Viekirax

Viekirax is indicated in combination with ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis.

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 Viekirax.
• Prior to initiation of Viekirax, assess baseline hepatic laboratory and clinical parameters.

Recommended Dosage In Adults

Viekirax is ombitasvir, paritaprevir and ritonavir fixed dose combination tablets.

The recommended dosage of Viekirax is two tablets taken orally once daily (in the morning). Take Viekirax with a meal without regard to fat or calorie content.

Viekirax is used in combination with ribavirin (RBV). When administered with Viekirax, 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.

Table 1 shows the recommended Viekirax treatment regimen and duration for HCV genotype 4 patients without cirrhosis.

Table 1: Treatment Regimen and Duration for Patients with HCV Genotype 4 without Cirrhosis

Dosage In Patients With Hepatic Impairment

Viekirax is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C).

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

Table 2: Drugs that are Contraindicated with Viekirax

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 Viekirax. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with Viekirax 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

Viekirax is not indicated in patients with cirrhosis.

Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported postmarketing in patients treated with ombitasvir, paritaprevir, ritonavir with and without dasabuvir and with and without ribavirin. Most patients with these severe outcomes had evidence of advanced 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. Because these events 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. Discontinue treatment in patients who develop evidence of hepatic decompensation.

Viekirax is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C).

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 Viekirax. Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended during Viekirax therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with Viekirax.

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 Viekirax.

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 Viekirax if ALT levels remain persistently greater than 10 times the ULN.
• Discontinue Viekirax 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, 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 Viekirax and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:

• Loss of therapeutic effect of Viekirax and possible development of resistance
• Possible clinically significant adverse reactions from greater exposures of concomitant drugs or components of Viekirax.

See Table 4 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 Viekirax therapy; review concomitant medications during Viekirax 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 Viekirax 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 Viekirax should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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 Viekirax with ribavirin. Inform patients to notify their health care provider immediately in the event of a pregnancy.

Drug Interactions

Inform patients that Viekirax 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 Viekirax.

Administration

Advise patients to take Viekirax 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 Viekirax for the duration that is recommended by the healthcare provider.

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).

Viekirax 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.

Viekirax is administered with ribavirin. Refer to the prescribing information for ribavirin for information on Impairment of Fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category B.

Risk Summary

Adequate and well controlled studies with Viekirax have not been conducted in pregnant women. In animal reproduction studies, no evidence of teratogenicity was observed with the administration of ombitasvir (mice and rabbits), paritaprevir or ritonavir (mice and rats) at exposures higher than the recommended clinical dose. Because animal reproduction studies are not always predictive of human response, Viekirax should be used during pregnancy only if clearly needed.

When Viekirax 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 of ribavirin in males and females of childbearing potential.

Data

Animal Data

In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals treated throughout pregnancy with ombitasvir and its major inactive human metabolites (M29, M36), paritaprevir or ritonavir. For ombitasvir, the highest dose tested produced exposures approximately 29-fold (mouse) or 4-fold (rabbit) the exposures in humans at the recommended clinical dose. The highest doses of the major, inactive human metabolites similarly tested produced exposures approximately 26-fold the exposures in humans at the recommended clinical dose. For paritaprevir, ritonavir, the highest doses tested produced exposures approximately 143-fold (mouse) or 12-fold (rat) the exposures of paritaprevir in humans at the recommended clinical dose.

Nursing Mothers

It is not known whether any of the components of Viekirax or their metabolites are present in human milk. 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 Viekirax and any potential adverse effects on the breastfed child from Viekirax or from the underlying maternal condition.

When Viekirax is administered with ribavirin, the nursing mother's information for ribavirin also applies to this combination regimen (see prescribing information for ribavirin).

Pediatric Use

Safety and effectiveness of Viekirax in pediatric patients less than 18 years of age have not been established.

Geriatric Use

No dosage adjustment of Viekirax is warranted in geriatric patients. Clinical study PEARL-I 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.

Hepatic Impairment

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

Renal Impairment

No dosage adjustment of Viekirax is required in patients with mild, moderate or severe renal impairment. Viekirax 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.

Viekirax should be administered with ribavirin (RBV). Refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions.

The following adverse reaction is described below and elsewhere in the labeling:

• Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
• Increased Risk of ALT Elevations

Clinical Trials Experience

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.

The safety assessment of Viekirax is based on data from a clinical study that included 135 HCV genotype 4-infected 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 without cirrhosis 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 (PEARL-I).

Adverse reactions that occurred in subjects treated with ombitasvir, paritaprevir and ritonavir with or without ribavirin for 12 weeks are listed in Table 3. The majority of adverse reactions in PEARL-I were mild in severity. None of the subjects who received ombitasvir, paritaprevir and ritonavir with ribavirin experienced a serious adverse reaction. None of the subjects receiving ombitasvir, paritaprevir and ritonavir with or without ribavirin discontinued treatment due to an adverse reaction.

Table 3: Selected Adverse Reactions (All Grades) with ≥ 5% Frequency Reported in Subjects Treated with Ombitasvir, Paritaprevir and Ritonavir with or without Ribavirin for 12 Weeks

Laboratory Abnormalities

Serum ALT Elevations

None of the 135 HCV GT4 infected subjects treated with Viekirax experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment.

Serum Bilirubin Elevations

Post-baseline elevations in bilirubin at least 2 times ULN were observed in 5% (7/134) of subjects receiving Viekirax; 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.

Anemia/Decreased Hemoglobin

The mean change from baseline in hemoglobin levels in subjects treated with Viekirax in combination with ribavirin was -2.1 g/dL and the mean change in subjects treated with Viekirax 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 Viekirax with ribavirin had a single hemoglobin level decrease to less than 8 g/dL during treatment. Four percent (4/91) of subjects treated with Viekirax with ribavirin underwent ribavirin dose reductions to manage anemia/decreased hemoglobin levels; none received a blood transfusion or erythropoietin. No subjects treated with Viekirax alone had a hemoglobin level less than 8 g/dL.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Viekirax. 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.

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.

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.

The pharmacokinetic properties of the components of Viekirax are provided in Table 5. 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 6.

Table 5: Pharmacokinetic Properties of the Components of Viekirax

Table 6: Steady-State Pharmacokinetic Parameters of Ombitasvir, Paritaprevir, and Ritonavir Following Oral Administration of Viekirax in HCV-Infected Subjects