Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir

Name: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir

Uses For ombitasvir, paritaprevir, ritonavir and dasabuvir

Ombitasvir, paritaprevir, ritonavir, and dasabuvir combination is used with or without ribavirin to treat chronic hepatitis C infection, including patients with compensated cirrhosis.

ombitasvir, paritaprevir, ritonavir and dasabuvir is available only with your doctor's prescription.

Pharmacology

Combines 3 direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action. Ombitasvir inhibits HCV NS5A, and interferes with viral RNA replication and virion assembly. Paritaprevir inhibits HCV NS3/4A protease and interferes with HCV coded polyprotein cleavage necessary for viral replication. Dasabuvir inhibits HCV RNA-dependent RNA polymerase (encoded by the NS5B gene) which is also necessary for viral replication.

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 (ie, AUC).

Distribution

Ombitasvir: Vdss: 173 L

Paritaprevir: Vdss: 103 L

Ritonavir: Vdss: 21.5 L

Dasabuvir: Vdss: 149 L

Metabolism

Ombitasvir: Metabolized by amide hydrolysis and oxidative metabolism

Paritaprevir: Metabolized by CYP3A4 and to a lesser extent CYP3A5

Ritonavir: Metabolized by CYP3A and to a lesser extent CYP2D6

Dasabuvir: Metabolized by CYP2C8 and to a lesser extent CYP3A

Excretion

Ombitasvir: Feces (90.2%, mainly as unchanged drug) and urine (1.91%)

Paritaprevir: Feces (88%, mainly as metabolites) and urine (8.8%)

Ritonavir: Feces (86.4%) and urine (11.3%)

Dasabuvir: Feces (94.4%, mainly as metabolites) and urine (~2%)

Time to Peak

Ombitasvir: ~5 hours

Paritaprevir: ~4 to 5 hours

Ritonavir: ~4 to 5 hours

Dasabuvir: ~4 hours (immediate release); 8 hours (ER)

Half-Life Elimination

Ombitasvir: 21 to 25 hours; Paritaprevir: 5.5 hours; Ritonavir: 4 hours; Dasabuvir 5.5 to 6 hours

Protein Binding

Ombitasvir: 99.9%; Paritaprevir: 97 to 98.6%; Ritonavir: >99%; Dasabuvir: >99.5%

Dosing Adult

Chronic hepatitis C (mono-infected or HCV/HIV-1 co-infected): Oral: Note: Viekira Pak is a copackaged product; ombitasvir, paritaprevir, and ritonavir are a fixed-dose combination tablet; dasabuvir is an individual tablet. Viekira XR is a fixed dose bilayer tablet; the immediate release layer contains ombitasvir, paritaprevir, and ritonavir; the extended release layer contains dasabuvir.

Genotype 1a, genotype 1 (unknown subtype), or genotype 1 (mixed subtype) without cirrhosis or with compensated cirrhosis (Child-Pugh A) (with concomitant ribavirin):

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning

Dasabuvir tablet: One tablet twice daily

Extended release: Three tablets once daily

Duration of therapy: 12 weeks (without cirrhosis) or 24 weeks (with compensated cirrhosis [Child-Pugh class A]); based on prior treatment history, some patients with compensated cirrhosis may be considered for a duration of therapy of 12 weeks.

Genotype 1b, without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 12 weeks

Dasabuvir tablet: One tablet twice daily for 12 weeks

Extended release: Three tablets once daily for 12 weeks

Genotype 1, liver transplant recipients, Metavir fibrosis score ≤2 (normal hepatic function, mild fibrosis) (regardless of genotype 1 subtype; with concomitant ribavirin): Note: If calcineurin inhibitor used concomitantly, calcineurin inhibitor dosage adjustment is needed.

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 24 weeks

Dasabuvir tablet: One tablet twice daily for 24 weeks

Extended release: Three tablets once daily for 24 weeks

Dosing Renal Impairment

CrCl ≥15 ml/minute: No dosage adjustment necessary.

End-stage renal disease (ESRD) on dialysis: No dosage adjustment necessary.

ALERT U.S. Boxed Warning

Hepatitis B virus reactivation

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment. HBV reactivation has been reported in hepatitis C virus (HCV)/HBV co-infected 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 co-infected patients for hepatitis flare or HBV reactivation during HCV treatment and posttreatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic effects: Hepatic decompensation and hepatic failure, including liver transplantation and fatal cases, have been reported with ombitasvir, paritaprevir, ritonavir, and dasabuvir; most patients experiencing these severe adverse events had advanced cirrhosis prior to treatment initiation. Typically occurs between 1 and 4 weeks of treatment initiation; characterized by acute elevation of direct bilirubin, without ALT elevation, and signs and symptoms of hepatic decompensation (eg, ascites, hepatic encephalopathy, variceal hemorrhage). In patients with cirrhosis, monitor for signs and symptoms of hepatic decompensation and perform hepatic function testing (including direct bilirubin) at baseline, during the first 4 weeks of treatment initiation, and as indicated thereafter. Discontinue treatment in patients who develop signs/symptoms of hepatic decompensation.

• Hepatic enzyme elevations: Elevations of ALT (>5 times ULN) have been reported. Elevations are usually asymptomatic, occur within 4 weeks of treatment initiation, and decline within 2 to 8 weeks with continued dosing. Monitor hepatic enzymes during the first 4 weeks of treatment initiation and thereafter as clinically indicated. If ALT is elevated, repeat testing and continue to monitor closely; patients should contact their health care professional immediately if they experience onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces. Consider discontinuation if ALT remains persistently >10 x ULN. Discontinue if ALT increase is accompanied by signs of hepatic inflammation, elevated direct bilirubin, alkaline phosphatase, or INR. Female patients taking ethinyl estradiol products are at increased risk. For management of women taking concomitant estrogen products, refer to Special Populations below.

Disease-related concerns:

• Hepatic impairment: Use is contraindicated in moderate to severe hepatic impairment (Child-Pugh class B or C).

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation has been reported in hepatitis C virus (HCV)/HBV co-infected patients who were receiving 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. Test all patients for evidence of current or prior HBV infection prior to initiation of treatment; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment and post-treatment follow-up. Initiate treatment for HBV infection as clinically indicated. HBV reactivation has been reported in HBsAg positive patients and in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) and is characterized by an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA level; reappearance of HBsAg may occur in patients with resolved HBV infection. Risk of HBV reactivation may be increased in patients receiving certain immunosuppressants or chemotherapeutic agents.

Concurrent drug therapy issues:

• Concomitant therapy: If used with concomitant ribavirin, contraindications of ribavirin, particularly pregnancy avoidance warnings, also apply. See ribavirin prescribing information.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Women taking concomitant estrogen products: Concurrent use of ethinyl estradiol-containing products is contraindicated; these products may be restarted approximately 2 weeks following completion of HCV therapy. Alternative methods of contraception (eg, nonhormonal methods, progestin only contraception) are recommended during therapy. Women using other estrogens (eg, estradiol, conjugated estrogens) have a rate of ALT elevation similar to patients not receiving any estrogens; coadminister with caution.

Other warnings/precautions:

• Risk of HIV-1 protease inhibitor drug resistance: Ritonavir, a component of the product, is also an HIV-1 protease inhibitor. In HCV/HIV coinfected patients, ritonavir can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 coinfected patients should also be taking a suppressive antiretroviral regimen to reduce resistance risk.

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