ombitasvir/paritaprevir/ritonavir (Discontinued)

Brand and Other Names:Technivie
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

May 24, 2018: Manufacturer announced this product if to be discontinued; it is estimated to be available until January 2019

tablet

  • 12.5mg/75mg/50mg

Chronic Hepatitis C

Indicated in combination with ribavirin for genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis

2 tablets PO qAM for 12 wk with a meal, without regard to fat or calorie content

Recommended to be used in combination with ribavirin, although may be considered for treatment-naïve patients without cirrhosis who cannot take or tolerate ribavirin

Dosage Modifications

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment required
  • Moderate or severe (Child-Pugh B, Child-Push C): Contraindicated

Renal impairment

  • CrCl >15 mL/min: No dosage adjustment necessary
  • End-stage renal disease: Not studied
  • For patients that require ribavirin, refer to the ribavirin prescribing information for information regarding use with renal impairment

Dosing Considerations

Prior to initiation, assess hepatic laboratory and clinical evidence of hepatic decompensation

Prior to initiation of ribavirin, assess for underlying cardiac disease

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

<18 years: Safety and efficacy not established

Chronic Hepatitis C (Orphan)

Orphan designation for treatment of pediatric patients with chronic HCV infection

Sponsor

  • AbbVie Inc; 1 North Waukegan Road; North Chicago, Illinois 60064
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Interactions

Interaction Checker

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            Adverse Effects

            >10%

            Asthenia (25%)

            1-10%

            Nausea (9%)

            Fatigue (7%)

            Insomnia (5%)

            Pruritus (5%)

            Skin reactions (5%)

            Elevated bilirubin, 2 x ULN (5%)

            Elevated ALT, 5 x ULN (1%)

            Postmarketing Reports

            Hypersensitivity reactions (including angioedema)

            Anaphylaxis

            Neutropenic sepsis

            Rhabdomyolysis

            Hepatotoxicity

            Cardiomyopathy

            Extravasation resulting in tissue necrosis

            Hepatic decompensation

            Hepatic failure

            Headache

            Change in mood

            Itching

            Trouble breathing

            Muscle or joint pain

            Dizziness

            Erythema multiforme

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            Warnings

            Black Box Warnings

            Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

            HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with DDAs and were not receiving HBV antiviral therapy

            Some cases have resulted in fulminant hepatitis, hepatic failure, and death

            Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up

            Initiate appropriate patient management for HBV infection as clinically indicated

            Contraindications

            If administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen; refer to the ribavirin prescribing information

            Moderate to severe hepatic impairment

            Patients with known hypersensitivity (eg, toxic epidermal necrolysis [TEN] or Stevens-Johnson syndrome) to ritonavir

            Coadministered drugs that are contraindicated

            • Drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events
            • Moderate to severe hepatic impairment
            • Drugs that are strong inducers of CYP3A and may lead to reduced efficacy of Technivie
            • Contraindicated drugs and potential toxicity explanation
              • Alpha1-adrenoreceptor antagonist (alfuzosin): Potential for hypotension
              • Anticonvulsants (carbamazepine, phenytoin, phenobarbital): Decreased exposure of ombitasvir, paritaprevir, and ritonavir leading to a potential loss of therapeutic activity
              • Antimycobacterial (rifampin): Decreased exposure of ombitasvir, paritaprevir, and ritonavir leading to a potential loss of therapeutic activity
              • Ergot derivatives (ergotamine, dihydroergotamine, ergonovine, methylergonovine): Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with coadministration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine
              • Ethinyl estradiol: Potential for increased ALT
              • St. John’s wort: Decreased exposure of ombitasvir, paritaprevir, and ritonavir leading to a potential loss of therapeutic activity
              • HMG-CoA reductase inhibitors (lovastatin, simvastatin): Increased risk of myopathy, including rhabdomyolysis
              • Neuroleptics (pimozide): Potential for cardiac arrhythmias
              • Lurasidone: Potential for serious and/or life-threatening reactions
              • Cisapride: Potential for serious and/or life threatening reactions such as cardiac arrhythmias
              • Ranolazine: Potential for serious and/or life-threatening Reactions
              • Dronedarone: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias
              • NNRTIs (efavirenz): Coadministration of efavirenz-based regimens with paritaprevir and ritonavir was poorly tolerated and resulted in liver enzyme elevations
              • PDE5 inhibitors (sildenafil [Revatio for treatment of PAH]): Increased potential for sildenafil-associated adverse events (eg, visual disturbances, hypotension, priapism, and syncope)
              • Sedatives/hypnotics (triazolam, oral midazolam): Extensively metabolized by CYP3A4; coadministration may cause large increases in the concentration of these benzodiazepine, possibly resulting in serious and/or life-threatening events (eg, prolonged or increased sedation or respiratory depression)

            Cautions

            Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DDAs, and who were not receiving HBV antiviral therapy; HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations)

            Not indicated in patients with decompensated cirrhosis

            Increased ALT to >5 x ULN occurred in ~1% of patients within the first 4 weeks of treatment; significantly more frequent in females taking ethinyl estradiol-containing medications (also see Contraindications); not indicated in patients with decompensated cirrhosis

            Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur; assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of therapy and at 2-to 3-month intervals thereafter until therapy is discontinued; withhold therapy for LVEF below lower limit of normal; permanently discontinue therapy for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks

            Extravasation, resulting in tissue necrosis requiring debridement, reported; evidence of tissue necrosis can occur more than 1 week after extravasation; there is no specific antidote for extravasation administer through a central venous line

            Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, reported mostly in patients with advanced cirrhosis; discontinue treatment in patients who develop evidence of hepatic decompensation

            If coadministered with ribavirin, the warnings and precautions for ribavirin, in particular the contraindication during pregnancy, apply to this combination regimen

            Patients with decompensated cirrhosis

            • Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage
            • Perform hepatic laboratory testing at baseline and during the first 4 weeks of starting treatment, including direct bilirubin levels, and as clinically indicated
            • Discontinue therapy in patients who develop evidence of hepatic decompensation

            Use in HCV/HIV-1 coinfection

            • The ritonavir component of Technivie is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions
            • Any HCV/HIV-1 coinfected patients treated with Technivie should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance

            Drug interaction overview

            • Concomitant use with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of Technivie and possible development of resistance, or clinically significant adverse reactions from greater exposures of concomitant drugs or components of drug formulation
            • Neutropenic sepsis, including fatal cases, reported; assess neutrophil count prior to administration of each dose and periodically throughout treatment cycle; withhold for neutrophil < 1500 cells/microliter on day of dosing; permanently reduce the for life-threatening or prolonged, severe neutropenia in preceding cycle
            • Also see Contraindications and the Drug Interaction Checker
            • Potential for Technivie to affect other drugs
              • Coadministration with drugs that are substrates of CYP3A, BCRP, OATP1B1, or OATP1B3 may result in increased plasma concentrations of such drugs (dose adjustment may be required)
              • CYP3A4 inhibitor: ritonavir
              • OATP1B1 and OATP1B3 inhibitor: paritaprevir
              • BCRP inhibitors: paritaprevir, ritonavir
            • Potential for other drugs to affect Technivie
              • Inhibition of CYP3A, P-gp, BCRP, OATP1B1, or OATP1B3 may increase the plasma concentrations of the various components of Technivie, although there is no dose adjustment for Technivie
              • Primarily metabolized by CYP3A enzymes: paritaprevir and ritonavir; coadministration with strong CYP3A inhibitors may increase paritaprevir and ritonavir concentrations
              • Metabolized via amide hydrolysis (CYP enzymes play a minor role): ombitasvir
              • Substrates of P-gp: ombitasvir, paritaprevir, and ritonavir
              • Substrates of BCRP: ombitasvir, paritaprevir
              • Substrates of OATP1B1 and OATP1B3: paritaprevir
            • Drugs without clinically significant interactions
              • No dose adjustments are recommended when coadministered with the following medications: duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, gemfibrozil, methadone, progestin-only contraceptives, raltegravir, rosuvastatin, warfarin, and zolpidem
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            Pregnancy

            Pregnancy

            If the drug combination is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant

            No adequate human data are available to establish whether or not the drug combination poses a risk to pregnancy outcomes; in animal reproduction studies, no adverse developmental effects were observed when each component of the drug combination was administered separately during organogenesis and lactation

            There is an Antiretroviral Pregnancy Registry that monitors pregnancy outcomes in women who are HCV/HIV-1 coinfected and taking concomitant antiretrovirals; physicians are encouraged to register patients by calling 1-800-258-4263

            Lactation

            It is not known whether the drug combination and its metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant

            If administered with ribavirin: Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue treatment

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Ombitasvir: Inhibits HCV NS5A protein, which is required for viral replication

            Paritaprevir: NS3/4A serine protease inhibitor; NS3/4A protease is needed for proteolytic cleavage of the HCV encoded polyprotein into mature forms

            Ritonavir: Protease inhibitor that is used as a "boosting agent" to increase paritaprevir serum levels

            Absorption

            Peak plasma time: 4-5 hr

            Steady-state achieved: ~12 days

            Absolute bioavailability (when administered with ritonavir): 48.1% (ombitasvir); 52.6% (paritaprevir)

            AUC

            • Ombitasvir: 1239 ng•hr/mL
            • Paritaprevir: 2276 ng•hr/mL
            • Ritonavir: 6072 ng•hr/mL

            Peak plasma concentration

            • Ombitasvir: 62 ng/mL
            • Paritaprevir: 194 ng/mL
            • Ritonavir: 543 ng/mL

            Distribution

            Protein bound

            • Ombitasvir: 99.9%
            • Paritaprevir: 98.6%
            • Ritonavir: >99%

            Vd

            • Ombitasvir: 173 L
            • Paritaprevir: 103 L
            • Ritonavir: 21.5 L

            Metabolism

            Ombitasvir: Predominantly metabolized by amide hydrolysis followed by oxidative metabolism

            Paritaprevir: Predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5

            Ritonavir: Predominantly metabolized by CYP3A, and to a lesser extent, by CYP2D6

            Elimination

            Half-life

            • Ombitasvir: 21-25 hr
            • Paritaprevir: 5.5 hr
            • Ritonavir: 4 hr

            Excretion

            • Ombitasvir: 90.2% feces; 1.91% urine
            • Paritaprevir: 88% feces; 8.8% urine
            • Ritonavir: 86.4% feces; 11.3% urine
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            Administration

            Instructions

            Take with a meal without regard to fat or calorie content

            Prior to initiation, assess baseline hepatic laboratory and clinical parameters

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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.