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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%)

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. A 4 hour hemodialysis session removed approximately 18% of administered dose.

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 (CHC) as a component of a combination antiviral treatment regimen.

Guideline recommendations: Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current AASLD/IDSA clinical practice guidelines for the most recent treatment recommendations.

Use: Unlabeled

Chronic hepatitis C: Treatment of genotype 5 or 6 chronic hepatitis C (CHC)

Contraindications

All contraindications also applicable to ribavirin and peginterferon alfa including women who are pregnant or who may become pregnant and use by male partners of pregnant women.

Also refer to Peginterferon Alfa and Ribavirin monographs for individual product contraindications.

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

Dosing: Adult

Chronic hepatitis C (CHC) infection in monoinfected (HCV) patients: Oral:

Manufacturer’s labeling: 400 mg daily with concomitant ribavirin and with or without peginterferon alfa (maximum: 400 mg daily).

Treatment regimen and duration based on HCV genotype and/or clinical scenario as noted below:

Sofosbuvir Combination Therapy Regimens and Treatment Durationa

Patient population

Treatment

Duration

aHepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current AASLD/IDSA clinical practice guidelines for the most recent treatment recommendations.

bSee ribavirin and peginterferon alfa monographs for dosing recommendation.

cCombination therapy with ribavirin or ribavirin/peginterferon are not recommended regimens in HCV treatment guidelines for patients with HCV, regardless of genotype (treatment-naïve or treatment-experienced) (AASLD/IDSA 2016).

Genotype 1 chronic hepatitis C

Patients who can receive interferon:400 mg once daily + peginterferon alfab,c + ribavirinb,c

12 weeks

Patients who cannot receive interferon:400 mg once daily + ribavirinb,c

24 weeks

Genotype 2 chronic hepatitis C

400 mg once daily + ribavirinb,c

12 weeks

Genotype 3 chronic hepatitis C

400 mg once daily + ribavirinb,c

24 weeks

Genotype 4 chronic hepatitis C

400 mg once daily + peginterferon alfab,c + ribavirinb,c

12 weeks

Hepatocellular carcinoma patients awaiting liver transplantation

400 mg once daily + ribavirinb,c

48 weeks or until the time of liver transplantation, whichever occurs first

Sofosbuvir Combination Therapy Regimens and Treatment Duration

Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current AASLD/IDSA clinical practice guidelines for the most recent treatment recommendations.

Refer to ribavirin and peginterferon alfa monographs for dosing recommendations.

Genotype 1:

Patients who can receive interferon: 400 mg once daily with concomitant peginterferon alfa and ribavirin for 12 weeks. Note: Combination therapy with ribavirin or ribavirin/peginterferon is not a recommended regimen in HCV treatment guidelines for patients with HCV regardless of genotype (treatment-naive or treatment-experienced) (AASLD/IDSA 2016).

Patients who cannot receive interferon: 400 mg once daily plus ribavirin for 24 weeks. Note: Combination therapy with ribavirin or ribavirin/peginterferon is not a recommended regimen in HCV treatment guidelines for patients with HCV regardless of genotype (treatment-naive or treatment-experienced) (AASLD/IDSA 2016).

Genotype 2: 400 mg once daily with concomitant ribavirin for 12 weeks. Note: Combination therapy with ribavirin or ribavirin/peginterferon is not a recommended regimen in HCV treatment guidelines for patients with HCV regardless of genotype (treatment-naive or treatment-experienced) (AASLD/IDSA 2016).

Genotype 3: 400 mg once daily with concomitant ribavirin for 24 weeks. Note: Combination therapy with ribavirin or ribavirin/peginterferon is not a recommended regimen in HCV treatment guidelines for patients with HCV regardless of genotype (treatment-naive or treatment-experienced) (AASLD/IDSA 2016).

Genoptype 4: 400 mg once daily with concomitant peginterferon alfa and ribavirin for 12 weeks. Note: Combination therapy with ribavirin or ribavirin/peginterferon is not a recommended regimen in HCV treatment guidelines for patients with HCV regardless of genotype (treatment-naive or treatment-experienced) (AASLD/IDSA 2016).

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: Combination therapy with ribavirin or ribavirin/peginterferon is not a recommended regimen in HCV treatment guidelines for patients with HCV regardless of genotype (treatment-naive or treatment-experienced) (AASLD/IDSA 2016).

Missed dose: If a dose is missed within the calendar day it is usually taken, take as soon as possible. If the calendar day when the dose is usually taken has passed, do not take the missed dose and resume the usual dosing schedule. Do not take >400 mg daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Sofosbuvir:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

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

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

Peginterferon Alfa and Ribavirin: Refer to individual monographs.

Dosing: Hepatic Impairment

Child-Pugh class A, B, or C: No dosage adjustment necessary.

Decompensated cirrhosis: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied).

Peginterferon Alfa and Ribavirin: Refer to individual monographs; peginterferon alfa is contraindicated in hepatic decompensation.

Dosing: Adjustment for Toxicity

Sofosbuvir requires no dosage adjustment; concomitant agents should be adjusted as described below:

Patients with Genotype 1 or 4: Dose reduction dependent upon ribavirin and/or peginterferon doses; refer to individual monographs.

Patients with Genotype 2 or 3 without cardiac history:

Hemoglobin 8.5 to <10 g/dL: Decrease ribavirin dose to 600 mg daily in divided doses (eg, 200 mg in the morning, 400 mg in the evening).

Hemoglobin <8.5 g/dL: Permanently discontinue treatment.

Patients with Genotype 2 or 3 with stable cardiac history:

Hemoglobin has decreased ≥2 g/dL during any 4-week period of treatment: Decrease ribavirin dose to 600 mg daily in divided doses (eg, 200 mg in the morning, 400 mg in the evening).

Hemoglobin has decreased to <12 g/dL despite 4 weeks at reduced dose: Permanently discontinue treatment.

Note: Once ribavirin has been withheld due to clinical adverse event or laboratory abnormality, an attempt to restart ribavirin at 600 mg daily (in divided doses) can be made, with a further ribavirin increase to 800 mg daily. Increasing the ribavirin dose to its original level (usually 1000-1200 mg daily) is not recommended.

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

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

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

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, severe depression, suicidal ideation

Warnings/Precautions

Concurrent drug therapy issues:

• Amiodarone: Symptomatic bradycardia (some requiring pacemaker intervention) has occurred in patients receiving amiodarone and sofosbuvir in combination with simeprevir or an investigational NS5A inhibitor. Fatal cardiac arrest occurred when a patient took 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 sofosbuvir. 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, including use with potent P-gp inducers (eg, rifampin, St John’s wort) or amiodarone in combination with an additional direct acting antihepaciviral. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: Combination therapy with ribavirin may cause birth defects and/or death of the exposed fetus; avoid pregnancy in females and female partners of male patients during therapy and for at least 6 months following treatment; two nonhormonal forms of effective contraception must be used. Combination therapy with ribavirin is contraindicated in pregnancy.

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 2015).

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.

Pretreatment and monthly pregnancy tests up to 6 months following discontinuation of therapy for women of childbearing age.

Alternate recommendations (AASLD/IDSA 2015):

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 Risk Factor

B (sofosbuvir)/X (in combination with ribavirin or peginterferon alfa/ribavirin)

Pregnancy Considerations

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

Adverse events were not observed in animal reproduction studies using sofosbuvir; however, 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 2015).

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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