Ombitasvir, paritaprevir, and ritonavir

Ombitasvir, paritaprevir, and ritonavir
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Allison Tu [2]

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Black Box Warning

RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete Boxed Warning. Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with ombitasvir, paritaprevir, and ritonavir. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals 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.

Overview

Ombitasvir, paritaprevir, and ritonavir is a combination of a hepatitis C virus NS5A inhibitor, a hepatitis C virus NS3/4A protease inhibitor, and a CYP3A inhibitor that is FDA approved for the treatment of genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis in combination with ribavirin. There is a Black Box Warning for this drug as shown here. Common adverse reactions include flushing, paresthesia, fatigue, dizziness, skin rash, pruritus, hypercholesterolemia, increased serum triglycerides, diarrhea, nausea, vomiting, abdominal pain, dysgeusia, dyspepsia, increased gamma-glutamyl transferase, musculoskeletal pain, weakness, increased creatine phosphokinase, cough, and oropharyngeal pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Ombitasvir, paritaprevir, and ritonavir is indicated in combination with ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis.

Dosing Information

• Ombitasvir, paritaprevir, and ritonavir is provided in fixed dose combination tablets.
• The recommended dosage of ombitasvir, paritaprevir, and ritonavir is two tablets taken orally once daily (in the morning). Take ombitasvir, paritaprevir, and ritonavir with a meal without regard to fat or calorie content.
• Ombitasvir, paritaprevir, and ritonavir is used in combination with ribavirin (RBV). When administered with ombitasvir, paritaprevir, and ritonavir, the recommended dosage of RBV is based on weight: 1000 mg per day for subjects less than 75 kg and 1200 mg per day for those weighing at least 75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information.

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Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ombitasvir, paritaprevir, and ritonavir in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ombitasvir, paritaprevir, and ritonavir in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Ombitasvir, paritaprevir, and ritonavir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ombitasvir, paritaprevir, and ritonavir in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ombitasvir, paritaprevir, and ritonavir in pediatric patients.

Contraindications

The contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin.

Ombitasvir, paritaprevir, and ritonavir is contraindicated:

• In patients with moderate to severe hepatic impairment (Child-Pugh B and C) due to risk of potential toxicity.
• With drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.
• With drugs that are moderate or strong inducers of CYP3A and may lead to reduced efficacy of ombitasvir, paritaprevir, and ritonavir.
• In patients with known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome).
• TABLE 2 lists drugs that are contraindicated with ombitasvir, paritaprevir, and ritonavir.

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Warnings

RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete Boxed Warning. Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with ombitasvir, paritaprevir, and ritonavir. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals 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.

• Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
  • Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
  • HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
  • Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with ombitasvir, paritaprevir, and ritonavir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with ombitasvir, paritaprevir, and ritonavir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
• Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
  • Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported in clinical trials and postmarketing in patients treated with ombitasvir, paritaprevir, ritonavir with and without ribavirin. Most patients with these severe outcomes had evidence of cirrhosis prior to initiating therapy. Reported cases typically occurred within one to four weeks of initiating therapy and were characterized by the acute onset of rising direct serum bilirubin levels without ALT elevations in association with clinical signs and symptoms of hepatic decompensation.
  • Ombitasvir, paritaprevir, and ritonavir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C)
  • For patients with compensated cirrhosis:
    • Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage).
    • Hepatic laboratory testing including direct bilirubin levels should be performed at baseline and during the first 4 weeks of starting treatment and as clinically indicated.
    • Discontinue ombitasvir, paritaprevir, and ritonavir in patients who develop evidence of hepatic decompensation.
• Increased Risk of ALT Elevations
  • During clinical trials with ombitasvir, paritaprevir and ritonavir with or without dasabuvir and with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of subjects.
  • ALT elevations were typically asymptomatic, occurred during the first 4 weeks of treatment, and declined within two to eight weeks of onset with continued dosing.
  • These ALT elevations were significantly more frequent in female subjects who were using ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with ombitasvir, paritaprevir, and ritonavir.
  • Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended during ombitasvir, paritaprevir, and ritonavir therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with ombitasvir, paritaprevir, and ritonavir.
  • Women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens. Due to the limited number of subjects taking these other estrogens in clinical studies, caution is warranted for co-administration with ombitasvir, paritaprevir, and ritonavir.
  • Hepatic laboratory testing should be performed during the first 4 weeks of starting treatment and as clinically indicated thereafter. If ALT is found to be elevated above baseline levels, it should be repeated and monitored closely:
    • Patients should be instructed 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 ombitasvir, paritaprevir, and ritonavir if ALT levels remain persistently greater than 10 times the ULN.
    • Discontinue ombitasvir, paritaprevir, and ritonavir if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or INR.
• Risks Associated With Ribavirin Combination Treatment
  • The warnings and precautions for ribavirin, in particular the pregnancy avoidance warning and use in patients with cardiac disease, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin.
• Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
  • The concomitant use of ombitasvir, paritaprevir, and ritonavir and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:
    • Loss of therapeutic effect of ombitasvir, paritaprevir, and ritonavir and possible development of resistance
    • Possible clinically significant adverse reactions from greater exposures of concomitant drugs or components of ombitasvir, paritaprevir, and ritonavir.
  • See TABLE 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations.
  • Consider the potential for drug interactions prior to and during ombitasvir, paritaprevir, and ritonavir therapy; review concomitant medications during ombitasvir, paritaprevir, and ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs.
• Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients
  • The ritonavir component of ombitasvir, paritaprevir, and ritonavir is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with ombitasvir, paritaprevir, and ritonavir should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.

Adverse Reactions

Clinical Trials Experience

Ombitasvir, paritaprevir, and ritonavir should be administered with ribavirin (RBV). Refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of ombitasvir, paritaprevir and ritonavir cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reaction in Subjects without Cirrhosis:

The safety assessment of ombitasvir, paritaprevir, and ritonavir is based on data from two clinical studies in subjects with HCV genotype 4 infection. PEARL-I was a study including 135 subjects without cirrhosis, 91 who received ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily with ribavirin for 12 weeks and 44 subjects who received ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily without ribavirin for 12 weeks.

Adverse reactions that occurred in subjects without cirrhosis treated with ombitasvir, paritaprevir and ritonavir with or without ribavirin for 12 weeks are listed in TABLE 3. The majority of adverse reactions in non-cirrhotic subjects were mild in severity, none were serious and none led to discontinuation of treatment.

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Adverse Events in Subjects with Compensated Cirrhosis:

AGATE-I was a study including 120 subjects with compensated cirrhosis who received ombitasvir, paritaprevir, and ritonavir once daily with ribavirin for a total of 12 weeks (n=60) or 16 weeks (n=60). Adverse events occurring up to and including 12 weeks of treatment (≤ 84 days) from both arms were included in the analysis of adverse events and are listed in TABLE 4.

Seven of 120 subjects (6%) experienced serious adverse events at or before 12 weeks of treatment. No adverse events led to the discontinuation of ombitasvir, paritaprevir, and ritonavir. Thirty-one subjects (26%) underwent ribavirin dose reductions; five discontinued ribavirin, three received transfusion and one received erythropoietin.

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Laboratory Abnormalities:

Serum ALT Elevations: None of the 135 subjects without cirrhosis and two (2%) of the 120 subjects with compensated cirrhosis treated with ombitasvir, paritaprevir, and ritonavir experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) and ≥2 times baseline after starting treatment.

Serum Bilirubin Elevations in Patients without Cirrhosis: Post-baseline elevations in bilirubin at least 2 times ULN were observed in 5% (7/134) of subjects without cirrhosis, receiving ombitasvir, paritaprevir, and ritonavir, all of whom were also receiving RBV. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and possibly ribavirin-induced hemolysis. Bilirubin elevations occurred early after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were generally not associated with serum ALT elevations.

Serum Bilirubin Elevations/Hepatic Decompensation in Patients with Compensated Cirrhosis: Among the 120 subjects with compensated cirrhosis, mean total bilirubin and mean indirect bilirubin levels increased to approximately 3 fold from baseline on treatment. Mean direct bilirubin levels increased to approximately 2 fold on treatment. Mean bilirubin elevations occurred early, peaked by Week 1, remained elevated on treatment and normalized by post treatment week 4. Bilirubin elevations were generally not associated with serum ALT elevations.

Over 40% (50/120) of subjects across both arms experienced elevated direct bilirubin levels (>ULN) at or before 12 weeks of treatment. Twelve percent (6/50) of these subjects experienced clinical bilirubin or liver related events including jaundice, ocular icterus and portal vein thrombosis.

One subject who did not have direct bilirubin elevations also experienced liver related adverse events of esophageal varices and ascites.

Anemia/Decreased Hemoglobin in Patients without Cirrhosis: The mean change from baseline in hemoglobin levels in subjects without cirrhosis treated with ombitasvir, paritaprevir, and ritonavir in combination with ribavirin was -2.1 g/dL and the mean change in subjects treated with ombitasvir, paritaprevir, and ritonavir alone was -0.4 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4. One subject treated with ombitasvir, paritaprevir, and ritonavir with ribavirin had a single hemoglobin level decrease to less than 8 g/dL during treatment. No subject treated with ombitasvir, paritaprevir, and ritonavir alone had hemoglobin levels less than 8 g/dL. Four percent (4/91) of subjects without cirrhosis treated with ombitasvir, paritaprevir, and ritonavir with ribavirin underwent ribavirin dose reductions to manage anemia/decreased hemoglobin levels. No subject received erythropoietin.

Anemia/Decreased Hemoglobin in Patients with Compensated Cirrhosis: Across both treatment arms, 4/120 cirrhotic subjects (3%) had anemia (hemoglobin less than LLN) prior to initiation of treatment. However, 88/120 (73%) had anemia (hemoglobin less than LLN) and/or a hemoglobin decrease of ≥ 2g/dl at or before 12 weeks of treatment. One subject (1%) had a single hemoglobin value less than 8.0 g/dL on treatment at or before 12 weeks of treatment. Reductions in hemoglobin are most likely primarily related to ribavirin in this population.

Of 64 subjects with a history of cardiovascular disease or diabetes mellitus, 9 (14%) experienced cardiac adverse events at or before 12 weeks of treatment. These 9 subjects had a mean hemoglobin decrease of 3.9 g/dL (range 1.1 to 5.3 g/dL) from baseline and experienced cardiac events including acute coronary syndrome, angina pectoris, chest pain, atrial fibrillation, palpitations, hypotension and hypertension. Among 56 subjects without a prior history of cardiovascular disease or diabetes, 2 (4%) experienced a cardiac event (mild or moderate hypertension).

Postmarketing Experience

The following adverse reactions have been identified during post approval use of ombitasvir, paritaprevir, and ritonavir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Immune System Disorders: Hypersensitivity reactions (including angioedema).
• Hepatobiliary Disorders: Hepatic decompensation, hepatic failure

Drug Interactions

• Potential for Ombitasvir, Paritaprevir, and Ritonavir to Affect Other Drugs
  • Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir and ritonavir are inhibitors of BCRP and P-gp. Ritonavir is an inhibitor of CYP3A4. Co-administration of ombitasvir, paritaprevir, and ritonavir with drugs that are substrates of CYP3A, P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs.
• Potential for Other Drugs to Affect Ombitasvir, Paritaprevir, or Ritonavir
  • Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of ombitasvir, paritaprevir, and ritonavir with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir and ritonavir are substrates of P-gp. Paritaprevir is a substrate of BCRP, OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of ombitasvir, paritaprevir, and ritonavir.
• Established and Other Potential Drug Interactions
  • If dosage adjustments of concomitant medications are made due to treatment with ombitasvir, paritaprevir, and ritonavir, dosages should be re-adjusted after administration of ombitasvir, paritaprevir, and ritonavir is completed. Dosage adjustment is not required for ombitasvir, paritaprevir, and ritonavir.

TABLE 5 provides the effect of co-administration of ombitasvir, paritaprevir, and ritonavir on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of ombitasvir, paritaprevir, and ritonavir. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir.

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Drugs without Clinically Significant Interactions with Ombitasvir, Paritaprevir, and Ritonavir: No dosage adjustments are recommended when ombitasvir, paritaprevir, and ritonavir is co-administered with the following medications: abacavir, dolutegravir, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, gemfibrozil, lamivudine, methadone, progestin only contraceptives, raltegravir, sofosbuvir, sulfamethoxazole, trimethoprim, rosuvastatin, warfarin and zolpidem.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Risk Summary
  • If ombitasvir, paritaprevir, and ritonavir is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy.
  • No adequate human data are available to establish whether or not ombitasvir, paritaprevir, and ritonavir poses a risk to pregnancy outcomes.
  • In animal reproduction studies, no adverse developmental effects were observed when the components of ombitasvir, paritaprevir, and ritonavir were administered separately during organogenesis and lactation. During organogenesis, the exposures were up to 29 and 4 times (mice and rabbits, respectively; ombitasvir), 12 and 143 times (mice and rats, respectively; paritaprevir, ritonavir) exposures at the recommended clinical dose of ombitasvir, paritaprevir, and ritonavir.
  • In rodent pre/postnatal developmental studies, maternal systemic exposures (AUC) to ombitasvir and paritaprevir were approximately 26 and 24 times, respectively, the exposure in humans at the recommended clinical dose.
  • The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
• Data
  • Animal data
    • Ombitasvir
      • Ombitasvir was administered orally to pregnant mice (0, 15, 50, or 150 mg/kg/day) and rabbits (0, 10 or 60 mg/kg/day) during the period of organogenesis (on gestation days (GD) 6 to 15, and GD 7 to 19, respectively). There were no ombitasvir-related maternal or embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The systemic exposures at the highest doses were 29-times higher (mice) and 4-times higher (rabbits) than the exposures in humans at the recommended clinical dose.
      • In a pre- and postnatal developmental study in mice, ombitasvir was administered orally at 0, 10, 40, or 200 mg/kg/day from GD 6 to lactation day 20. There were no ombitasvir-related effects at maternal exposures 26-times higher than exposures in humans at the recommended clinical dose.
      • The major human metabolites of ombitasvir, M29 and M36, were tested in pregnant mice during the period of organogenesis from GD 6 to 15. M29 was administered orally at doses of 0, 1, 2.5 or 4.5 mg/kg/day. M36 was dosed orally at doses 1.5, 3, or 6 mg/kg/day. In both cases, there were no treatment related maternal effects or embryofetal effects (malformations or fetal toxicity) at any dose level. The highest doses produced exposures approximately 26-times higher than the exposures in humans at the recommended clinical dose.
    • Paritaprevir/ritonavir
      • Paritaprevir/ritonavir was administered orally to pregnant rats (0/0, 30/15, 100/15, 450/45 mg/kg/day) and mice (0/0, 30/30, 100/30, or 300/30 mg/kg/day) during the period of organogenesis (on GD 6 to 17, and GD 6 to 15, respectively). There were no test article-related maternal or embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The highest systemic exposure of paritaprevir was 12-times higher (rats) and 143-times higher (mice) than the exposures in humans at the recommended clinical dose.
      • In a pre- and postnatal developmental study in rats, paritaprevir/ritonavir were administered orally at 0/0, 6/30, 30/30, or 300/30 mg/kg/day from GD 7 to lactation day 20. There were no treatment related effects at maternal exposures 24-times higher than exposures in humans at the recommended clinical dose.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ombitasvir, paritaprevir, and ritonavir in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Ombitasvir, paritaprevir, and ritonavir during labor and delivery.

Nursing Mothers

• It is not known whether ombitasvir, paritaprevir, and ritonavir and its metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. Unchanged ombitasvir, paritaprevir and its hydrolysis product M13 were the predominant components observed in the milk of lactating rats, without effect on nursing pups.
• The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ombitasvir, paritaprevir, and ritonavir and any potential adverse effects on the breastfed child from ombitasvir, paritaprevir, and ritonavir or from the underlying maternal condition.
• If ombitasvir, paritaprevir, and ritonavir is administered with ribavirin, the nursing mother’s information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation.
• Data
  • Animal data
    • Ombitasvir
      • No effects of ombitasvir on growth and postnatal development were observed in nursing pups at the highest dose tested, 200 mg/kg/day.
      • Maternal systemic exposure (AUC) to ombitasvir was approximately 26 times the exposure in humans at the recommended clinical dose. Although not measured directly, ombitasvir was likely present in the milk of lactating mice in this study, since systemic exposure was observed in nursing pups on post-natal day 21 (approximately 3-16 % of the maternal exposure).
      • When administered to lactating rats 10 to 11 days after parturition at a dose of 5 mg/kg, the 24 hr AUC in milk was 4 times higher than in plasma and the majority of the radioactivity in the milk was unchanged parent drug (91%).
    • Paritaprevir/ritonavir
      • No effects of paritaprevir/ritonavir on growth and postnatal development were observed in nursing pups at the highest dose tested 300/30 mg/kg/day paritaprevir/ritonavir.
      • Maternal systemic exposure (AUC) to paritaprevir was approximately 24 times the exposure in humans at the recommended clinical dose. Although not measured directly, paritaprevir was likely present in the milk of lactating rats at the high dose in this study, since systemic exposure was observed in nursing pups on post-natal day 15 (approximately 0.3% of the maternal exposure).
      • When administered to lactating rats 10 to 11 days after parturition at a dose of 30/15 mg/kg paritaprevir/ritonavir, the 24 hr AUC in milk was half that in plasma and the majority of the radioactivity in the milk was the hydrolysis product M13 (84%) followed by unchanged parent drug (16%).

Pediatric Use

Safety and effectiveness of ombitasvir, paritaprevir, and ritonavir in pediatric patients less than 18 years of age have not been established.

Geriatic Use

No dosage adjustment of ombitasvir, paritaprevir, and ritonavir is warranted in geriatric patients. Clinical studies PEARL-I and AGATE-1 did not include sufficient numbers of patients older than 65 years of age to assess safety or efficacy, or to determine if they responded differently than younger patients.

Gender

There is no FDA guidance on the use of Ombitasvir, paritaprevir, and ritonavir with respect to specific gender populations.

Race

There is no FDA guidance on the use of Ombitasvir, paritaprevir, and ritonavir with respect to specific racial populations.

Renal Impairment

No dosage adjustment of ombitasvir, paritaprevir, and ritonavir is required in patients with mild, moderate or severe renal impairment. Ombitasvir, paritaprevir, and ritonavir has not been studied in patients on dialysis. For patients that require ribavirin, refer to the ribavirin prescribing information for information regarding use in patients with renal impairment.

Hepatic Impairment

No dosage adjustment of ombitasvir, paritaprevir, and ritonavir is required in patients with mild hepatic impairment (Child-Pugh A). Ombitasvir, paritaprevir, and ritonavir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C).

Females of Reproductive Potential and Males

If ombitasvir, paritaprevir, and ritonavir is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

Immunocompromised Patients

There is no FDA guidance one the use of Ombitasvir, paritaprevir, and ritonavir in patients who are immunocompromised.

Administration and Monitoring

Administration

Testing Prior to the Initiation of Therapy

• Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with ombitasvir, paritaprevir, and ritonavir.
• Prior to initiation of ombitasvir, paritaprevir, and ritonavir, assess hepatic laboratory and clinical evidence of hepatic decompensation. Prior to initiation of ribavirin, assess for underlying cardiac disease and refer to the ribavirin prescribing information.
• Ombitasvir, paritaprevir, and ritonavir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C)

Monitoring

There is limited information regarding Ombitasvir, paritaprevir, and ritonavir Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Ombitasvir, paritaprevir, and ritonavir and IV administrations.

Overdosage

In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

Pharmacology

Mechanism of Action

Ombitasvir, paritaprevir, and ritonavir combines two direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action.

Ritonavir is not active against HCV. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e., area under the curve).

Structure

Ombitasvir, paritaprevir, and ritonavir is a fixed-dose combination tablet containing ombitasvir, paritaprevir, and ritonavir for oral administration.

Ombitasvir, paritaprevir, ritonavir fixed dose combination tablet includes a hepatitis C virus NS5A inhibitor (ombitasvir), a hepatitis C virus NS3/4A protease inhibitor (paritaprevir), and a CYP3A inhibitor (ritonavir) that inhibits CYP3A mediated metabolism of paritaprevir, thereby providing increased plasma concentration of paritaprevir.

Ombitasvir: The chemical name of ombitasvir is Dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate hydrate. The molecular formula is C50H67N7O8•4.5H2O (hydrate) and the molecular weight for the drug substance is 975.20 (hydrate). The drug substance is white to light yellow to light pink powder, and is practically insoluble in aqueous buffers but is soluble in ethanol. Ombitasvir has the following molecular structure:

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Paritaprevir: The chemical name of paritaprevir is (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4] diazacyclopentadecine-14a(5H)-carboxamide dihydrate. The molecular formula is C40H43N7O7S•2H2O (dihydrate) and the molecular weight for the drug substance is 801.91 (dihydrate). The drug substance is white to off-white powder with very low water solubility. Paritaprevir has the following molecular structure:

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Ritonavir: The chemical name of ritonavir is [5S-(5R*,8R*,10R*,11R*)]10-Hydroxy-2-methyl-5-(1-methyethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid,5-thiazolylmethyl ester. The molecular formula is C37H48N6O5S2 and the molecular weight for the drug substance is 720.95. The drug substance is white to off white to light tan powder practically insoluble in water and freely soluble in methanol and ethanol. Ritonavir has the following molecular structure:

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Pharmacodynamics

Cardiac Electrophysiology

The effect of a combination of ombitasvir, paritaprevir and ritonavir plus dasabuvir on QTc interval was evaluated in a randomized, double blind, placebo and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 60 healthy subjects. At concentrations approximately 6 and 1.8 times the therapeutic concentrations of paritaprevir and ombitasvir, the combination did not prolong QTc to any clinically relevant extent.

Pharmacokinetics

The pharmacokinetic properties of the components of ombitasvir, paritaprevir, and ritonavir are provided in TABLE 6. Based on the population pharmacokinetic analysis, the median steady-state pharmacokinetic parameters of ombitasvir, paritaprevir, and ritonavir in HCV-infected subjects are provided in TABLE 7.

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Specific Populations

Hepatic Impairment:

The single dose pharmacokinetics of ombitasvir, paritaprevir, ritonavir and another antiviral drug were evaluated in non-HCV infected subjects with mild hepatic impairment (Child-Pugh A; score of 5-6), moderate hepatic impairment (Child-Pugh B, score of 7-9) and severe hepatic impairment (Child-Pugh C, score of 10-15).

Relative to subjects with normal hepatic function, ombitasvir, paritaprevir and ritonavir mean AUC values decreased by 8%, 29% and 34%, respectively, in subjects with mild hepatic impairment.

Relative to subjects with normal hepatic function, ombitasvir and ritonavir mean AUC values decreased by 30% and 30%, respectively and paritaprevir mean AUC values increased by 62% in subjects with moderate hepatic impairment.

Relative to subjects with normal hepatic function, paritaprevir and ritonavir mean AUC values increased by 945% and 13% respectively and ombitasvir mean AUC values decreased by 54% in subjects with severe hepatic impairment.

Renal Impairment:

The single dose pharmacokinetics of ombitasvir, paritaprevir and ritonavir were evaluated in non-HCV infected subjects with mild (CLcr: 60 to 89 mL/min), moderate (CLcr: 30 to 59 mL/min), and severe (CLcr: 15 to 29 mL/min) renal impairment.

Overall, changes in exposure of ombitasvir, paritaprevir, and ritonavir in non-HCV infected subjects with mild-, moderate- and severe renal impairment are not expected to be clinically relevant. Pharmacokinetic data are not available on the use of ombitasvir, paritaprevir, and ritonavir in non-HCV infected subjects with End Stage Renal Disease (ESRD).

Relative to subjects with normal renal function, ritonavir AUC values increased by 40%, while ombitasvir and paritaprevir AUC values were unchanged in subjects with mild renal impairment.

Relative to subjects with normal renal function, ritonavir AUC values increased by 76%, while ombitasvir and paritaprevir AUC values were unchanged in subjects with moderate renal impairment.

Relative to subjects with normal renal function, paritaprevir and ritonavir AUC values increased by 25% and 108%, respectively, while ombitasvir AUC values were unchanged in subjects with severe renal impairment.

Pediatric Population:

The pharmacokinetics of ombitasvir, paritaprevir, and ritonavir in pediatric patients less than 18 years of age has not been established.

Sex:

No dosage adjustment is recommended based on sex or body weight.

Race/Ethnicity:

No dosage adjustment is recommended based on race or ethnicity.

Age:

No dosage adjustment is recommended in geriatric patients.

Drug Interactions

The effects of drugs discussed in TABLE 5 on the exposures of the individual components of ombitasvir, paritaprevir, and ritonavir are shown in TABLE 8.

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TABLE 9 summarizes the effects of ombitasvir, paritaprevir, and ritonavir on the pharmacokinetics of co-administered drugs which showed clinically relevant changes.

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Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis:

• Ombitasvir
  • Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (150 mg per kg per day). Similarly, ombitasvir was not carcinogenic in a 2-year rat study up to the highest dose tested (30 mg per kg per day), resulting in ombitasvir exposures approximately 16-fold higher than those in humans at 25 mg.
  • Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
• Paritaprevir, ritonavir:
  • Paritaprevir, ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (300/30 mg per kg per day). Similarly, paritaprevir, ritonavir was not carcinogenic in a 2-year rat study up to the highest dose tested (300/30 mg per kg per day), resulting in paritaprevir exposures approximately 11-fold higher than those in humans at 150 mg.
  • Paritaprevir was positive in an in vitro chromosome aberration test using human lymphocytes. Paritaprevir was negative in a bacterial mutation assay, and in two in vivo genetic toxicology assays (rat bone marrow micronucleus and rat liver Comet tests).
  • Ombitasvir, paritaprevir, and ritonavir is administered with ribavirin. Refer to the prescribing information for ribavirin for information on carcinogenesis and mutagenesis.

Impairment of Fertility:

• Ombitasvir
  • Ombitasvir had no effects on embryo-fetal viability or on fertility when evaluated in mice up to the highest dose of 200 mg per kg per day. Ombitasvir exposures at this dose were approximately 26-fold the exposure in humans at the recommended clinical dose.
• Paritaprevir, ritonavir
  • Paritaprevir, ritonavir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dose of 300/30 mg per kg per day. Paritaprevir exposures at this dose were approximately 3- to 8-fold the exposure in humans at the recommended clinical dose.
  • Ombitasvir, paritaprevir, and ritonavir is administered with ribavirin. Refer to the prescribing information for ribavirin for information on Impairment of Fertility.

Clinical Studies

Description of Clinical Trials

The efficacy and safety of ombitasvir, paritaprevir, and ritonavir was evaluated in two clinical trials in subjects with genotype 4 (GT4) chronic hepatitis virus (HCV) infection. In both trials, ombitasvir, paritaprevir, and ritonavir was administered with food and weight based ribavirin (1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg).The primary endpoint in both trials was sustained virologic response defined as HCV RNA below the lower limit of quantification (<LLOQ) 12 weeks after the end of treatment (SVR12) using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System, which has an LLOQ of 25 IU per mL. Previous exposure to HCV direct-acting antivirals was prohibited.

Clinical Trial Results in Adults with Chronic GT4 HCV Infection without Cirrhosis

PEARL-I was a randomized, global, multicenter, open-label trial that enrolled 135 adults without cirrhosis who were either treatment-naïve or did not achieve a virologic response with prior treatment with pegylated interferon/ribavirin (pegIFN/RBV). Treatment-naïve subjects were randomized in a 1:1 ratio to receive one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule once-daily with food with or without ribavirin for 12 weeks. PegIFN/RBV treatment-experienced subjects received were assigned to receive the same doses as treatment naïve subjects.

Subjects had a median age of 51 years (range: 19 to 70); 64% were treatment-naïve, 17% were prior pegIFN/RBV null responders; 7% were prior pegIFN/RBV partial responders, 13% were prior pegIFN/RBV relapsers; 65% were male; 9% were Black; 14% had a body mass index at least 30 kg/m2; 70% had baseline HCV RNA levels at least 800,000 IU/mL; 79% had IL28B (rs12979860) non-CC genotype; 7% had bridging fibrosis (F3).

Table 10 presents the SVR12 rates.

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Among the 131 HCV genotype 4 infected subjects in PEARL-I who achieved SVR12, virologic response data at post-treatment week 24 were available from 129 subjects, and 129/129 (100%) subjects maintained their response through 24 weeks post-treatment (SVR24).

Clinical Trial Results in Adults with Chronic GT4 HCV Infection with Compensated Cirrhosis

AGATE-I was a global multicenter, open-label trial in 120 HCV genotype 4 infected adults with compensated cirrhosis who were either treatment-naïve or pegIFN/RBV treatment-experienced and were treated for 12 weeks (n=59) or 16 weeks (n=61) with ombitasvir, paritaprevir, and ritonavir given once daily with weight based RBV. ombitasvir, paritaprevir, and ritonavir was administered as coformulated ombitasvir, paritaprevir, ritonavir tablets.

Of the 59 subjects in the 12 week arm, median age was 56 years (range: 43 to 81); 51% were treatment-naïve, 29% were prior pegIFN/RBV null responders; 8% were prior pegIFN/RBV partial responders, 12% were prior pegIFN/RBV relapsers; 76% were male; 17% were Black; 29% had a body mass index of at least 30 kg/m2; 76% had baseline HCV RNA levels of at least 800,000 IU per mL; 86% had IL28B (rs12979860) non‑CC genotype; 12% had platelet counts of less than 90 x 109 per L; and 5% had albumin less than 3.5 mg per dL.

Table 11 presents the SVR12 rates for HCV genotype 4 infected subjects with compensated cirrhosis treated with ombitasvir, paritaprevir, and ritonavir with RBV for 12 weeks. Treatment with 16 weeks was not shown to increase SVR12 rates therefore, ombitasvir, paritaprevir, and ritonavir with RBV for 16 week arm is not presented in Table 11.

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How Supplied

Ombitasvir, paritaprevir, and ritonavir is dispensed in a monthly carton for a total of 28 days of therapy. Each monthly carton contains four weekly cartons. Each weekly carton contains seven daily dose packs.

Each child resistant daily dose pack contains two ombitasvir, paritaprevir, and ritonavir tablets. The NDC number is 0074-3082-28.

Ombitasvir, paritaprevir, and ritonavir is a pink-colored, film-coated, oblong, biconvex-shaped tablet debossed with “AV1” on one side. Each tablet contains 12.5 mg ombitasvir, 75 mg paritaprevir and 50 mg ritonavir.

Storage

Store at or below 30°C (86°F).

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Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling. Inform patients to review the Medication Guide for ribavirin.

• Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
  • Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of hepatitis B virus infection
• Risk of ALT Elevations or Hepatic Decompensation and Failure
  • Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, onset of confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur.
• Pregnancy
  • Advise patients to avoid pregnancy during treatment and within 6 months of stopping treatment with ombitasvir, paritaprevir, and ritonavir with ribavirin. Inform patients to notify their health care provider immediately in the event of a pregnancy.
• Drug Interactions
  • Inform patients that ombitasvir, paritaprevir, and ritonavir may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication or herbal products.
  • Inform patients that contraceptives containing ethinyl estradiol are contraindicated with ombitasvir, paritaprevir, and ritonavir.
• Administration
  • Advise patients to take ombitasvir, paritaprevir, and ritonavir every day at the regularly scheduled time with a meal without regard to fat or calorie content.
  • Inform patients that it is important not to miss or skip doses and to take ombitasvir, paritaprevir, and ritonavir for the duration that is recommended by the healthcare provider.

Precautions with Alcohol

Alcohol-Ombitasvir, paritaprevir, and ritonavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

TECHNIVIE

Look-Alike Drug Names

There is limited information regarding Ombitasvir, paritaprevir, and ritonavir Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.