Anti-Hepatitis Agents

Renal dosing:  
(CrCl 20-49 ml/min): 10 mg every 48 hours  
(CrCl 10-19 ml/min):  10 mg every 72 hours.  
(CrCl < 10 ml/min):  no recommendation available.   
(Hemodialysis): 10 mg every 7 days following dialysis.  

Supplied: 10 mg tablet.

Initial U.S. Approval:  2015

INDICATIONS AND USAGE: DAKLINZA is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection [see Dosage and Administration and Clinical Studies].
Limitations of Use:
Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving DAKLINZA in combination with sofosbuvir for 12 weeks

HOW SUPPLIED:
Tablet: 60 mg and 30 mg

Initial U.S. Approval:  2016

Mechanism of Action:
EPCLUSA is a fixed-dose combination of sofosbuvir and velpatasvir which are direct-acting antiviral agents against the hepatitis C virus

INDICATIONS AND USAGE:
EPCLUSA is a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, and velpatasvir, an HCV NS5A inhibitor, and is indicated for the treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection (1):

without cirrhosis or with compensated cirrhosis.
with decompensated cirrhosis for use in combination with ribavirin.

DOSAGE AND ADMINISTRATION
Recommended dosage: One tablet (400 mg of sofosbuvir and 100 mg of velpatasvir) taken orally once daily with or without food (2.1).
See recommended treatment regimen and duration in patients with genotypes 1, 2, 3, 4, 5, or 6 HCV in table below: (2.1).

• A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease.

HOW SUPPLIED:

Tablets: 400 mg sofosbuvir and 100 mg velpatasvir.

Initial U.S. Approval:  2014

Mechanism of Action: HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir which are direct-acting antiviral agents against the hepatitis C virus

INDICATIONS AND USAGE:  HARVONI is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1, 4, 5 or 6 infection

HOW SUPPLIED: Tablets: 90 mg ledipasvir and 400 mg sofosbuvir

DOSAGE AND ADMINISTRATION
Dosing (Adults): Treatment of chronic hepatitis B infection: 
1) Nucleoside treatment naive: 0.5 mg orally once daily.
2) Lamivudine-resistant viremia (or known lamivudine-resistant mutations): 1 mg orally once daily

Renal dosing:
CrCl 30-49 ml/min: Administer 50% of usual dose.
CrCl 10-29 ml/min: Administer 30% of usual dose.
CrCl <10 ml/min (including dialysis): Administer 10% of usual dose. Administer after hemodialysis.

Supplied: 0.5 mg, 1 mg tablet. 0.05 mg/mL (210 mL) oral solution.

DOSAGE AND ADMINISTRATION 
Dosing (Adults): hepatitis B: 100 mg daily. HIV: 150 mg twice daily or 300 mg once daily. <50 kg: 4 mg/kg twice daily (maximum: 150 mg twice daily).

Renal dosing: See package insert.

Supplied:  Epivir ®: 150 mg, 300 mg tablet.  Epivir-HBV ®: 100 mg tab. Oral solution: Epivir®: 10 mg/mL (240 mL). Epivir-HBV®: 5 mg/mL (240 mL).

Chronic hepatitis B: 180 mcg SQ once weekly for 48 weeks.

Renal dosing:
CrCl <50 ml/min: Use caution - monitor for toxicity.  End-stage renal disease - hemodialysis: 135 mcg/week - monitor for toxicity.

Supplied:  Injection:  180 mcg/0.5 ml (0.5 ml) prefilled syringe. 
  180 mcg/mL (1 ml).

Renal dosing: Monitor for signs and symptoms of toxicity and if toxicity occurs then adjust dose. Do not use in patients with CrCl <50 mL/minute. Patients were excluded from the clinical trials if serum creatinine >1.5 times the upper limits of normal.

Supplied:  Injection (powder for reconstitution) - syringe or vial: 50 mcg, 80 mcg, 120 mcg, 150 mcg.

Renal dosing: Patients with CrCl <50 ml/min should not receive ribavirin.
Supplied: [Rebetol Capsules - 200mg  + Intron A Injection combination package].  Refrigerate.

DOSAGE AND ADMINISTRATION
Adult (usual):  
( 75 kg or less): ribavirin, 400 mg orally qam and 600 mg orally qpm.
(>75 kg):  ribavirin, 600 mg orally bid (given in the morning and evening).

Renal dosing:
Patients with CrCl <50 ml/min should not receive ribavirin.

Initial U.S. Approval:  2015

Mechanism of Action: TECHNIVIE combines two direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action [see Microbiology (12.4)].
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).

INDICATIONS AND USAGE:  TECHNIVIE is a fixed-dose combination of ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, and ritonavir, a CYP3A inhibitor and is indicated in combination with ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis.

HOW SUPPLIED:  Tablets: 12.5 mg ombitasvir, 75 mg paritaprevir, 50 mg ritonavir.

INCIVEK must not be used as monotherapy and must only be used in combination with peginterferon alfa and ribavirin.

A high proportion of previous null responders (particularly those with cirrhosis) did not achieve Sustained Virologic Response (SVR) and had telaprevir resistance-associated substitutions emerge on treatment with INCIVEK.

IINCIVEK efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes INCIVEK or other HCV NS3/4A protease inhibitors.

DOSAGE AND ADMINISTRATION
750 mg taken 3 times a day (7-9 hours apart) with food (not low fat).

INCIVEK must be administered with both peginterferon alfa and ribavirin for all patients for 12 weeks, followed by a response-guided regimen of either 12 or 36 additional weeks of peginterferon alfa and ribavirin depending on viral response and prior response status.

For specific dosage instructions for peginterferon alfa and ribavirin, refer to their respective prescribing information.

SSee PACKAGE INSERT for additional information.

HOW SUPPLIED
375 mg tablets

WARNINGS:  LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS AND SEVERE ACUTE EXACERBATIONS OF HEPATITIS B
See full prescribing information for complete boxed warning.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues.
Severe acute exacerbations of hepatitis B have been reported in patients who discontinued anti-hepatitis B therapy, including Tyzeka. Hepatic function should be monitored closely in patients who discontinue therapy. Resumption of anti-hepatitis B therapy may be warranted .

INDICATIONS AND USAGE:
Tyzeka is an HBV nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease

DOSAGE AND ADMINISTRATION:
Adults and Adolescents (16 years of age and older): 600 mg once daily, taken orally, with or without food.
Renal Impairment: Dose adjustment required in patients with creatinine clearance less than 50 mL per min,  as follows:

1. When administered on hemodialysis days, administer Tyzeka after hemodialysis

DOSAGE FORMS AND STRENGTHS:
Tablet: 600 mg tablets.
Oral Solution: 100 mg per 5 mL solution.

CONTRAINDICATIONS:
Combination of Tyzeka with pegylated interferon alfa-2a: Increased risk of peripheral neuropathy

WARNINGS AND PRECAUTIONS
Lactic acidosis and severe hepatomegaly with steatosis: If suspected, treatment should be suspended.

Severe acute exacerbations of hepatitis B after discontinuation: Monitor hepatic function closely for at least several months.

Myopathy: Tyzeka should be interrupted if myopathy is suspected; and discontinued if confirmed. It is unknown whether risk of myopathy is increased with concomitant use of other medications associated with myopathy.

Peripheral neuropathy: Risk increased when Tyzeka used in combination with alfa interferons, avoid concomitant use. Tyzeka should be interrupted if peripheral neuropathy is suspected; and discontinued if confirmed.

ADVERSE REACTIONS
In clinical trials, the most common adverse reactions (greater than or equal to 3%), of any severity, were: fatigue, increased creatine kinase (CK), headache, cough, diarrhea, abdominal pain, nausea, pharyngolaryngeal pain, arthralgia, pyrexia, rash, back pain, dizziness, myalgia, ALT increased, dyspepsia, insomnia, and abdominal distension. The most common adverse events resulting in Tyzeka discontinuation included increased CK, nausea, diarrhea, fatigue, myalgia, and myopathy.

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Coadministration of Tyzeka with drugs that affect renal function may alter plasma concentrations of Tyzeka and/or coadministered drug.
Coadministration of Tyzeka with pegylated interferon alfa-2a increases the risk and severity of peripheral neuropathy.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs [see Warnings and Precautions (5.1)].

Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may result in severe acute exacerbations of hepatitis B. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VEMLIDY. If appropriate, resumption of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)].

Initial U.S. Approval:  2016

Mechanism of Action: Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Tenofovir alafenamide as a lipophilic cell-permeant compound enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is then converted to tenofovir through hydrolysis primarily by carboxylesterase 1 (CES1) in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated by cellular kinases to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain-termination.

Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase ? and there is no evidence of toxicity to mitochondria in cell culture.

INDICATIONS AND USAGE:  VEMLIDY is a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor and is indicated for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease.

DOSAGE AND ADMINISTRATION:
Testing: Prior to initiation of VEMLIDY, test patients for HIV infection. VEMLIDY alone should not be used in patients with HIV infection. Assess serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein before initiating VEMLIDY and during therapy in all patients as clinically appropriate. (2.1)

Recommended dosage: 25 mg (one tablet) taken orally once daily with food. (2.2)

Renal Impairment: VEMLIDY is not recommended in patients with estimated creatinine clearance below 15 mL per minute. (2.3)

Hepatic Impairment: VEMLIDY is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment. (2.4)

HOW SUPPLIED:
Tablets: 25 mg of tenofovir alafenamide.

Initial U.S. Approval:  2014

Mechanism of Action: VIEKIRA PAK combines three direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action [see Microbiology (12.4)].
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).

INDICATIONS AND USAGE:  VIEKIRA PAK with or without ribavirin is indicated for the treatment of patients with genotype 1 chronic hepatitis C virus (HCV) infection including those with compensated cirrhosis.

HOW SUPPLIED: VIEKIRA PAK is ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets.
Ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets are pink-colored, film-coated, oblong biconvex shaped, debossed with "AV1" on one side.
Dasabuvir 250 mg tablets are beige-colored, film-coated, oval-shaped, debossed with "AV2" on one side. Each tablet contains 270.3 mg dasabuvir sodium monohydrate equivalent to 250 mg dasabuvir.

Drug UPDATES:  VIEKIRA XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets, for oral use
[Drug information  /  PDF]     REVIEW PACKAGE INSERT FOR POSSIBLE UPDATES
PACKAGE INSERT -Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014 -  Extended-release tablets - 2016

INDICATIONS AND USAGE:
VIEKIRA XR includes dasabuvir, a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor, ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, and ritonavir, a CYP3A inhibitor and is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV):

genotype 1b infection without cirrhosis or with compensated cirrhosis
genotype 1a infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin.

DOSAGE AND ADMINISTRATION:
Testing Prior to Initiation - Assess for laboratory and clinical evidence of hepatic decompensation. (2.1)

Recommended dosage: Three tablets taken once daily. VIEKIRA XR must be taken with a meal because administration under fasting conditions may result in reduced virologic response and possible development of resistance.
Treatment Regimen and Duration by Patient Population:

HCV/HIV-1 co-infection: For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in the table above. (2.2)
Liver Transplant Recipients: In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score </=2), the recommended duration of VIEKIRA XR with ribavirin is 24 weeks. (2.4)

HOW SUPPLIED:
Extended-release tablets: 200 mg dasabuvir, 8.33 mg ombitasvir, 50 mg paritaprevir, and 33.33 mg ritonavir

Initial U.S. Approval:  2016

Mechanism of Action:
ZEPATIER is a fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus

INDICATIONS AND USAGE:
ZEPATIER is a fixed-dose combination product containing elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor, and is indicated with or without ribavirin for treatment of chronic HCV genotypes 1 or 4 infection in adults.

DOSAGE AND ADMINISTRATION:
See links above

HOW SUPPLIED:
DOSAGE FORMS AND STRENGTHS
Tablets: 50 mg elbasvir and 100 mg grazoprevir