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Sofosbuvir

Pronunciation

(soe FOS bue vir)

Index Terms

  • Sovaldi

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Sovaldi: 400 mg

Brand Names: U.S.

  • Sovaldi

Pharmacologic Category

  • Antihepaciviral, Polymerase Inhibitor (Anti-HCV)
  • NS5B RNA Polymerase Inhibitor

Pharmacology

Sofosbuvir, a direct-acting antiviral agent against the hepatitis C virus, is a prodrug converted to its pharmacologically active form (GS-461203) via intracellular metabolism. It inhibits HCV NS5B RNA-dependent RNA polymerase, essential for viral replication, and acts as a chain terminator.

Metabolism

Hepatic; forms pharmacologically active nucleoside (uridine) analog triphosphate GS-461203; dephosphorylation results in the formation of nucleoside inactive metabolite GS-331007

Excretion

Urine (80%; primarily as metabolite); feces (14%)

Time to Peak

~0.5 to 2 hours

Half-Life Elimination

0.4 hours

Protein Binding

~61% to 65%

Special Populations: Renal Function Impairment

AUC0-inf was higher in mild (eGFR ≥50 and <80 mL/minute/1.73 m2), moderate (eGFR ≥30 and <50 mL/minute/1.73 m2), and severe (eGFR <30 mL/minute/1.73 m2) renal impairment.

Special Populations: Hepatic Function Impairment

AUC0-24 was higher in moderate and severe hepatic impairment

Use: Labeled Indications

Chronic hepatitis C: Treatment of genotype 1, 2, 3, or 4 chronic hepatitis C virus (HCV) infection in adults and genotype 2 or 3 chronic HCV infection in pediatric patients ≥12 years or weighing ≥35 kg, without cirrhosis or with compensated cirrhosis, as a component of a combination antiviral treatment regimen.

Contraindications

There are no contraindications listed in the manufacturer's labeling. When administered with ribavirin and peginterferon alfa, the contraindications to ribavirin and peginterferon alfa also apply. See Ribavirin and Peginterferon Alfa monographs.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to sofosbuvir or any component of the formulation; males whose female partners may become pregnant

Dosing: Adult

Chronic hepatitis C (CHC) infection (monoinfection or coinfected with HIV-1): Oral: Note: Treatment-experienced refers to patients who have failed prior treatment with peginterferon and ribavirin. Combination therapy with ribavirin or ribavirin/peginterferon is not a recommended regimen in HCV treatment guidelines for patients with HCV (treatment-naive or treatment-experienced), regardless of genotype (AASLD/IDSA 2016).

Genotype 1:

Manufacturer’s labeling:

Treatment-naïve patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily with concomitant peginterferon alfa and ribavirin for 12 weeks; for patients that cannot receive peginterferon alfa, administer with concomitant ribavirin for 24 weeks.

Alternate dosing (AASLD/IDSA 2016):

Genotype 1a (treatment-naïve or treatment-experienced patients without cirrhosis): 400 mg once daily in combination with simeprevir or daclatasvir for 12 weeks.

Genotype 1a (treatment-naïve patients with compensated cirrhosis): 400 mg once daily in combination with simeprevir or daclatasvir, with or without ribavirin for 24 weeks. Note: Combination therapy with simeprevir should only be used in patients in whom no Q80K polymorphism is detected.

Genotype 1a (treatment-experienced patients with compensated cirrhosis): 400 mg once daily in combination with simeprevir or daclatasvir, with or without ribavirin for 24 weeks.

Genotype 1b (treatment-naïve or treatment-experienced patients without cirrhosis): 400 mg once daily in combination with simeprevir or daclatasvir for 12 weeks.

Genotype 1b (treatment-naïve or treatment experienced patients with compensated cirrhosis): 400 mg once daily in combination with simeprevir or daclatasvir, with or without ribavirin for 24 weeks.

Genotype 1, regardless of subtype (patients without cirrhosis who have failed prior treatment with an HCV protease inhibitor plus peginterferon and ribavirin): 400 mg once daily in combination with daclatasvir for 12 weeks.

Genotype 1, regardless of subtype (patients with compensated cirrhosis who have failed prior treatment with an HCV protease inhibitor plus peginterferon and ribavirin): 400 mg once daily in combination with daclatasvir with or without ribavirin for 24 weeks.

Genotype 2:

Manufacturer’s labeling:

Treatment-naïve and treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily with concomitant ribavirin for 12 weeks.

Alternate dosing (AASLD/IDSA 2016):

Treatment-naïve or treatment-experienced patients: 400 mg once daily in combination with daclatasvir for 12 weeks (without cirrhosis) or 16 to 24 weeks (with compensated cirrhosis).

Treatment-experienced patients who failed prior treatment with sofosbuvir and ribavirin (with or without compensated cirrhosis): 400 mg once daily in combination with daclatasvir with or without ribavirin for 24 weeks.

Genotype 3:

Manufacturer’s labeling:

Treatment-naïve or treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily with concomitant ribavirin for 24 weeks.

Alternate dosing (AASLD/IDSA 2016):

Treatment-naïve or treatment-experienced patients without cirrhosis: 400 mg once daily in combination with daclatasvir for 12 weeks.

Treatment-naïve patients with compensated cirrhosis: 400 mg once daily in combination with daclatasvir with or without ribavirin for 24 weeks.

Treatment-experienced patients with compensated cirrhosis: 400 mg once daily in combination with daclatasvir and ribavirin for 24 weeks.

Treatment-experienced patients who failed prior treatment with sofosbuvir and ribavirin (with or without compensated cirrhosis): 400 mg once daily in combination with daclatasvir and ribavirin for 24 weeks.

Genotype 4: Treatment-naïve patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily with concomitant peginterferon alfa and ribavirin for 12 weeks.

Hepatocellular carcinoma patients awaiting liver transplantation: 400 mg once daily with concomitant ribavirin for 48 weeks or until the time of liver transplantation, whichever occurs first. Note: Safety and efficacy have not been established in post-liver transplant patients.

Discontinuation of therapy: If the other agents used in combination with sofosbuvir are permanently discontinued, sofosbuvir should also be discontinued.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chronic hepatitis C (CHC) infection (monoinfection or coinfected with HIV-1): Treatment-naïve or treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): Children and Adolescents ≥12 years or ≥35 kg: Oral: Note: Treatment-experienced refers to patients who have failed prior treatment with interferon based regimen with or without ribavirin

Genotype 2: 400 mg once daily with concomitant ribavirin for 12 weeks

Genotype 3: 400 mg once daily with concomitant ribavirin for 24 weeks

Dosing: Renal Impairment

Estimated glomerular filtration rate (eGFR) ≥30 mL/minute: No dosage adjustment necessary.

eGFR <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Predominant metabolite accumulates in impaired renal function.

End stage renal disease (ESRD), including hemodialysis patients: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Predominant metabolite accumulates in impaired renal function.

Dosing: Hepatic Impairment

Mild, moderate, or severe impairment (Child-Pugh class A, B, or C): No dosage adjustment necessary.

Administration

Administer with or without food.

Storage

Store below 30°C (86°F). Dispense only in original container.

Drug Interactions

Amiodarone: Sofosbuvir may enhance the bradycardic effect of Amiodarone. Avoid combination

CarBAMazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Modafinil: May decrease the serum concentration of Sofosbuvir. Avoid combination

OXcarbazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Sofosbuvir. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

PHENobarbital: May decrease the serum concentration of Sofosbuvir. Avoid combination

Primidone: May decrease the serum concentration of Sofosbuvir. Avoid combination

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifabutin: May decrease the serum concentration of Sofosbuvir. Avoid combination

Rifapentine: May decrease the serum concentration of Sofosbuvir. Avoid combination

Tipranavir: May decrease the serum concentration of Sofosbuvir. Avoid combination

Vitamin K Antagonists (eg, warfarin): Antihepaciviral NS5B RNA Polymerase Inhibitors may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

Adverse reactions reported with combination therapy.

>10%:

Central nervous system: Fatigue (30% to 59%), headache (24% to 36%), insomnia (15% to 25%), chills (2% to 17%), irritability (10% to 13%)

Dermatologic: Pruritus (11% to 27%), skin rash (8% to 18%)

Gastrointestinal: Nausea (22% to 34%), decreased appetite (18%), diarrhea (9% to 12%)

Hematologic & oncologic: Decreased hemoglobin (<10 g/dL: 6% to 23%; <8.5 g/dL: ≤2%), anemia (6% to 21%), neutropenia (<1% [interferon-free regimen] to 17% [interferon-containing regimen]), decreased neutrophils (≥0.5 to <0.75 times 109/L: <1% [interferon-free regimen] to 15%; <0.5 times 109/L: ≤5%)

Neuromuscular & skeletal: Weakness (5% to 21%), myalgia (6% to 14%)

Respiratory: Flu-like symptoms (6% to 16%)

Miscellaneous: Fever (4% to 18%)

1% to 10%:

Gastrointestinal: Increased serum lipase (>3 times ULN: ≤2%)

Hematologic & oncologic: Thrombocytopenia (≤1%)

Hepatic: Increased serum bilirubin (>2.5 times ULN: 3%)

Renal: Increased creatine kinase (≥10 times ULN: 1% to 2%)

<1% (Limited to important or life-threatening): Bradycardia, pancytopenia, reactivation of HBV (FDA Safety Alert Dec. 8, 2016), severe depression, suicidal ideation

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 with sofosbuvir. 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 post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Warnings/Precautions

Disease-related concerns:

• 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 sofosbuvir; 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:

• Amiodarone: Symptomatic bradycardia (some requiring pacemaker intervention) has occurred in patients receiving amiodarone and a sofosbuvir-containing regimen. Fatal cardiac arrest occurred in a patient taking amiodarone and the ledipasvir/sofosbuvir combination product. Bradycardia generally occurred within hours to days following coadministration, however some cases have occurred 2 weeks following the initiation of sofosbuvir. The risk of bradycardia may be increased in patients taking beta blockers or patients with underlying cardiac comorbidities and/or advanced liver disease. Bradycardia generally resolves following discontinuation of HCV treatment. Coadministration of amiodarone and sofosbuvir in combination with another direct acting antiviral (DAA) is not recommended. However, if patients have no treatment alternatives, patients should have inpatient cardiac monitoring for the first 48 hours, followed by daily outpatient or self-monitoring of heart rate for at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, cardiac monitoring (as described) is also recommended if amiodarone was discontinued just prior to beginning treatment with sofosbuvir. Patients should seek medical attention immediately if they experience fainting or near-fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems.

• 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:

• Hepatic impairment: Safety and efficacy have not been established in patients with decompensated cirrhosis.

Other warnings/precautions:

• Appropriate use: Do not use as monotherapy; use only as part of a multiple drug regimen for treatment of HCV; consult current HCV treatment guidelines for guidance (AASLD/IDSA 2016).

Monitoring Parameters

Manufacturer’s labeling:

Bilirubin, liver enzymes, and serum creatinine at baseline and periodically when clinically indicated. If used in combination with amiodarone and another direct acting antiviral (DAA) (or in patients who discontinued amiodarone just prior to initiating sofosbuvir in combination with a DAA), inpatient cardiac monitoring for the first 48 hours of coadministration, then daily outpatient or self monitoring of heart rate through at least the first 2 weeks of treatment.

Serum HCV-RNA at baseline, during treatment, at the end of treatment, during treatment follow-up, and when clinically indicated.

Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up.

Alternate recommendations (AASLD/IDSA 2016):

Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), calculated GFR

Baseline (at any time prior to starting antiviral therapy): HCV genotype and subtype, quantitative HCV viral load

During therapy: CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6).

Pregnancy Considerations

Use in combination with ribavirin is contraindicated in pregnant women and males whose female partners are pregnant.

Sofosbuvir is only to be used in combination with ribavirin or peginterferon alfa/ribavirin for the treatment of hepatitis C virus (HCV) (according to the manufacturer's labeling), and ribavirin use is contraindicated in pregnancy. If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed.

Mother-to-child transmission of HCV does not occur if the woman is not viremic, therefore, HCV-infected women of childbearing potential should postpone pregnancy until therapy is complete. Treatment of HCV is not recommended for women who are already pregnant (AASLD/IDSA 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, or insomnia. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) and severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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