ombitasvir/paritaprevir/ritonavir/dasabuvir

General

Genetic Implications: Genetic Implications

Pronunciation:
om-bit-as-vir/par-i-ta-pre-vir/ri-toe-na-vir/da-sa-bue-vir


Trade Name(s)

  • Holkira PakCanadian Tradename
  • Viekira Pak

Ther. Class.
antivirals

Pharm. Class.
NS5 inhibitors
protease inhibitors
enzyme inhibitors
non-nucleoside NS5B palm

Indications

Genetic implicationTreatment of (with or without ribavirin) genotype 1 chronic hepatitis C infection (HCV) including those with compensated cirrhosis.

Action

Ombitasvir–is an inhibitor of HCV NS5A which is necessary for RNA replication and virion assembly. Paritaprevir–is an inhibitor of NS3/4A protease an enzyme necessary for viral replication. Ritonavir is not active against HCV, but inhibits CYP3A resulting in ↑ blood levels and effectiveness of paritaprevir. Dasabuvir–inhibits RNA-dependent RNA polymerase necessary for viral genome replication.

Therapeutic Effect(s):

Decreased levels of HCV with sustained virologic response and lessened sequelae of chronic HCV infection.

Pharmacokinetics

Absorption: Well absorbed following oral administration: ombitasvir–48%, paritaprevir–53%, dasabuvir–70%.

Distribution: Ritonavir–poor CNS penetration.

Protein Binding: Ombitasvir–99.9%, paritaprevir–97–98.6%, ritonavir–>99%, dasabuvir–>99.5%.

Metabolism and Excretion: Ombitasvir–metabolized by amide hydrolysis and then oxidative metabolism, excreted mainly in feces mostly as unchanged drug, minimal urinary excretion; paritaprevir–primarily metabolized by CYP3A, 88% excreted in feces mostly as metabolites; negligible urinary excretion; ritonavir–highly metabolized by CYP3A and CYP2D6, 86% excreted in feces (mostly as metabolites), 11.8% excreted in urine, dasabuvir–mostly metabolized by CYP2C8 and smaller amounts by CYP3A, 95% excreted in feces (26% as unchanged drug), minimal urinary excretion.

Half-life: Ombitasvir–21–25 hr, paritaprevir–5.5 hr, ritonavir–4 hr, dasabuvir–5.5–6 hr.

TIME/ACTION PROFILE (blood levels)

ROUTEONSETPEAKDURATION
ombitasvir POunknown4–5 hr24 hr
paritaprevir POunknown4–5 hr24 hr
ritonavir POrapid4 hr24 hr
dasabuvir POunknown4–5 hr†12 hr
†Peak is 8 hr for dasabuvir in ER formulation.

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity to any components including previous history of Stevens-Johnson syndrome or toxic epidermal necrolysis from ritonavir;
  • Concurrent use of medications that are metabolized by CYP3A4, strong/moderate inducers of CYP3A4, or strong inducers/inhibitors of CYP2C8;
  • Moderate-to-severe hepatic impairment;
  • OB: When used with ribavirin should not be used in pregnant patients or male patients whose partners are pregnant.

Use Cautiously in:

  • Diabetes mellitus;
  • Hemophilia (↑ risk of bleeding);
  • Structural heart disease, conduction abnormalities, ischemic heart disease, or heart failure (↑ risk of heart block);
  • Concurrent HIV infection (additional HIV-suppressive regimen required);
  • Receiving immunosuppressant or chemotherapy medications (↑ risk of hepatitis B virus reactivation);
  • OB: If used without ribavirin consider maternal benefits and possible adverse effects on the fetus;
  • Lactation: Consider maternal benefits and possible adverse effects on infants; breast feeding not recommended in concurrently HIV-infected patients;
  • Rep: Women of reproductive potential;
  • Pedi: Safety and effectiveness not established.

Adverse Reactions/Side Effects

CNS: fatigue, insomnia (↑ with ribavirin), weakness (↑ with ribavirin)

GI: HEPATOTOXICITY, nausea (↑ with ribavirin), ↑ liver enzymes

Derm: ERYTHEMA MULTIFORME, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, pruritus, rash

Misc: hepatitis B virus reactivation

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  • ↑ levels and risk of serious adverse reactions with alfuzosin (hypotension); dihydroergotamine, ergotamine, or methylergonovine (ergot toxicity); dronedarone (arrhythmias); atorvastatin, lovastatin or simvastatin (myopathy/rhabdomyolysis); pimozide (arrhythmias); efavirenz (↑ liver enzymes); ranolazine (serious or life-threatening reactions); sildenafil (when used for pulmonary hypertension ↑ risk of visual disturbances/hypotension/priapism/syncope), triazolam (↑ sedation/respiratory depression); ethinyl estradiol containing preparations including oral hormonal contraceptives (↑ liver enzymes); colchicine (serious or life-threatening reactions in patients with renal or hepatic impairment); everolimus, sirolimus, or tacrolimus (serious or life-threatening immunosuppressant adverse reactions); lurasidone (serious or life-threatening reactions); and gemfibrozil (QT interval prolongation); concurrent use contraindicated.
  • Levels and antiviral effectiveness are ↓ by carbamazepine, phenobarbital, phenytoin, and rifampin; concurrent use contraindicated.
  • ↑ levels and risk of digoxin toxicity; ↓ digoxin dose by 30–50%, monitor carefully.
  • ↑ levels and risk of adverse cardiovascular reactions with amiodarone, disopyramide, flecainide, lidocaine, mexiletine, propafenone, and quinidine; careful monitoring recommended.
  • ↑ levels and risk of adverse reactions with ketoconazole (daily dose of ketoconazole should not exceed 200 mg).
  • ↓ levels and effectiveness of voriconazole; concurrent use is not recommended.
  • ↑ levels and risk of adverse reactions with quetiapine; ↓ quetiapine dose to ⅙th and monitor carefully, consider alternative anti-HCV treatments).
  • ↑ levels and risk of hypotension with amlodipine, nifedipine, diltiazem, and verapamil; ↓ dose of amlodipine by ≥50%.
  • ↑ levels and effects of furosemide; monitor and adjust dose.
  • Concurrent use with atazanavir, atazanavir/ritonavir, or lopinavir/ritonavir ↑ levels of paritaprevir; concurrent use is not recommended.
  • ↓ levels and may ↓ effectiveness of darunavir; darunavir (800 mg once daily) without ritonavir should be taken at the same time as ombitasvir/paritaprevir/ritonavir.
  • ↑ levels and risk of adverse cardiovascular reactions with rilpivirine; concurrent use is not recommended.
  • ↑ levels and risk of adverse muscular reactions with pravastatin; pravastatin dose should not exceed 40 mg/day.
  • ↑ levels and risk of adverse reactions with cyclosporine; ↓ cyclosporine dose to ⅕th, monitor and readjust carefully.
  • ↑ levels and risk of adverse cardiovascular reactions with salmeterol; Concurrent use is not recommended.
  • ↑ levels of buprenorphine; monitor for sedation/cognitive impairment.
  • ↑ levels of hydrocodone; ↓ hydrocodone dose by 50% and monitor for sedation and respiratory depression.
  • ↓ levels and effectiveness of omeprazole; ↑ dose of omeprazole if necessary, but should not exceed 40 mg/day.
  • ↑ levels and effects of alprazolam; monitor for sedation/cognitive impairment and adjust dose.
  • ↓ levels and effectiveness of diazepam; ↑ dose of diazepam, if necessary.
  • May ↑ levels of valsartan, losartan, and candesartan; ↓ dose of angiotensin II receptor blocker and monitor for hypotension and renal impairment.
  • ↑ risk of lactic acidosis with metformin; concomitant use in patients with renal or hepatic impairment not recommended.
  • May ↓ levels and effectiveness of carisoprodol or cyclobenzaprine; ↑ dose of carisoprodol or cyclobenzaprine, if necessary.
  • May cause fluctuations in INR when used with warfarin; closely monitor INR.

Drug-Natural Products:

Levels and antiviral effectiveness are ↓ by St. John's wort; concurrent use contraindicated.

Route/Dosage

Viekira Pak

PO (Adults) Genotype 1a without cirrhosis–Two tablets (each tablet containing ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg) once daily with dasabuvir 250 mg twice daily with ribavirin for 12 wk; Genotype 1a with compensated cirrhosis–Two tablets (each tablet containing ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg) once daily with dasabuvir 250 mg twice daily with ribavirin for 24 wk (some patients may respond to 12 wk); Genotype 1b with or without compensated cirrhosis–Two tablets (each tablet containing ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg) once daily with dasabuvir 250 mg twice daily for 12 wk; Liver transplant patients–Two tablets (each tablet containing ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg) once daily with dasabuvir 250 mg twice daily with ribavirin for 24 wk.

Availability

Tablets (Viekira Pak): ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg (copackaged with dasabuvir 250 mg in a 28–day convenience pak separated into weekly amounts)

Assessment

  • Monitor signs of hepatitis (jaundice, fatigue, anorexia, pruritus) during therapy.
  • Assess for rash periodically during therapy. May cause Stevens-Johnson syndrome or Toxic Epidermal Necrolysis. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.
  • Monitor for signs and symptoms of worsening liver disease (ascites, hepatic encephalopathy, variceal hemorrhage, increases in direct serum bilirubin).
  • Monitor for signs and symptoms of hepatitis B reactivation (jaundice, dark urine, light colored stools, fatigue, weakness, loss of appetite, nausea, vomiting, stomach pain) during therapy.

Lab Test Considerations:

Determine current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV therapy. In patients with HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation (rapid ↑ in serum HBV DNA level) during HCV therapy and during post-therapy follow-up.

  • For patients with compensated cirrhosis: Monitor liver function tests including direct bilirubin levels at baseline and during first 4 wk of therapy and as clinically indicated. Signs of hepatic decompensation usually include ↑ bilirubin without ↑ ALT, and ascites, hepatic encephalopathy, variceal hemorrhage. Discontinue therapy if signs of hepatic decompensation occur.
  • Monitor liver function tests prior to and during first 4 wks of therapy. If ALT is ↑, repeat test and monitor closely. Discontinue therapy if ALT levels are persistently ↑ >10 × upper limit of normal or if accompanied by signs of liver inflammation or ↑ direct bilirubin, alkaline phosphatase, or INR.
  • May cause ↑ serum bilirubin; peaks by wk 1 of therapy and not associated with ↑ ALT.
  • May cause ↓ hemoglobin requiring dose reduction.

Potential Diagnoses

Implementation

  • PO Administer 2 ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg tablets once daily (in the morning) and 1 dasabuvir 250 mg tablet twice daily (morning and evening) with a meal without regard to fat or calorie content. Usually given in combination with ribavirin.

Patient/Family Teaching

  • Instruct patient to take Viekira Pak as directed. Take missed doses of ombitasvir/paritaprevir/ritonavir within 12 hrs or of dasabuvir within 6 hrs; if more than 12 hrs or 6 hrs, respectively, since missed dose, skip dose and take next dose at scheduled time; do not double doses. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
  • Advise patient to notify health care professional promptly if signs and symptoms of liver dysfunction (fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, discolored feces) occur.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, or herbal products, especially St. John's wort. Medications containing ethinyl estradiol must be stopped; if taking for birth control, another method must be used.
  • Rep: Inform patient about teratogenic effects of Viekira Pak and ribavirin. Instruct women with childbearing potential, and men, to use 2 forms of effective non-hormonal contraception (ethinyl estradiol-containing medications including oral hormonal contraceptives are contraindicated due to ↑ risk of liver impairment; effective alternative contraception is recommended) during and for at least 2 mo following conclusion of therapy. Men must use a condom. Avoid breast feeding during use. Advise patient to notify health care professional if pregnancy occurs.

Evaluation/Desired Outcomes

Protection from liver damage caused by chronic hepatitis C infection; decreases viral load.

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