- ACRONYMS AND DEFINITIONS
- AASLD - American Association for the Study of Liver Diseases
- CP - Child-Pugh liver failure classification
- GT - Genotype
- HBV - Hepatitis B virus
- HCV - Hepatitis C virus
- PegIFN - Pegylated interferon
- RBV - Ribavirin
- ULN - Upper limit of normal
- DRUGS IN CLASS
- Viekira Pak is part of a new generation of antiviral medications that are highly effective against hepatitis C
- Viekira Pak is a combination pill that contains 4 medications: ombitasvir, paritaprevir, dasabuvir, and ritonavir
- MECHANISM OF ACTION
- Ombitasvir
- Ombitasvir is an inhibitor of the HCV NS5A protein which is essential for viral replication and virion assembly
- Paritaprevir
- Paritaprevir is HCV NS3/4A protease inhibitor. HCV NS3/4A protease cleaves HCV-encoded polyprotein into the individual proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins form a complex that is necessary for viral replication.
- Dasabuvir
- Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome
- Ritonavir
- Ritonavir has no activity against hepatitis C virus. Ritonavir is a strong CYP3A4 inhibitor that is added to the formulation to inhibit paritaprevir metabolism and increase its blood levels
- FDA-APPROVED INDICATIONS
- HCV genotypes 1 (with or without ribavirin) - in patients without cirrhosis or with Child-Pugh A
- Genotype 1b: Viekira Pak only
- Genotype 1a: Viekira Pak + ribavirin
- HEPATITIS C TREATMENT
- In trials, Viekira Pak was > 90% effective in eradicating HCV genotype 1a and 1b
- SIDE EFFECTS
- General
- The two tables below show side effects that occurred with ≥ 5% incidence in Viekira Pak™ trials
- The first table is from the SAPPHIRE trials where Viekira Pak™ + ribavirin was compared to placebo
- The second table is from the PEARL trials where Viekira Pak™ was compared to Viekira Pak™ + ribavirin
| Side effect | Viekira Pak™ + RBV for 12 weeks (N=770) |
Placebo for 12 weeks (N=255) |
|---|---|---|
| Fatigue | 34% | 26% |
| Nausea | 22% | 15% |
| Pruritus (itching) | 18% | 7% |
| Skin reactions (rash, erythema, eczema, etc.) |
16% | 9% |
| Insomnia | 14% | 8% |
| Asthenia (weakness) |
14% | 7% |
| Side effect | Viekira Pak™ + RBV for 12 weeks (N=401) |
Viekira Pak™ for 12 weeks (N=509) |
|---|---|---|
| Nausea | 16% | 8% |
| Pruritus (itching) | 13% | 7% |
| Insomnia | 12% | 5% |
| Asthenia (weakness) |
9% | 4% |
- Liver enzyme elevations
- In trials, 1% of patients treated with Viekira Pak™ experienced ALT elevations > 5 X ULN
- The incidence increased to 25% (4/16) among women taking combined oral contraceptives containing ethinyl estradiol. Viekira Pak™ is contraindicated with combined oral contraceptives.
- The incidence of relevant ALT elevations was 3% among women taking other estrogens such as estradiol and conjugated estrogens (2/59)
- The ALT elevations typically occurred during the first 4 weeks of treatment and resolved with ongoing therapy [1]
- Bilirubin elevations
- In trials, bilirubin elevations ≥ 2 X ULN were seen in 15% of patients treated with Viekira Pak™ + ribavirin and 2% of patients treated with Viekira Pak™ alone
- Elevations were likely due to inhibition of the bilirubin transporter OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis
- Bilirubin elevations predominantly occurred during the first week of therapy, and generally resolved with ongoing therapy [1]
- Anemia/Decreased hemoglobin
- In trials, average hemoglobin levels decreased by 2.4 g/dl in patients treated with Viekira Pak™ + ribavirin, and by 0.5 g/dl in patients treated with Viekira Pak™ alone
- Hemolytic anemia is a well-documented side effect of ribavirin. See ribavirin for more.
- CONTRAINDICATIONS
- Known hypersensitivity to ritonavir
- Child-Pugh B or C
- Concomitant use with drugs that are highly dependent on CYP3A4 for clearance for which elevated levels may lead to toxicity. See Viekira Pak PI [sec 4] for a list of drugs that are contraindicated.
- CYP3A4 moderate and strong inducers
- CYP2C8 strong inducers
- CYP2C8 strong inhibitors - may increase dasabuvir levels and increase the risk for prolonged QT syndrome
- PRECAUTIONS
- Kidney disease
- No dose adjustment is necessary in mild, moderate, or severe kidney disease [1]
- Liver disease
- Child-Pugh A: no dose adjustment necessary
- Child-Pugh B and C: DO NOT USE
- Cirrhosis: Monitor for signs of hepatic decompensation. Check liver function tests at baseline, during the first 4 weeks of therapy, and as clinically indicated. Stop therapy for signs of decompensation.
- Postmarketing cases of liver failure have occurred in patients receiving Viekira Pak. In most cases, patients 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.
- HIV coinfection
- The ritonavir component of Viekira Pak is also an HIV-1 protease inhibitor and may select for protease inhibitor-resistant HIV strains
- Patients with HIV should be on suppressive therapy when taking Viekira Pak
- The incidence of side effects may also be higher in patients coinfected with HIV [1]
- Hepatitis B coinfection
- In October 2016, the FDA placed a boxed warning on all new hepatitis C drugs about the possible reactivation of hepatitis B infection in coinfected patients who are taking direct-acting antiviral hepatitis C drugs
- At the time of the warning, the FDA had identified 24 cases of hepatitis B reactivation in patients taking these drugs. Reactivation occurred in patients who were HBsAg positive and in those who were HBsAg negative and anti-HBc positive (see interpreting HBV screening results for more).
- The FDA recommends that providers check all patients for hepatitis B coinfection (HBsAg and anti-HBc) before starting therapy and that they monitor patients for reactivation during and after therapy
- See AASLD guidelines for HBV coinfected patients for more
- MONITORING THERAPY
- Viekira Pak
- The manufacturer recommends monitoring liver function tests during the first 4 weeks of therapy and as clinically indicated thereafter. During the first 4 treatment weeks of the PEARL trials, monitoring was done at 0, 1, 2, and 4 weeks.
- If ALT levels remain persistently elevated greater than 10 X ULN, then consider stopping therapy
- Discontinue Viekira Pak if ALT elevations are accompanied by signs or symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or INR
- Patients should notify their doctor if they develop signs of liver toxicity (fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces)
- AASLD recommendations
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Drug interactions and contraindications
- The four drugs in Viekira Pak are metabolized and eliminated through a number of pathways that can lead to significant drug interactions (see metabolism and elimination below)
- Viekira Pak is contraindicated with a number of medications, and it has the potential to interact with many others
- See the Viekira Pak PI for a list of drug contraindications (section 4) and drug interactions (section 7).
- Metabolism and clearance
- Ombitasvir
- Primarily metabolized by amide hydrolysis
- UGT1A1 - inhibitor
- P-glycoprotein - substrate
- BCRP - substrate
- Paritaprevir
- CYP3A4 - major substrate
- UGT1A1 - inhibitor
- OATP1B1 - OATP1B1/P1B3 substrate and inhibitor
- BCRP - substrate and inhibitor
- P-glycoprotein - substrate and inhibitor
- Dasabuvir
- CYP2C8 - major substrate
- UGT1A1 - inhibitor
- BCRP - substrate and inhibitor
- P-glycoprotein - substrate
- Ritonavir
- CYP3A4 - substrate and strong inhibitor
- BCRP - inhibitor
- P-glycoprotein - substrate and inhibitor
- DOSING
- Dosage forms
- Viekira Pak comes in a carton that has 28 days of therapy. Each monthly carton has 4 weekly cartons that contain 7 daily dosage packs.
- Two types of tablets come in each carton:
- OPR tablet - ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg
- Dasabuvir tablet - dasabuvir 250 mg
- Dosing
- OPR tablet - take 2 tablets once daily in the morning with a meal
- Dasabuvir tablet - take 1 tablet twice a day with a meal
| Viekira Pak Treatment Regimens | ||
|---|---|---|
| Patient population | Treatment | Duration |
| GT 1a without cirrhosis | Viekira Pak + Ribavirin | 12 weeks |
| GT 1a with Child-Pugh A | Viekira Pak + Ribavirin | 24 weeks✝ |
| GT 1b without cirrhosis or Child-Pugh A | Viekira Pak | 12 weeks |
| Liver transplant with Metavir ≤ 2 (GT 1a or 1b) | Viekira Pak + Ribavirin | 24 weeks |
- HEPATITIS C TREATMENT RECOMMENDATIONS
- See hepatitis C treatment recommendations for complete treatment guidelines
- LONG TERM SAFETY
- Viekira Pak™ was FDA-approved in 2014
- There is no long-term safety data for the medications
- BIBLIOGRAPHY
- 1 - Viekira Pak™ PI
- 2 - PMID 24720703 - SAPPHIRE I
- 3 - PMID 24720679 - SAPPHIRE II
- 4 - PMID 24818763 - PEARL II
- 5 - PMID 24795200 - PEARL III and IV
- 6 - PMID 24725237 - TURQUOISE II