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Technivie

Generic Name: Ombitasvir, Paritaprevir, and Ritonavir
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: C50H67N7O8C40H43N7O7SC37H48N6O5S2
CAS Number: 1258226-87-7

Introduction

Antiviral; fixed combination of ombitasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]), paritaprevir (HCV NS3/4A protease inhibitor), and ritonavir (CYP3A inhibitor).1 Ritonavir increases paritaprevir exposures and is not active against HCV.1

Uses for Technivie

Chronic HCV Infection

Treatment of chronic HCV genotype 4 infection in treatment-naive (previously untreated) or previously treated adults without cirrhosis;1 119 used in conjunction with ribavirin.1 119

Fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) commercially available alone (Technivie) for use in HCV treatment regimens.1 Fixed combination of ombitasvir/paritaprevir/ritonavir also commercially available copackaged with dasabuvir (Viekira Pak) for use when a multiple-drug regimen of ombitasvir/paritaprevir/ritonavir with dasabuvir indicated.180

Efficacy and safety of ombitasvir/paritaprevir/ritonavir in conjunction with ribavirin not established for treatment of chronic HCV infection caused by genotypes other than genotype 4.1

Contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh class B or C) and should not be used in patients with cirrhosis.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

Technivie Dosage and Administration

General

  • Prior to and during treatment, assess hepatic function using appropriate laboratory tests.1 (See Hepatic Effects under Cautions.)

Administration

Oral Administration

Administer ombitasvir/paritaprevir/ritonavir orally once daily (in the morning) 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

Dosage

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

Adults

Treatment of Chronic HCV Infection
HCV Genotype 4 Infection
Oral

Treatment-naive or previously treated without cirrhosis: 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) given in conjunction with ribavirin.1 Duration of treatment is 12 weeks.1

Treatment-naive without cirrhosis who cannot take or tolerate ribavirin: Manufacturer states consider using recommended dosage of ombitasvir/paritaprevir/ritonavir without ribavirin.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 Technivie

Contraindications

  • 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.)

  • When ombitasvir/paritaprevir/ritonavir used in conjunction with ribavirin, 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).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 with dasabuvir.14 180 Most patients with severe outcomes had evidence of advanced cirrhosis prior to receiving ombitasvir/paritaprevir/ritonavir with or without dasabuvir;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 receiving ombitasvir/paritaprevir/ritonavir (with or without dasabuvir and with or without ribavirin) in clinical trials.1 These ALT elevations typically were asymptomatic, occurred during first 4 weeks of treatment, and declined within 2–8 weeks after onset despite continued use of the regimen.1

ALT elevations during ombitasvir/paritaprevir/ritonavir 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.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.1 (See Interactions.)

Evaluate liver function using appropriate laboratory tests prior to initiation of ombitasvir/paritaprevir/ritonavir, 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 if ALT concentrations are persistently >10 times ULN.1

Discontinue ombitasvir/paritaprevir/ritonavir 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

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 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

When ombitasvir/paritaprevir/ritonavir 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 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 and possible development of resistance.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.1

Consider potential drug interactions prior to initiating ombitasvir/paritaprevir/ritonavir.1 Review drugs used concomitantly with ombitasvir/paritaprevir/ritonavir 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 and can select for HIV protease inhibitor resistance-associated substitutions.1 HCV-infected patients coinfected with HIV receiving ombitasvir/paritaprevir/ritonavir for treatment of HCV infection also should be receiving a suppressive antiretroviral drug regimen to reduce risk of HIV protease inhibitor resistance.1 119

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

Specific Populations

Pregnancy

Category B.1

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

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

When 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.)

Lactation

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

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

When used in conjunction with ribavirin, consider potential for adverse reactions to ribavirin in nursing infants;1 decide whether to discontinue nursing or the ribavirin-containing regimen, 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

Hepatic Impairment

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

Do not use in patients with cirrhosis.1

Renal Impairment

Studies in individuals with mild, moderate, or severe renal impairment (without HCV infection) indicate no overall differences in ombitasvir, paritaprevir, or ritonavir exposures expected compared with those reported in patients with normal renal function.1

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

Common Adverse Effects

Ombitasvir/paritaprevir/ritonavir with or without ribavirin: Asthenia,1 2 fatigue,1 2 headache,2 irritability,2 nausea,1 2 diarrhea,2 insomnia,1 2 myalgia,2 nasopharyngitis,2 pruritus,1 2 rash or other skin reactions,1 increased serum bilirubin concentrations.1 2

Interactions for Technivie

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

Paritaprevir and ritonavir inhibit P-glycoprotein (P-gp) transport;1 ombitasvir, paritaprevir, and ritonavir are substrates of P-gp.1

Paritaprevir and ritonavir inhibit breast cancer resistance protein (BCRP);1 paritaprevir is a substrate of BCRP.1

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

Ombitasvir, paritaprevir, and ritonavir 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 Ombitasvir, paritaprevir, and ritonavir are neither inhibitors or substrates of OCT1.1

The following interactions are based on studies using ombitasvir/paritaprevir/ritonavir or studies using ombitasvir/paritaprevir/ritonavir given with dasabuvir.1 When ombitasvir/paritaprevir/ritonavir used, consider interactions associated with each drug in the fixed combination.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

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

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp substrates: Possible pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir (increased concentrations of P-gp substrate).1

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

Drugs Affecting or Affected by Breast Cancer Resistance Protein

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

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

Drugs Affecting or Affected by Organic Anion Transport Polypeptides

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

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

Specific Drugs

Drug

Interaction

Comments

Alfuzosin

Hypotension may occur1

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, further reduce dosage 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: Decreased concentrations and AUCs of ombitasvir, paritaprevir, and ritonavir expected;1 may lead to loss of therapeutic effect of the HCV treatment regimen1

Phenobarbital, phenytoin: Possible decreased ombitasvir, paritaprevir, and ritonavir 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, and ritonavir exposures;1 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 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, initiate and titrate quetiapine dosage based on manufacturer instructions1

Atazanavir

Unboosted atazanavir: Increased paritaprevir concentrations and AUC1

Ritonavir-boosted atazanavir: Increased paritaprevir concentrations and AUC expected

Unboosted or ritonavir-boosted atazanavir: Concomitant use not recommended1

Benzodiazepines (alprazolam, midazolam, triazolam)

Alprazolam: Increased alprazolam AUC expected1

Oral midazolam or triazolam: Substantially increased midazolam or triazolam concentrations expected;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 expected1

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)

Fluticasone (inhaled or intranasal): Possible 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

Darunavir: If used concomitantly, administer darunavir 800 mg without ritonavir at the same time as ombitasvir/paritaprevir/ritonavir1

Digoxin

Increased digoxin concentrations1

Reduce digoxin dosage by 30–50%;1 monitor serum digoxin concentrations1

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

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

Furosemide

Increased furosemide concentrations expected1

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

Gemfibrozil

No clinically important interactions1

Dosage adjustments not needed1

HMG-CoA reductase inhibitors (statins)

Lovastatin: May result in myopathy and rhabdomyolysis1

Pravastatin: Increased pravastatin AUC1

Rosuvastatin: No clinically important interactions1

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: Dosage adjustments not needed1

Simvastatin: Concomitant use contraindicated1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: Increased cyclosporine AUC and trough concentrations1

Tacrolimus: Increased tacrolimus AUC1

Cyclosporine: If initiating ombitasvir/paritaprevir/ritonavir 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 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

Methadone

No clinically important interactions1

Dosage adjustments not needed1

Proton-pump inhibitors (omeprazole)

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 expected;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

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 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

Warfarin

No clinically important interactions1

Dosage adjustments not needed1

Zolpidem

No clinically important interactions1

Dosage adjustments not needed1

Technivie Pharmacokinetics

Absorption

Bioavailability

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

Absolute oral bioavailability of ombitasvir and paritaprevir administered with ritonavir is approximately 48 and 53%, respectively.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

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

Steady-state drug exposures of ombitasvir, paritaprevir, and ritonavir 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, 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 and ritonavir each decreased by 30% 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 and ritonavir increased by 945 and 13%, respectively, compared with AUCs in those with normal hepatic function.1

Mild renal impairment (Clcr 60–89 mL/minute) without HCV infection: AUC of ritonavir increased by 40% and AUCs of ombitasvir and paritaprevir unchanged compared with AUCs in those with normal renal function.1

Moderate renal impairment (Clcr 30–59 mL/minute) without HCV infection: AUC of ritonavir is increased by 76% and AUCs of ombitasvir and paritaprevir 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 and ritonavir are increased by 25 and 108%, 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

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

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;1 11% 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

Stability

Storage

Oral

Tablets

≤30º C.1

Actions and Spectrum

  • Ombitasvir/paritaprevir/ritonavir provides fixed combination containing 2 direct-acting antivirals (DAAs) with activity against HCV.1

  • Ombitasvir and paritaprevir have different mechanisms of action against HCV and non-overlapping resistance profiles.1 No in vitro evidence of antagonistic anti-HCV effects between ombitasvir and paritaprevir in HCV replicon studies.180

  • 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 Exact role of NS5A has not been fully elucidated,9 10 11 but is essential for viral replication and virion assembly.1 9 10 11 In vitro studies using cell-based replicon assays indicate that ombitasvir is active against HCV genotype 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a.1 9 10 11 Certain amino acid substitutions in NS5A of HCV genotype 4a (e.g., L28V) and genotype 4d (e.g., L28V, T58S) selected in cell culture and associated with reduced in vitro susceptibility to ombitasvir.1 3

  • Paritaprevir is an HCV NS3/4A protease inhibitor.1 Inhibits HCV NS3/4A protease, thereby blocking enzyme activity and formation of proteins essential for viral replication (i.e., NS3, NS4A, NS4B, NS5A, NS5B).1 Based on biochemical assays, paritaprevir active against HCV genotypes 4a;1 in vitro studies using cell-based replicon assays indicate that paritaprevir is active against genotypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, and 6a.1 Certain amino acid substitutions in NS3 of HCV genotype 4a (e.g., R155C, A156T/V, D168H/V) and genotype 4d (e.g., Y56H, D168V) have been selected in cell culture and have been associated with reduced in vitro susceptibility.1 In HCV genotype 4d replicons, combination of Y56H and D168V substitutions reduced paritaprevir activity relative to single Y56H or D168V substitutions.1 3

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

  • Impact of prior treatment with ombitasvir or paritaprevir on efficacy of other NS5A inhibitors or NS3/4A protease inhibitors not evaluated.1 Efficacy of ombitasvir/paritaprevir/ritonavir 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

  • Advise patients to take ombitasvir/paritaprevir/ritonavir once daily (in the morning) 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 the 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

  • 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 of liver inflammation (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 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.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

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Ombitasvir 12.5 mg, Paritaprevir 75 mg, and Ritonavir 50 mg

Technivie

AbbVie

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

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

2. Hézode C, Asselah T, Reddy KR et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet. 2015; 385:2502-9. [PubMed 25837829]

3. Schnell G, Tripathi R, Beyer J et al. Hepatitis C virus genotype 4 resistance and subtype demographic characterization of patients treated with ombitasvir plus paritaprevir/ritonavir. Antimicrob Agents Chemother. 2015; 59:6807-15. [PubMed 26282418]

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]

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 2016 Mar 1.

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

349. Merck Sharp & Dohme Corporation. Rebetol (ribavirin) capsules and oral solution prescribing information. Whitehouse Station, NJ; 2015 May.

377. Genentech. Copegus (ribavirin) tablets prescribing information. South San Francisco, CA; 2015 Aug.

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