HCV treatment regimen1

Rifampin: Concomitant use contraindicated1

Antipsychotics (pimozide, quetiapine)

Pimozide: May increase risk of cardiac arrhythmias1

Quetiapine: Increased quetiapine concentrations expected1

Pimozide: Concomitant use contraindicated1

Quetiapine: Consider alternative HCV treatment;1 if ombitasvir/paritaprevir/ritonavir with dasabuvir necessary in patient receiving quetiapine, reduce quetiapine dosage to one-sixth of original dosage and monitor for quetiapine efficacy and adverse effects;1 if quetiapine necessary in patient receiving ombitasvir/paritaprevir/ritonavir with dasabuvir, initiate and titrate quetiapine dosage based on manufacturer instructions1

Atazanavir

Ritonavir-boosted atazanavir: Increased paritaprevir concentrations and AUC;1 increased atazanavir AUC1

Cobicistat-boosted atazanavir: Data not available200

Unboosted atazanavir: Use atazanavir 300 mg once daily (give at same time as morning dose of HCV treatment)1 200

Ritonavir-boosted or cobicistat-boosted atazanavir: Do not use concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir;1 200 may be substituted for unboosted atazanavir after HCV treatment regimen completed1 200

Benzodiazepines (alprazolam, midazolam, triazolam)

Alprazolam: Increased alprazolam AUC;1 no clinically important effect on the HCV antivirals1

Oral midazolam or triazolam: Substantially increased midazolam or triazolam concentrations;1 may result in serious or life-threatening adverse effects (e.g., prolonged or increased sedation, respiratory depression)1

Alprazolam: Consider reducing alprazolam dosage;1 clinical monitoring recommended1

Oral midazolam or triazolam: Concomitant use contraindicated1

Buprenorphine, buprenorphine/naloxone

Increased buprenorphine and norbuprenorphine AUCs1

Dosage adjustments not needed;1 closely monitor patient for sedation and cognitive effects1

Calcium-channel blockers (amlodipine, diltiazem, nifedipine, verapamil)

Amlodipine: Increased amlodipine AUC;1 no clinically important effects on the HCV antivirals1

Diltiazem, nifedipine, verapamil: Possible increased calcium-channel blocker concentrations1

Amlodipine: Reduce amlodipine dosage by at least 50%1

Diltiazem, nifedipine, verapamil: Reduce dosage of the calcium-channel blocker1

All calcium-channel blockers: Monitor clinically for edema and/or signs and symptoms of hypotension;1 if such events occur, further reduce dosage of calcium-channel blocker or consider alternative to the calcium-channel blocker1

Colchicine

May result in serious or life-threatening adverse effects in patients with renal and/or hepatic impairment1

Concomitant use contraindicated1

Corticosteroids

Fluticasone (inhaled or intranasal): Increased fluticasone concentrations;1 may reduce serum cortisol concentrations1

Fluticasone (inhaled or intranasal): Consider alternative corticosteroid, particularly for long-term use1

Darunavir

Ritonavir-boosted darunavir: Decreased darunavir trough concentrations1

Cobicistat-boosted darunavir: Data not available200

Ritonavir-boosted darunavir or cobicistat-boosted darunavir: Concomitant use not recommended1 200

Digoxin

No clinically important interactions1

Dosage adjustments not needed1

Duloxetine

No clinically important interactions1

Dosage adjustments not needed1

Efavirenz

Concomitant use with efavirenz-containing regimens poorly tolerated;1 liver enzyme elevations observed1

Concomitant use contraindicated1

Elvitegravir

Elvitegravir with a ritonavir-boosted HIV PI: concomitant use not recommended200

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF): Concomitant use not recommended200

Emtricitabine

Fixed combination of emtricitabine and tenofovir disoproxil fumarate (emtricitabine/tenofovir DF): No clinically important interactions1

Emtricitabine/tenofovir DF: Dosage adjustments not needed1

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)

May cause ergot alkaloid-associated toxicity (e.g., vasospasm, tissue ischemia)1

Concomitant use contraindicated1

Estrogens/progestins (ethinyl estradiol, norgestimate, progestin-only contraceptives)

Ethinyl estradiol-containing preparations (e.g., oral contraceptives, contraceptive patches, contraceptive vaginal rings): Increased ALT concentrations reported1

Oral contraceptives containing ethinyl estradiol and norgestimate: Increased concentrations and AUC of ethinyl estradiol and active metabolites of norgestimate (norelgestromin, norgestrel)1

Progestin-only contraceptives: No clinically important interactions1

Ethinyl estradiol-containing preparations (e.g., oral contraceptives, contraceptive patches, contraceptive vaginal rings): Concomitant use contraindicated;1 must be discontinued prior to initiation of the HCV treatment regimen;1 may be restarted approximately 2 weeks after completion of the HCV treatment regimen1

Other estrogens (e.g., estradiol, conjugated estrogens): Use concomitantly with caution1

Progestin-only contraceptives: Dosage adjustments not needed1

Etravirine

Possible decreased concentrations of the HCV antivirals

Concomitant use not recommended200

Fosamprenavir

Fosamprenavir or ritonavir-boosted fosamprenavir: Concomitant use not recommended200

Furosemide

Increased furosemide concentrations1

Clinical monitoring recommended;1 individualize furosemide therapy based on patient response1

Gemfibrozil

Substantially increased dasabuvir AUC;1 may increase risk of QT interval prolongation1

Concomitant use contraindicated1

HMG-CoA reductase inhibitors (statins)

Lovastatin: May result in myopathy and rhabdomyolysis1

Pravastatin: Increased pravastatin AUC1

Rosuvastatin: Increased rosuvastatin concentrations and AUC1

Simvastatin: May result in myopathy and rhabdomyolysis1

Lovastatin: Concomitant use contraindicated1

Pravastatin: If used concomitantly, do not exceed pravastatin dosage of 40 mg daily1

Rosuvastatin: If used concomitantly, do not exceed rosuvastatin dosage of 10 mg daily1

Simvastatin: Concomitant use contraindicated1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: Increased cyclosporine AUC1

Tacrolimus: Increased tacrolimus AUC1

Cyclosporine: If initiating ombitasvir/paritaprevir/ritonavir with dasabuvir in patient receiving cyclosporine, reduce cyclosporine dosage by one-fifth and base subsequent dosage on cyclosporine blood concentrations;1 frequently assess renal function and monitor for cyclosporine-related adverse effects1

Tacrolimus: If initiating ombitasvir/paritaprevir/ritonavir with dasabuvir in patient receiving tacrolimus, omit tacrolimus daily dosage on first day of HCV treatment regimen;1 reinitiate tacrolimus on second day and base this and subsequent dosage on tacrolimus blood concentrations;1 frequently assess renal function and monitor for tacrolimus-related adverse effects1

Lopinavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Increased paritaprevir concentrations and AUC1

Lopinavir/ritonavir: Concomitant use not recommended1 200

Maraviroc

Increased maraviroc concentrations expected200

Concomitant use not recommended200

Methadone

No clinically important interactions1

Dosage adjustments not needed1

Nevirapine

Possible decreased concentrations of the HCV antivirals

Concomitant use not recommended200

Proton-pump inhibitors

Omeprazole: Decreased omeprazole concentrations and AUC1

Omeprazole: Monitor patient for decreased omeprazole efficacy;1 consider increased omeprazole dosage if symptoms not well controlled;1 avoid omeprazole dosages >40 mg daily1

Raltegravir

No clinically important interactions1

Dosage adjustments not needed1

Rilpivirine

Increased rilpivirine AUC;1 may cause QT interval prolongation1

Concomitant use not recommended1

Ritonavir

Increases paritaprevir concentrations and AUC;1 used to therapeutic advantage in fixed combination of ombitasvir/paritaprevir/ritonavir1

Salmeterol

May increase salmeterol concentrations and increase risk of adverse cardiovascular effects (e.g., QT interval prolongation, palpitations, sinus tachycardia)1

Concomitant use not recommended1

Saquinavir

Ritonavir-boosted saquinavir: Concomitant use not recommended200

Sildenafil

Sildenafil dosages used for treatment of pulmonary arterial hypertension (PAH): May increase risk of sildenafil-associated adverse effects (e.g., visual disturbances, hypotension, priapism, syncope)1

Sildenafil dosages used for treatment of PAH: Concomitant use contraindicated1

SSRIs

Escitalopram: No clinically important interactions1

Escitalopram: Dosage adjustments not needed1

St. John's wort (Hypericum perforatum)

May decrease ombitasvir/paritaprevir/ritonavir with dasabuvir concentrations;1 may lead to loss of therapeutic effect of the HCV treatment regimen1

Concomitant use contraindicated1

Tenofovir

Emtricitabine/tenofovir DF: No clinically important interactions1

Emtricitabine/tenofovir DF: Dosage adjustments not needed1

Tipranavir

Ritonavir-boosted tipranavir: Concomitant use not recommended200

Warfarin

No clinically important interactions1

Dosage adjustments not needed1

Zolpidem

No clinically important interactions1

Dosage adjustments not needed1

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

Actions and Spectrum

  • Ombitasvir/paritaprevir/ritonavir commercially available copackaged with dasabuvir provides a multiple-drug regimen containing 3 direct-acting antivirals (DAAs) with activity against HCV.1

  • Each antiviral (ombitasvir, paritaprevir, dasabuvir) has a different mechanism of action against HCV;1 the drugs have non-overlapping resistance profiles.1 No in vitro evidence of antagonistic anti-HCV effects between ombitasvir, paritaprevir, and dasabuvir in HCV replicon studies.1

  • Ritonavir, a potent CYP3A inhibitor, is included in the fixed combination to increase paritaprevir plasma concentrations and AUC;1 does not have activity against HCV.1

  • Ombitasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor).1 9 10 11 13 Exact role of NS5A not fully elucidated,9 10 11 but it is essential for viral replication and virion assembly.1 9 10 11 Active against HCV genotype 1a and genotype 1b;1 9 10 11 some activity against genotypes 2a, 3a, 4a, 5a, and 6a in vitro in cell-based replicon assays.1 9 10 11 Certain amino acid substitutions in NS5A of HCV genotype 1a (e.g., M28T/V, Q30E/R, L31V, H58D, Y93C/H/L/N) and genotype 1b (e.g., L28T, L31F/V, Y93H) selected in cell culture have been associated with reduced in vitro susceptibility to ombitasvir.1 Combinations of ombitasvir resistance-associated substitutions in HCV genotype 1a or 1b replicons further reduce ombitasvir antiviral activity.1

  • Paritaprevir is an HCV NS3/4A protease inhibitor;1 binds to active site of HCV NS3/4A protease, thereby blocking enzyme activity and formation of proteins essential for viral replication (i.e., NS3, NS4A, NS4B, NS5A, NS5B).1 Active against HCV genotypes 1a and 1b;1 may have activity against genotypes 2a, 2b, 3a, and 4a based on biochemical assays.1 Certain amino acid substitutions in NS3 of HCV genotype 1a (e.g., F43L, R155G/K/S, A156T, D168A/E/F/H/N/V/Y, Q80K) and genotype 1b (e.g., A156T, D168A/H/V) selected in cell culture have been associated with reduced in vitro susceptibility to paritaprevir.1 In HCV genotype 1a replicons, combinations of V36M, Y56H, or E357K with R155K or D168 substitutions reduced paritaprevir activity relative to the single R155K or D168 substitutions;1 in HCV genotype 1b replicons, combination of Y56H and D168 substitutions reduced activity of paritaprevir relative to the single D168 substitution.1

  • Dasabuvir is a nonnucleoside NS5B polymerase inhibitor;1 12 binds to HCV RNA-dependent RNA polymerase encoded by the NS5B gene targeting the palm domain and is referred to as a nonnucleoside NS5B palm polymerase inhibitor.1 12 Biochemical assays indicate dasabuvir inhibits HCV genotype 1a and 1b NS5B polymerases;1 has reduced activity against NS5B polymerases from HCV genotypes 2a, 2b, 3a, and 4a.1 Certain amino acid substitutions in NS5B of HCV genotype 1a (e.g., C316Y, M414I/T, E446K/Q, Y448C/H, A553T, G554S, S556G/R, Y561H) and genotype 1b (e.g., C316H/N/Y, S368T, N411S, M414I/T, Y448C/H, A553V, S556G, D559G) selected in cell culture have been associated with reduced in vitro susceptibility to dasabuvir.1 12

  • Cross-resistance expected within each HCV antiviral class (e.g., NS5A inhibitors, NS3/4A protease inhibitors, NS5B palm polymerase inhibitors).1

  • Impact of prior treatment with ombitasvir, paritaprevir, or dasabuvir on efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B polymerase inhibitors not evaluated.1 Efficacy of ombitasvir/paritaprevir/ritonavir with dasabuvir not evaluated in patients in whom previous treatment with a regimen that contained an NS5A inhibitor, NS3/4A protease inhibitor, or NS5B polymerase inhibitor failed.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

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: July 30, 2015
Last reviewed: October 13, 2016
Date modified: November 09, 2016

References

1. AbbVie, Inc. Viekira Pak (ombitasvir, paritaprevir, and ritonavir copackaged with dasabuvir ) tablets prescribing information. North Chicago, IL; 2016 Jan.

2. Feld JJ, Kowdley KV, Coakley E et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014; 370:1594-603. [PubMed 24720703]

3. Ferenci P, Bernstein D, Lalezari J et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014; 370:1983-92. [PubMed 24795200]

4. Poordad F, Hezode C, Trinh R et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014; 370:1973-82. [PubMed 24725237]

5. Zeuzem S, Jacobson IM, Baykal T et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014; 370:1604-14. [PubMed 24720679]

6. Andreone P, Colombo MG, Enejosa JV et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology. 2014; 147:359-365.e1. [PubMed 24818763]

7. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 206619: Summary Review. From FDA website

8. Kwo PY, Mantry PS, Coakley E et al. An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med. 2014; 371:2375-82. [PubMed 25386767]

9. Stirnimann G. Ombitasvir (ABT-267), a novel NS5A inhibitor for the treatment of hepatitis C. Expert Opin Pharmacother. 2014; 15:2609-22. [PubMed 25347030]

10. Gentile I, Buonomo AR, Borgia G. Ombitasvir: a potent pan-genotypic inhibitor of NS5A for the treatment of hepatitis C virus infection. Expert Rev Anti Infect Ther. 2014; 12:1033-43. [PubMed 25074011]

11. DeGoey DA, Randolph JT, Liu D et al. Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A. J Med Chem. 2014; 57:2047-57. [PubMed 24400777]

12. Gentile I, Buonomo AR, Borgia G. Dasabuvir: A Non-Nucleoside Inhibitor of NS5B for the Treatment of Hepatitis C Virus Infection. Rev Recent Clin Trials. 2014; :. [PubMed 24882169]

13. Asselah T, Marcellin P. Optimal IFN-free therapy in treatment-naïve patients with HCV genotype 1 infection. Liver Int. 2015; 35 Suppl 1:56-64. [PubMed 25529088]

14. Food and Drug Administration. FDA drug safety communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. Silver Spring, MD; 2015 Oct 22. From FDA website

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2016Mar 1.

179. AbbVie, Inc. Technivie (ombitasvir, paritaprevir, and ritonavir) tablets prescribing information. North Chicago, IL; 2016 Jan.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (Jan 28, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website.

349. Merck Sharp & Dohme Corporation. Rebetol (ribavirin) capsules and oral solution prescribing information. Whitehouse Station, NJ; 2013 Nov.

377. Genentech. Copegus (ribavirin) tablets prescribing information. South San Francisco, CA; 2013 Feb.

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