ombitasvir/paritaprevir/ritonavir and dasabuvir (Viekira Pak, Viekira XR)

Dosing and uses of Viekira Pak, Viekira XR (ombitasvir/paritaprevir/ritonavir and dasabuvir)

• Adult
• Pediatric

 

Adult dosage forms and strengths

Viekira Pak

• Contains ombitasvir, paritaprevir, and ritonavir as a fixed-dose combination tablet copackaged with a dasabuvir tablet
• ombitasvir/paritaprevir/ritonavir
  • coformulated tablet: 12.5mg/75mg/50mg
• dasabuvir
  • tablet: 250mg

Viekira Xr

• Coformulated tablet containing ombitasvir, paritaprevir, ritonavir and dasabuvir as a fixed-dose combination tablet
• Ombitasvir/paritaprevir/ritonavir/dasabuvir
  • coformulated tablet: 8.33mg/50mg/33.33mg/200mg

 

Chronic Hepatitis C

Indicated for chronic hepatitis C virus (HCV) genotype 1 infection, including patients with compensated cirrhosis; may be used for patients with HCV/HIV-1 coinfection

Viekira: 2 tablets (ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg) PO qDay, PLUS dasabuvir 250 PO BID with a meaL

Viekira XR: 3 tablets (~ombitasvir 25 mg, paritaprevir 150 mg, ~ritonavir 100 mg, dasabuvir 600 mg) PO qDay with a meaL

Used in combination with ribavirin in certain patient populations

Use with ribavirin, regimen by genotype, duration

• Used in combination with ribavirin in certain patient populations
• When administered with Viekira Pak or Viekira XR, ribavirin dose is based on weight: 1000 mg for patients ≤75 kg and 1200 mg/day for those >75 kg, divide daily dose BID and administered with food
• Treatment regimen and duration according to genotype
  • Genotype 1a, without cirrhosis: Viekira Pak or Viekira XR plus ribavirin for 12 weeks
  • Genotype 1a, with compensated cirrhosis (Child-Pugh A): Viekira Pak or Viekira XR plus ribavirin for 24 weeks*
  • Genotype 1b, with or without compensated cirrhosis: Viekira Pak or Viekira XR for 12 weeks
  • Note: Follow the genotype 1a dosing if genotype 1 subtype is unknown or with mixed genotype 1 infection
  • Use in liver transplant recipients: With normal hepatic function and mild fibrosis (Metavir fibrosis score ≤2), the recommended duration of Viekira Pak or Viekira XR with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype
  • *Viekira Pak or Viekira XR administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history

 

Dosage modifications

Hepatic impairment

• Mild (Child-Pugh A): No dosage adjustment required
• Moderate to severe hepatic impairment (Child-Pugh B and C): Contraindicated

Renal impairment

• Mild, moderate, or severe: No dosage adjustment required
• Dialysis: Not studied
• For patients who require ribavirin, refer to the ribavirin prescribing information for information regarding use with renal impairment

 

Dosing Considerations

Monitor liver function tests before initiating and during therapy

 

Pediatric dosage forms and strengths

<18 years: Safety and efficacy not established

 

Hepatitis C (Orphan)

Orphan designation for treatment of pediatric patients with hepatitis C virus infection (aged birth through 16 yr)

Sponsor

• Abbvie, Inc; 1 North Waukegan Road; North Chicago, IL 60064

 

Viekira Pak, Viekira XR (ombitasvir/paritaprevir/ritonavir and dasabuvir) adverse (side) effects

>10%

Data listed below are from 2 placebo-controlled trials (SAPHHIRE-I and –II); treatment included ribavirin

Fatigue (34%)

Nausea (22%)

Pruritus (18%)

Skin reactions (16%)

Insomnia (14%)

Asthenia (14%)

 

Postmarketing reports

Hypersensitivity reactions including angioedema

Hepatic decompensation

Hepatic failure

 

Warnings

Black box warnings

Direct-acting antivirals (DDAs) may reactivate hepatitis B virus (HBV) in patients who have a current or previous HBV infection while being treated for hepatitis C virus

In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death

Patients should be screened for evidence of current or prior HBV infection before starting treatment with DAAs, and monitored for HBV flare-ups or reactivation during DAA treatment and posttreatment follow-up

 

Contraindications

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

Severe hepatic impairment (Child-Pugh B and C) due to risk for toxicity

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 or strong inducers of CYP3A and strong inducers of CYP2C8 that may lead to reduced efficacy of therapy
• Drugs that are strong inhibitors of CYP2C8 and may increase dasabuvir plasma concentrations and the risk of QT prolongation
• Contraindicated drugs and potential toxicity
  • Alpha1-adrenoreceptor antagonist (alfuzosin): Potential for hypotension
  • Anticonvulsants (carbamazepine, phenytoin, phenobarbital): Decreased exposure of ombitasvir, paritaprevir, ritonavir, and dasabuvir, leading to a potential loss of therapeutic activity
  • Antihyperlipidemic (gemfibrozil): Increase in dasabuvir exposures by 10-fold, which may increase the risk of QT prolongation
  • Antimycobacterial (rifampin): Decreased exposure of ombitasvir, paritaprevir, ritonavir, and dasabuvir, 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
  • HMG-CoA reductase inhibitors (lovastatin, simvastatin): Increased risk of myopathy, including rhabdomyolysis
  • Neuroleptics (pimozide): Potential for cardiac arrhythmias
  • NNRTIs (efavirenz): Coadministration of efavirenz-based regimens with paritaprevir, ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme elevations
  • PDE5 inhibitors (sildenafil [Revatio for treatment of PAH]): There is 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 benzodiazepines, possibly leading to serious and/or life -hreatening events (eg, prolonged or increased sedation or respiratory depression)
  • Ranolazine and lurasidone: Potential for serious and/or life-threatening reactions
  • Dronedarone and cisapride: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias
  • Lurasidone: Potential for serious and/or life-threatening reactions

 

Cautions

Increased ALT to >5 xULN 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)

If ALT found to be elevated above baseline levels, repeat and monitor closely; instruct patients to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces; consider discontinuing therapy if ALT levels remain persistently greater than 10 times the ULN; discontinue therapy if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or INr

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 cirrhosis

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

Use in HCV/HIV-1 coinfection

• Viekira Pak with ribavirin was assessed in 63 subjects with HCV/HIV-1 coinfection who were on stable antiretroviral therapy
• The most common adverse events occurring in at least 10% of patients were fatigue (48%), insomnia (19%), nausea (17%), headache (16%), pruritus (13%), cough (11%), irritability (10%), and ocular icterus (10%)
• Elevations in total bilirubin greater than 2 x ULN (mostly indirect) occurred in 34 (54%) individuals

Use in Liver transplant recipients

• Safety assessed in 34 post-liver transplantation recipients with recurrent HCV infection
• Adverse events occurring in >20% of patients included fatigue (50%), headache (44%), cough (32%), diarrhea (26%), insomnia (26%), asthenia (24%), nausea (24%), muscle spasms (21%), and rash (21%)
• Ten patients (29%) had at least one post-baseline hemoglobin value of <10 g/dL

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 Viekira Pak and possible development of resistance, or clinically significant adverse reactions from greater exposures of concomitant drugs or components of Viekira Pak
• Also see Contraindications and the Drug Interaction Checker
• Potential for Viekira Pak to affect other drugs
  • Coadministration with drugs that are substrates of CYP3A, UGT1A1, BCRP, OATP1B1, or OATP1B3 may result in increased plasma concentrations of such drugs (dose adjustment may be required)
  • UGT1A1 inhibitors: ombitasvir, paritaprevir, and dasabuvir
  • CYP3A4 inhibitor: ritonavir
  • OATP1B1 and OATP1B3 inhibitor: paritaprevir
  • BCRP inhibitors: paritaprevir, ritonavir, and dasabuvir
• Potential for other drugs to affect Viekira Pak
  • Inhibition of CYP3A, CYP2C8, P-gp, BCRP, OATP1B1, or OATP1B3 may increase the plasma concentrations of the various components of Viekira Pak, although there is no dose adjustment for Viekira Pak
  • Primarily metabolized by CYP3A enzymes: paritaprevir and ritonavir; coadministration with strong CYP3A inhibitors may increase paritaprevir and ritonavir concentrations
  • Primarily metabolized by CYP2C8: dasabuvir; coadministration with strong CYP2C8 inhibitors may increase dasabuvir concentrations
  • Metabolized via amide hydrolysis (CYP enzymes play a minor role): ombitasvir
  • Substrates of P-gp: ombitasvir, paritaprevir, dasabuvir, and ritonavir
  • Substrates of BCRP: ombitasvir, paritaprevir, and dasabuvir
  • Substrates of OATP1B1 and OATP1B3: paritaprevir
• Drugs without clinically significant interactions
  • No dose adjustments are recommended when Viekira Pak is coadministered with the following medications: digoxin, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, methadone, progestin-only contraceptives, raltegravir, warfarin, and zolpidem

 

Pregnancy and lactation

Pregnancy category: B; however, contraindicated if administered with ribavirin in pregnant women and men whose partners are pregnant

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: Unknown if distributed in human breast milk

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.

 

Pharmacology of Viekira Pak, Viekira XR (ombitasvir/paritaprevir/ritonavir and dasabuvir)

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

Dasabuvir: Nonnucleoside NS5B RNA-dependent polymerase inhibitor; its inhibition, in turn, suppresses viral replication

 

Absorption

Peak plasma time: 4-5 hr

Steady-state achieved: ~12 days

Bioavailability: 70% (dasabuvir)

AUC

• Ombitasvir: 1000 ng•hr/mL
• Paritaprevir: 2220 ng•hr/mL
• Ritonavir: 6180 ng•hr/mL
• Dasabuvir: 3240 ng•hr/mL

Peak plasma concentration

• Ombitasvir: 68 ng/mL
• Paritaprevir: 262 ng/mL
• Ritonavir: 682 ng/mL
• Dasabuvir: 667 ng/mL

 

Distribution

Protein bound

• Ombitasvir: 99.9%
• Paritaprevir: 98.6%
• Ritonavir: 99%
• Dasabuvir: >99.5%

Vd

• Ombitasvir: 50.1 L
• Paritaprevir: 16.7 L
• Ritonavir: 21.5 L
• Dasabuvir: 396 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

Dasabuvir: Predominantly metabolized by CYP2C8 and to a lesser extent by CYP3A

 

Elimination

Half-life

• Ombitasvir: 21-25 hr
• Paritaprevir: 5.5 hr
• Ritonavir: 4 hr
• Dasabuvir: 5.5-6 hr

Excretion

• Ombitasvir: 90.2% feces; 1.91% urine
• Paritaprevir: 88% feces; 8.8% urine
• Ritonavir: 86.4% feces; 11.3% urine
• Dasabuvir: 94.4% feces; 2% urine

 

Administration

Oral Administration

Viekira Pak or Viekira XR: Take with a meal without regard to fat or calorie content; if administered under fasting conditions, may result in reduced virologic response and possible development of resistance

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

Viekira Xr

• Swallow tablets whole; splitting, crushing, or chewing tablets may compromise the extended-release performance, efficacy, and/or safety
• For optimal release of dasabuvir, alcohol should not be consumed within 4 hr of taking Viekira XR