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Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir

Class: HCV Polymerase Inhibitors
Chemical Name: N-[6-[5-(3,4-Dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-3-(1,1-dimethylethyl)-2-methoxyphenyl]-2-naphthalenyl]-methanesulfonamide
Molecular Formula: C26H27N3O5SC50H67N7O8C40H43N7O7SC37H48N6O5S2
CAS Number: 1132935-63-7
Brands: Viekira Pak, Viekira XR

Warning

    Risk of HBV Reactivation in Patients Coinfected with HCV and HBV
  • HBV reactivation, including cases resulting in fulminant hepatitis, hepatic failure, and death, reported in patients coinfected with HCV and HBV who were receiving or had completed treatment with HCV direct-acting antivirals (DAAs) and were not receiving HBV antiviral therapy.1 25 175 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • Test all patients for evidence of current or prior HBV infection before initiating fixed combination of dasabuvir, ombitasvir, paritaprevir, and ritonavir (dasabuvir/ombitasvir/paritaprevir/ritonavir) or fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with dasabuvir.1 25 175

  • Monitor patients coinfected with HCV and HBV for hepatitis flare or HBV reactivation during and after HCV treatment.1 25 175 Initiate appropriate management for HBV infection as clinically indicated.1 175

Introduction

HCV antiviral; fixed combination containing dasabuvir (HCV NS5B polymerase inhibitor), ombitasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]), paritaprevir (HCV NS3/4A protease inhibitor), and ritonavir (CYP3A inhibitor used to increase paritaprevir exposures) (dasabuvir/ombitasvir/paritaprevir/ritonavir; Viekira XR).175 A fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with dasabuvir (ombitasvir/paritaprevir/ritonavir with dasabuvir; Viekira Pak) also commercially available.1

Uses for Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir

Chronic HCV Infection

Treatment of chronic HCV genotype 1 infection in adults without cirrhosis or with compensated cirrhosis (Child-Pugh class A) 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.1 119 175

Multiple-drug regimen of dasabuvir, ombitasvir, paritaprevir, and ritonavir can be administered as dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination)175 or as ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged).1 (See Dosage and Administration.)

Efficacy not evaluated for treatment of chronic HCV genotype 1 infection in patients in whom previous treatment with a regimen that contained an HCV NS5B polymerase inhibitor, HCV NS5A replication complex inhibitor, or HCV NS3/4A protease inhibitor failed.1 175

Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 175 (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

Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir Dosage and Administration

General

  • Prior to initiating HCV treatment, test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc).1 25 119 175 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • Prior to and during treatment, perform appropriate laboratory tests and clinical evaluation to assess for evidence of hepatic decompensation.1 175 (See Hepatic Effects under Cautions.)

Administration

Oral Administration

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination): Administer orally once daily with a meal.175 Swallow whole; do not split, crush, or chew.175 Do not consume alcohol until ≥4 hours after the dose.175

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

Dosage

Dasabuvir component available as dasabuvir sodium; dosage expressed in terms of dasabuvir.1 175

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination): Each fixed combination tablet contains dasabuvir 200 mg, ombitasvir 8.33 mg, paritaprevir 50 mg, and ritonavir 33.33 mg.175

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged): 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

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) in those without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 3 tablets once daily (total of 600 mg of dasabuvir, 25 mg of ombitasvir, 150 mg of paritaprevir, and 100 mg of ritonavir).175 Duration of treatment is 12 or 24 weeks depending on patient type.175 For certain patients, treatment regimen also should include ribavirin.175 (See Table 1.)

Manufacturer states a treatment duration of 12 weeks can be considered for some patients based on prior treatment history.175

Table 1. Recommended Treatment Regimen and Duration of Dasabuvir/Ombitasvir/Paritaprevir/Ritonavir (Fixed Combination) in Adults119175

Patient Type

Treatment Regimen

Duration of Treatment

HCV genotype 1a infection (without cirrhosis)

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) in conjunction with ribavirin

12 weeks

HCV genotype 1a infection (with compensated cirrhosis)

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) in conjunction with ribavirin

24 weeks

HCV genotype 1b infection (with or without compensated cirrhosis)

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination)

12 weeks

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) in those without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 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 on patient type.1 For certain patients, treatment regimen also should include ribavirin.1 (See Table 2.)

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

Table 2. Recommended Treatment Regimen and Duration of Ombitasvir/Paritaprevir/Ritonavir with Dasabuvir (Copackaged) in Adults1119

Patient Type

Treatment Regimen

Duration of Treatment

HCV genotype 1a infection (without cirrhosis)

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) in conjunction with ribavirin

12 weeks

HCV genotype 1a infection (with compensated cirrhosis)

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) in conjunction with ribavirin

24 weeks

HCV genotype 1b infection (with or without compensated cirrhosis)

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged)

12 weeks

Adults with unknown genotype 1 subtype or mixed genotype 1 subtypes without cirrhosis or with compensated cirrhosis (Child-Pugh class A): Follow treatment recommendations for HCV genotype 1a infection.1 175 (See Table 1 and Table 2.)

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 usual dosage of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) in conjunction with ribavirin for 24 weeks.1 175

HCV Genotype 1 Infection in Individuals Coinfected with HIV
Oral

Use same dosage of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) and same HCV genotype-specific multiple-drug regimen and treatment duration recommended for patients without HIV infection.1 175 (See Table 1 and Table 2.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.1 175

Moderate or severe hepatic impairment (Child-Pugh class B or C): Contraindicated.1 175 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild, moderate, or severe renal impairment, including those on dialysis: Dosage adjustments not needed.1 175

Geriatric Patients

Dosage adjustments not needed based solely on age.1 175 (See Geriatric Use under Cautions.)

Cautions for Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir

Contraindications

  • Known hypersensitivity to ritonavir (e.g., toxic epidermal necrolysis [TEN], Stevens-Johnson syndrome).1 175

  • Moderate or severe hepatic impairment (Child-Pugh class B or C).1 175 (See Hepatic Impairment under Cautions.)

  • If a regimen of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) and ribavirin or a regimen of ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) and ribavirin is being considered, the contraindications for ribavirin apply.1 175 (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).1 175 (See Interactions.)

Warnings/Precautions

Warnings

Risk of HBV Reactivation in Patients Coinfected with HCV and HBV

Postmarketing reports of reactivation of HBV infection when DAAs were used for treatment of HCV infection in patients with HBV coinfection;1 25 175 fulminant hepatitis, hepatic failure, and death reported in some cases.1 25 175

HBV reactivation (abrupt increase in HBV replication manifested as rapid increase in serum HBV DNA levels or detection of HBsAg in an individual who was previously HBsAg negative and anti-HBc positive) reported in patients with HCV and HBV coinfection receiving HCV treatment with a regimen that included HCV DAAs without interferon alfa.1 25 175 HBV reactivation usually occurred within 4–8 weeks after initiation of HCV treatment.25

Patients with HBV reactivation heterogeneous in terms of HCV genotype and baseline HBV disease.25 Some patients were HBsAg positive; others had serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).1 25 175

HBV reactivation also reported in patients receiving certain immunosuppressant or chemotherapeutic drugs;1 175 risk of reactivation associated with HCV DAAs may be increased in such patients.1 175

Mechanism for HBV reactivation in coinfected patients receiving HCV DAAs unknown.25 Although HCV DAAs not known to cause immunosuppression, HBV reactivation in coinfected patients may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses.25

Prior to initiating treatment with an HCV DAA, including dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged), screen all patients for evidence of current or prior HBV infection by measuring HBsAg, anti-HBs, and anti-HBc.1 25 119 175 If there is serologic evidence of HBV infection, measure baseline HBV DNA level.25 119

In all patients with evidence of current or prior HBV infection, monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs.1 25 119 175 Initiate appropriate management for HBV infection as clinically indicated.1 119 175

Advise coinfected patients to immediately contact a clinician if they develop any signs or symptoms of serious liver injury.25 (See Advice to Patients.)

When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consult a clinician with expertise in managing HBV infection.25 119

Sensitivity Reactions

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

Other Warnings/Precautions

Hepatic Effects

Hepatic decompensation and hepatic failure, sometimes requiring liver transplantation or resulting in death, reported during postmarketing experience.1 14 175 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 14 175 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 14 175

Increased ALT concentrations (>5 times ULN) observed in approximately 1% of patients in clinical trials.1 175 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).1 175

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.1 175 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.1 175

Because of increased incidence of elevated ALT concentrations, concomitant use of ethinyl estradiol-containing preparations (including combination oral contraceptives) is contraindicated.1 175 Ethinyl estradiol-containing preparations must be discontinued prior to initiation of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged).1 175 Alternative methods of contraception (e.g., progestin-only or nonhormonal contraception) recommended.1 175 Caution recommended if other estrogens (e.g., estradiol, conjugated estrogens) used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir.1 175 (See Interactions.)

Evaluate liver function in all patients using appropriate laboratory tests prior to initiation of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged), during first 4 weeks of treatment, and as clinically indicated thereafter.1 175 If ALT concentrations increase above baseline levels, repeat laboratory tests and closely monitor.1 175 Consider discontinuing if ALT concentrations are persistently >10 times the ULN; discontinue if ALT elevations are accompanied by signs or symptoms of liver inflammation, increasing serum concentrations of direct bilirubin or alkaline phosphatase, or increasing INR.1 175 (See Hepatic Impairment under Cautions.)

If used in patients with compensated cirrhosis, evaluate liver function using appropriate laboratory tests, including direct bilirubin concentrations, at baseline, during first 4 weeks of treatment, and as clinically indicated thereafter;1 175 monitor for signs of hepatic decompensation (e.g., ascites, hepatic encephalopathy, variceal hemorrhage).1 175 Discontinue in those who develop evidence of hepatic decompensation.1 175

Instruct patients to immediately contact a clinician if they experience onset of fatigue, weakness, lack of appetite, nausea, vomiting, jaundice, or discolored feces.1 175

Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens

Consider cautions, precautions, contraindications, and drug interactions associated with all drugs in the multiple-drug regimen.1 175 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.1 175

If dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) 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.349 377 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 with certain drugs is contraindicated or requires particular caution.1 175 Concomitant use with some drugs may result in drug interactions leading to loss of therapeutic effect of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) and possible development of resistance in HCV.1 175 Certain drug interactions may result in clinically important adverse effects due to higher exposures of the concomitant drugs or components of the HCV antiviral.1 175

Consider potential drug interactions prior to initiating dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged).1 175 Review drugs used concomitantly during course of HCV treatment;1 175 monitor patient for adverse effects associated with these drugs.1 175

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

Ritonavir is included in dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) and ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) since it is a potent CYP3A inhibitor and increases paritaprevir plasma concentrations and AUC;1 175 ritonavir is an HIV protease inhibitor (PI) and can select for HIV PI resistance-associated substitutions.1 175 HCV-infected patients coinfected with HIV receiving dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) for treatment of HCV infection also should be receiving a suppressive antiretroviral drug regimen to reduce risk of HIV PI resistance.1 119 175

Do not use dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) in HIV-infected patients who are not receiving antiretroviral therapy.119

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women;1 175 animal studies have not revealed evidence of teratogenicity with dasabuvir, ombitasvir, paritaprevir, or ritonavir at exposures higher than recommended clinical dosage.1 175

If dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) is used in conjunction with ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women.1 175 (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 dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) are distributed into human milk, affect human milk production, or have effects on the breast-fed infant.1 175 In lactating rats, unchanged ombitasvir, paritaprevir and its metabolite (M13), and dasabuvir distributed into milk without apparent effects on nursing pups.1 175

Consider benefits of breast-feeding and importance of the HCV antivirals to the woman along with the potential adverse effects on the breast-fed child from the drugs or from the underlying maternal condition.1 175

If dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) is used in conjunction with ribavirin, consider potential for adverse reactions to ribavirin in nursing infants;1 175 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.1 175

Geriatric Use

No overall differences in safety and efficacy observed between patients ≥65 years of age and younger adults.1 175 Greater sensitivity in some older individuals cannot be ruled out.1 175

Hepatic Impairment

Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 175

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 14 175 Evaluate liver function using appropriate laboratory tests, including direct bilirubin concentrations, prior to initiation of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged), during the first 4 weeks of treatment, and as clinically indicated.1 175 If there is evidence of hepatic decompensation (with or without increased bilirubin or transaminase concentrations), discontinue the drugs.1 14 175

Renal Impairment

Studies in individuals with mild, moderate, or severe renal impairment (without HCV infection) indicated overall changes in dasabuvir, ombitasvir, paritaprevir, and ritonavir exposures not expected to be clinically important in patients with renal impairment.1 175

Pharmacokinetic data not available regarding use of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) in individuals with end-stage renal disease (ESRD).1 175

Common Adverse Effects

Components of dasabuvir/ombitasvir/paritaprevir/ritonavir given as ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) without ribavirin: Nausea,1 175 pruritus,1 175 rash or other skin reactions,1 175 insomnia.1 175

Components of dasabuvir/ombitasvir/paritaprevir/ritonavir given as ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) in conjunction with ribavirin: Fatigue,1 175 nausea,1 175 diarrhea,1 175 pruritus,1 175 rash or other skin reactions,1 175 headache,1 175 insomnia,1 175 dyspnea,1 175 cough,1 175 irritability,1 175 ocular icterus,1 175 muscle spasms,1 175 asthenia.1 175

Interactions for Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir

Paritaprevir and ritonavir metabolized principally by CYP3A;1 175 dasabuvir metabolized principally by CYP2C8.1 175 Ritonavir inhibits CYP3A4.1 175

Ombitasvir, paritaprevir, and dasabuvir inhibit UGT1A1.1 175

Ombitasvir, paritaprevir, dasabuvir, and ritonavir are substrates of P-glycoprotein (P-gp) transport.1 175

Paritaprevir, ritonavir, and dasabuvir inhibit breast cancer resistance protein (BCRP);1 175 ombitasvir, paritaprevir, and dasabuvir are substrates of BCRP.1 175

Paritaprevir is a substrate and inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3.1 175

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.1 175

Specific drug interaction studies not performed using dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination).175 The following interactions are based on studies using ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) or studies using the individual components alone.1 175 Consider interactions associated with each drug in the multiple-drug regimen.1 175

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).1 175

CYP3A4 substrates: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased concentrations of CYP3A4 substrate).1 175

CYP2C8 inhibitors: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased dasabuvir concentrations).1 175

Drugs Affecting or Metabolized by UGT1A1

UGT1A1 substrates: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased concentrations of UGT1A1 substrate).1 175

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).1 175

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).1 175

BCRP inhibitors: Possible pharmacokinetic interactions (increased concentrations of various components of ombitasvir/paritaprevir/ritonavir with dasabuvir).1 175

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).1 175

OATP1B1 or OATP1B3 substrates: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir (increased concentrations of OATP1B1 or OATP1B3 substrate).1 175

Specific Drugs

Drug

Interaction

Comments

Abacavir

No clinically important interactions1 175

Dosage adjustments not needed1 175

Alfuzosin

Increased alfuzosin concentrations may occur and result in hypotension1 175

Concomitant use contraindicated1 175

Angiotensin II receptor antagonists (candesartan, losartan, valsartan)

Increased concentrations of the angiotensin II receptor antagonist1 175

Reduce dosage of the angiotensin II receptor antagonist and monitor for signs and symptoms of hypotension and/or worsening renal function;1 175 if such events occur, reduce dosage further or consider use of an alternative to the angiotensin II receptor antagonist1 175

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

Amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine: Increased concentrations of the antiarrhythmic agent1 175

Dronedarone: May result in serious and/or life-threatening adverse effects, including cardiac arrhythmias1 175

Amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine: Use concomitantly with caution;1 therapeutic drug monitoring of antiarrhythmic agent recommended, if available1 175

Dronedarone: Concomitant use contraindicated1 175

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Carbamazepine: Decreased dasabuvir, ombitasvir, paritaprevir, and ritonavir exposures;1 175 may lead to loss of therapeutic effect of the HCV treatment regimen1 175

Phenobarbital, phenytoin: Possible decreased dasabuvir, ombitasvir, paritaprevir, and ritonavir exposures;1 175 may lead to loss of therapeutic effect of the HCV treatment regimen1 175

Carbamazepine, phenobarbital, phenytoin: Concomitant use contraindicated1 175

Antifungals, azoles

Ketoconazole: Increased ketoconazole AUC1 175

Voriconazole: Possible decreased voriconazole concentrations1 175

Ketoconazole: If used concomitantly, do not exceed ketoconazole dosage of 200 mg daily1 175

Voriconazole: Concomitant use not recommended unless benefits justify risks1 175

Antimycobacterial agents (rifampin)

Rifampin: Possible decreased ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures; may lead to loss of therapeutic effect of the HCV treatment regimen1 175

Rifampin: Concomitant use contraindicated1 175

Antipsychotics (lurasidone, pimozide, quetiapine)

Lurasidone or pimozide: May result in serious and/or life-threatening adverse effects1 175

Quetiapine: Increased quetiapine concentrations expected1 175

Lurasidone or pimozide: Concomitant use contraindicated1 175

Quetiapine: Consider alternative HCV treatment;1 175 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;1 175 if quetiapine necessary in patient receiving ombitasvir/paritaprevir/ritonavir with dasabuvir, initiate and titrate quetiapine dosage based on manufacturer instructions1 175

Atazanavir

Ritonavir-boosted atazanavir: Increased paritaprevir concentrations and AUC;1 175 increased atazanavir AUC1 175

Cobicistat-boosted atazanavir: Data not available200

Unboosted atazanavir: Use atazanavir 300 mg once daily (give at same time as morning dose of HCV treatment)1 175 200

Ritonavir-boosted or cobicistat-boosted atazanavir: Do not use concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir;1 175 200 may be substituted for unboosted atazanavir after HCV treatment regimen completed1 175 200

Benzodiazepines (alprazolam, diazepam, midazolam, triazolam)

Alprazolam: Increased alprazolam AUC;1 175 no clinically important effect on the HCV antivirals1 175

Diazepam: Decreased AUC of diazepam and nordiazepam (metabolite of diazepam)1 175

Oral midazolam or triazolam: Substantially increased midazolam or triazolam concentrations;1 175 may result in serious or life-threatening adverse effects (e.g., prolonged or increased sedation, respiratory depression)1 175

Alprazolam: Consider reducing alprazolam dosage;1 175 clinical monitoring recommended1 175

Diazepam: Increase diazepam dosage if clinically indicated1 175

Oral midazolam or triazolam: Concomitant use contraindicated1 175

Buprenorphine, buprenorphine/naloxone

Increased buprenorphine and norbuprenorphine AUCs1 175

Dosage adjustments not needed;1 175 closely monitor patient for sedation and cognitive effects1 175

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

Amlodipine: Increased amlodipine AUC;1 175 no clinically important effects on the HCV antivirals1 175

Diltiazem, nifedipine, verapamil: Possible increased calcium-channel blocker concentrations1 175

Amlodipine: Reduce amlodipine dosage by at least 50%1 175

Diltiazem, nifedipine, verapamil: Reduce dosage of the calcium-channel blocker1 175

All calcium-channel blockers: Monitor clinically for edema and/or signs and symptoms of hypotension;1 175 if such events occur, further reduce dosage of calcium-channel blocker or consider alternative to the calcium-channel blocker1 175

Cisapride

May result in serious and/or life-threatening adverse effects, including cardiac arrhythmias1 175

Concomitant use contraindicated1 175

Colchicine

May result in serious and/or life-threatening adverse effects in patients with renal and/or hepatic impairment1 175

Concomitant use contraindicated1 175

Corticosteroids

Fluticasone (inhaled or intranasal): Increased fluticasone concentrations;1 175 may reduce serum cortisol concentrations1 175

Fluticasone (inhaled or intranasal): Consider alternative corticosteroid, particularly for long-term use1 175

Darunavir

Ritonavir-boosted darunavir: Decreased darunavir trough concentrations1 175

Cobicistat-boosted darunavir: Data not available200

Cobicistat-boosted darunavir: Concomitant use not recommended200

Darunavir in antiretroviral-naive patients or antiretroviral-experienced patients with no darunavir-associated resistance substitutions: Use darunavir 800 mg once daily (without ritonavir)1 175

Ritonavir-boosted darunavir in antiretroviral-experienced patients with ≥1 darunavir-associated resistance substitution or in patients with no baseline resistance information: Concomitant use with ritonavir-boosted darunavir (600 mg of darunavir and 100 mg of ritonavir) twice daily not recommended1 175

Digoxin

No clinically important interactions1 175

Dosage adjustments not needed1 175

Dolutegravir

No clinically important interactions1 175

Dosage adjustments not needed1 175

Duloxetine

No clinically important interactions1 175

Dosage adjustments not needed1 175

Efavirenz

Concomitant use with efavirenz-containing regimens poorly tolerated;1 175 liver enzyme elevations observed1 175

Concomitant use contraindicated1 175

Elvitegravir

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF): 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 175

Emtricitabine/tenofovir DF: Dosage adjustments not needed1 175

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)

May cause ergot alkaloid-associated toxicity (e.g., vasospasm, tissue ischemia)1 175

Concomitant use contraindicated1 175

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 175

Oral contraceptives containing ethinyl estradiol and norgestimate: Increased concentrations and AUC of ethinyl estradiol and active metabolites of norgestimate (norelgestromin, norgestrel)1 175

Progestin-only contraceptives: No clinically important interactions1 175

Ethinyl estradiol-containing preparations (e.g., oral contraceptives, contraceptive patches, contraceptive vaginal rings): Concomitant use contraindicated;1 175 must be discontinued prior to initiation of the HCV treatment regimen;1 175 may be restarted approximately 2 weeks after completion of the HCV treatment regimen1 175

Other estrogens (e.g., estradiol, conjugated estrogens): Use concomitantly with caution1 175

Progestin-only contraceptives: Dosage adjustments not needed1 175

Etravirine

Possible decreased concentrations of the HCV antivirals200

Concomitant use not recommended200

Fosamprenavir

Fosamprenavir or ritonavir-boosted fosamprenavir: Concomitant use not recommended200

Furosemide

Increased furosemide concentrations1 175

Clinical monitoring recommended;1 175 individualize furosemide therapy based on patient response1 175

Gemfibrozil

Substantially increased dasabuvir AUC;1 175 may increase risk of QT interval prolongation1 175

Concomitant use contraindicated1 175

HMG-CoA reductase inhibitors (statins)

Atorvastatin, lovastatin, simvastatin: May result in myopathy and rhabdomyolysis1 175

Pravastatin: Increased pravastatin AUC1 175

Rosuvastatin: Increased rosuvastatin concentrations and AUC1 175

Atorvastatin, lovastatin, simvastatin: Concomitant use contraindicated1 175

Pravastatin: If used concomitantly, do not exceed pravastatin dosage of 40 mg daily1 175

Rosuvastatin: If used concomitantly, do not exceed rosuvastatin dosage of 10 mg daily1 175

Hydrocodone

Fixed combination of hydrocodone and acetaminophen (hydrocodone/acetaminophen): Increased hydrocodone concentrations;1 175 no effect on dasabuvir, ombitasvir, paritaprevir, ritonavir, or acetaminophen concentrations1 175

Hydrocodone/acetaminophen: Reduce hydrocodone dosage by 50% and frequently monitor for respiratory depression and sedation;1 175 after completion of HCV treatment, adjust dosage of hydrocodone and monitor for opiate withdrawal1 175

Immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus)

Cyclosporine, everolimus, sirolimus, tacrolimus: Increased immunosuppressant AUC1 175

Cyclosporine: If initiating dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) in patient receiving cyclosporine, reduce cyclosporine dosage by one-fifth and base subsequent dosage on cyclosporine blood concentrations;1 175 frequently assess renal function and monitor for cyclosporine-related adverse effects1 175

Everolimus, sirolimus, tacrolimus: Concomitant use contraindicated1 175

Lamivudine

No clinically important interactions1 175

Dosage adjustments not needed1 175

Lopinavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Increased paritaprevir concentrations and AUC1 175

Lopinavir/ritonavir: Concomitant use not recommended1 175 200

Maraviroc

Increased maraviroc concentrations expected200

Concomitant use not recommended200

Metformin

Pharmacokinetic interaction not expected1 175

Monitor for signs of lactic acidosis (e.g., respiratory distress, somnolence, nonspecific abdominal distress, worsening renal function)1 175

Concomitant use in patients with renal or hepatic impairment not recommended1 175

Methadone

No clinically important interactions1 175

Dosage adjustments not needed1 175

Nevirapine

Possible decreased concentrations of the HCV antivirals200

Concomitant use not recommended200

Proton-pump inhibitors

Omeprazole: Decreased omeprazole concentrations and AUC1 175

Omeprazole: Monitor patient for decreased omeprazole efficacy;1 175 consider increased omeprazole dosage if symptoms not well controlled;1 175 avoid omeprazole dosages >40 mg daily1 175

Raltegravir

No clinically important interactions1 175

Dosage adjustments not needed1 175

Ranolazine

May result in serious and/or life-threatening adverse effects1 175

Concomitant use contraindicated1 175

Rilpivirine

Increased rilpivirine AUC;1 175 may cause QT interval prolongation1 175

Concomitant use not recommended1 175

Ritonavir

Increases paritaprevir concentrations and AUC;1 175 used to therapeutic advantage in dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) and ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged)1 175

Salmeterol

May increase salmeterol concentrations and increase risk of adverse cardiovascular effects (e.g., QT interval prolongation, palpitations, sinus tachycardia)1 175

Concomitant use not recommended1 175

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)1 175

Sildenafil dosages used for treatment of PAH: Concomitant use contraindicated1 175

Skeletal muscle relaxants (carisoprodol, cyclobenzaprine)

Carisoprodol: Decreased carisoprodol concentrations;1 175 no effect on concentrations of dasabuvir, ombitasvir, paritaprevir, ritonavir, or meprobamate (metabolite of carisoprodol)1 175

Cyclobenzaprine: Decreased concentrations of cyclobenzaprine and norcyclobenzaprine (metabolite of cyclobenzaprine);1 175 no effect on concentrations of dasabuvir, ombitasvir, paritaprevir, or ritonavir1 175

Carisoprodol, cyclobenzaprine: Increase dosage of skeletal muscle relaxant if clinically indicated1

Sofosbuvir

No clinically important interactions1 175

Dosage adjustments not needed1 175

SSRIs

Escitalopram: No clinically important interactions1 175

Escitalopram: Dosage adjustments not needed1 175

St. John's wort (Hypericum perforatum)

May decrease ombitasvir/paritaprevir/ritonavir with dasabuvir concentrations;1 175 may lead to loss of therapeutic effect of the HCV treatment regimen1 175

Concomitant use contraindicated1 175

Sulfamethoxazole and trimethoprim

Sulfamethoxazole or trimethoprim: Clinically important interactions not expected1

Sulfamethoxazole or trimethoprim: Dosage adjustments not needed1

Tenofovir

Emtricitabine/tenofovir DF: No clinically important interactions1 175

Emtricitabine/tenofovir DF: Dosage adjustments not needed1 175

Tipranavir

Ritonavir-boosted tipranavir: Concomitant use not recommended200

Warfarin

Manufacturer states no clinically important interactions;1 175 subtherapeutic INRs reported when components of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) initiated in patients receiving warfarin27

Manufacturer states dosage adjustments not needed;1 175 some clinicians state closely monitor INR when the HCV antivirals initiated27

Zolpidem

No clinically important interactions1 175

Dosage adjustments not needed1 175

Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir Pharmacokinetics

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) tablets consist of an extended-release layer containing dasabuvir and an immediate-release layer containing ombitasvir, paritaprevir, and ritonavir.175

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) is a kit containing immediate-release, fixed-combination tablets containing ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with immediate-release tablets containing dasabuvir.1

Absorption

Bioavailability

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination): Peak plasma concentrations of dasabuvir, ombitasvir, paritaprevir, and ritonavir occur at 8, 5, 5, and 4 hours, respectively, after a dose.175

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged): Peak plasma concentrations of the drugs occur approximately 4–5 hours after a dose.1

Absolute bioavailability of dasabuvir, ombitasvir, and paritaprevir is 70, 48, and 53%, respectively.1

Food

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination): Dasabuvir AUC increased 5.92-fold, ombitasvir AUC increased 1.96-fold, paritaprevir AUC increased 4.6-fold, and ritonavir AUC increased 2.13-fold when administered with high-fat meal relative to administration in fasting state.175

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged): Ombitasvir AUC increased 1.76-fold, paritaprevir AUC increased 2.8-fold, ritonavir AUC increased 1.44-fold, and dasabuvir AUC increased 1.22-fold when administered with high-fat meal relative to administration in fasting state.1

Plasma Concentrations

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

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

Steady-state drug exposures of ombitasvir, paritaprevir, ritonavir, and dasabuvir occur after approximately 12 days.1 175

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

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination): ≤30º C.175

Ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged): ≤30º C.1

Actions and Spectrum

  • Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) and ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) provide a multiple-drug regimen containing 3 direct-acting antivirals (DAAs) with activity against HCV.1 175

  • Each antiviral (dasabuvir, ombitasvir, paritaprevir) has a different mechanism of action against HCV;1 175 the drugs have non-overlapping resistance profiles.1 175 No in vitro evidence of antagonistic anti-HCV effects between dasabuvir, ombitasvir, and paritaprevir in HCV replicon studies.1 175

  • Ritonavir, a potent CYP3A inhibitor, is included in the fixed combination to increase paritaprevir plasma concentrations and AUC;1 175 does not have activity against HCV.1 175

  • 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

  • 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

  • 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 dasabuvir, ombitasvir, or paritaprevir on efficacy of other HCV NS5B polymerase inhibitors, HCV NS5A inhibitors, or HCV NS3/4A protease inhibitors not evaluated.1 175 Efficacy of dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) not evaluated in patients in whom previous treatment with a regimen that contained an HCV NS5B polymerase inhibitor, HCV NS5A inhibitor, or HCV NS3/4A protease inhibitor failed.1 175

Advice to Patients

  • If dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) used, advise patients that the drug should be taken once daily with a meal at a regularly scheduled time.175 Advise patients to swallow the tablet whole and to not consume alcohol within 4 hours of taking the dose.175

  • If ombitasvir/paritaprevir/ritonavir (copackaged) used, advise patients that the ombitasvir/paritaprevir/ritonavir component is taken once daily (in the morning) with a meal and the dasabuvir component is taken twice daily (morning and evening) with a meal.1

  • Importance of not missing or skipping doses and importance of taking the drug for the duration recommended by their clinician.1 175

  • Inform patients that reactivation of HBV infection has occurred in coinfected patients being treated for HCV infection.1 25 175 Importance of informing clinician of any history of HBV infection or other liver problems (e.g., cirrhosis).1 25 175 Importance of immediately contacting a clinician if any signs or symptoms of serious liver injury (e.g., fatigue, weakness, loss of appetite, nausea and vomiting, yellowing of the eyes or skin, light-colored bowel movements) occur.1 25 175 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • 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 14 175

  • 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.1 175

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 175 If dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged) is used in conjunction with ribavirin, advise men and women of the importance of avoiding pregnancy during and for 6 months after ribavirin therapy.1 175 Inform patients that contraceptives containing ethinyl estradiol are contraindicated during treatment with ombitasvir/paritaprevir/ritonavir with dasabuvir.1 175 (See Hepatic Effects under Cautions.)

  • Importance of informing patients of other important precautionary information.1 175 (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.

Dasabuvir Sodium, Ombitasvir, Paritaprevir, and Ritonavir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Dasabuvir Sodium 200 mg (of dasabuvir), Ombitasvir 8.33 mg, Paritaprevir 50 mg, and Ritonavir 33.33 mg

Viekira XR

AbbVie

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 2017, Selected Revisions October 2, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AbbVie, Inc. Viekira Pak (ombitasvir, paritaprevir, and ritonavir copackaged with dasabuvir ) tablets prescribing information. North Chicago, IL; 2017 Mar.

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; :.

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

15. Feld JJ, Moreno C, Trinh R et al. Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks. J Hepatol. 2016; 64:301-7. [PubMed 26476290]

25. US Food and Drug Administration. FDA drug safety communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. 2016 Oct 4. From FDA website.

27. DeCarolis DD, Westanmo AD, Chen YC et al. Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin. Ann Pharmacother. 2016; 50:909-917. [PubMed 27465881]

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2017 May 8.

175. AbbVie, Inc. Viekira XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets prescribing information. North Chicago, IL; 2017 Mar.

179. AbbVie, Inc. Technivie (ombitasvir, paritaprevir, and ritonavir) tablets prescribing information. North Chicago, IL; 2017 Mar.

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 (July 14, 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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