ombitasvir/paritaprevir/ritonavir (Technivie)

Dosing and uses of Technivie (ombitasvir/paritaprevir/ritonavir)

• Adult
• Pediatric

 

Adult dosage forms and strengths

ombitasvir/paritaprevir/ritonavir

tablet

• 12.5mg/75mg/50mg

 

Chronic Hepatitis C

Indicated in combination with ribavirin for genotype 4 chronic hepatitis C virus (HCV) infection without 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 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
• DEnd-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

Monitor liver function tests before initiating and during therapy

 

Pediatric dosage forms and strengths

<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

 

Technivie (ombitasvir/paritaprevir/ritonavir) adverse (side) 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

 

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

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

Not indicated in patients with 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 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

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

 

Pregnancy

Pregnancy

Pregnancy category: B; however, contraindicated if administered with ribavirin in pregnant women and in 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 Technivie (ombitasvir/paritaprevir/ritonavir)

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

 

Administration

Instructions

Take with a meal without regard to fat or calorie content

Prior to initiation, assess baseline hepatic laboratory and clinical parameters