Sofosbuvir

Sofosbuvir comes as a tablet to take by mouth. It is usually taken with or without food once a day. Take sofosbuvir at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take sofosbuvir exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Continue to take sofosbuvir even if you feel well. Sofosbuvir must be taken in combination with peginterferon alfa and ribavirin or in combination with ribavirin alone. If sofosbuvir is taken in combination with peginterferon alfa and ribavirin, it is usually taken for 12 weeks. If sofosbuvir is taken in combination with ribavirin alone, it is usually taken for 12 or 24 weeks. If you have liver cancer and are waiting for a liver transplant, you will take sofosbuvir with ribavirin for up to 48 weeks or until you have a liver transplant. The length of your treatment depends on your condition, how well you respond to the medication, and whether you experience severe side effects. Do not stop taking sofosbuvir, peginterferon alfa, or ribavirin, unless told to do so by your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

Sofosbuvir is used in combination with ribavirin (Rebetol, Copegus) or ribavirin plus interferon to treat hepatitis C virus (HCV) genotypes 1, 2, 3, or 4 infection.

The most common side effects reported by patients include:

• Fatigue
• Headache
• Nausea
• Insomnia
• Anemia
• Itching

Other side effects include:

• Decreased appetite
• Diarrhea
• Irritability
• Rash
• Muscle pain
• Flu-like symptoms
• Reduced blood cells,
• Severe depression, and
• Increases in bilirubin levels

Dosage Forms And Strengths

Each VOSEVI tablet contains 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir. The tablets are beige, capsule-shaped, film-coated, and debossed with “GSI” on one side and “ 3 ” on the other side.

Storage And Handling

Each VOSEVI tablet contains 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir. The tablets are beige, capsule-shaped, film-coated, and debossed with “GSI” on one side and “ 3 ” on the other side. Each bottle contains 28 tablets (NDC 61958-2401-1), polyester coil, silica gel desiccant, and is closed with a child-resistant closure.

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

Distributed by: Gilead Sciences, Inc., Foster City, CA 94404. Revised: July 2017.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if sofosbuvir crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using sofosbuvir.

Sofosbuvir is an antiviral medication that prevents hepatitis C virus (HCV) from multiplying in your body.

Sofosbuvir is used in combination with other medications to treat hepatitis C in adults and children who are at least 12 years old or who weigh at least 77 pounds (35 kilograms).

Sofosbuvir is sometimes used in people who also have HIV, or people who have liver cancer and are going to have a liver transplant. Sofosbuvir is not a treatment for HIV or AIDS.

Sofosbuvir must be given in combination with other antiviral medications and should not be used alone. Sofosbuvir is usually given with ribavirin (Copegus, Rebetol, Ribasphere, RibaTab) with or without peginterferon alfa (Pegasys, PegIntron).

Sofosbuvir may also be used for purposes not listed in this medication guide.

Taking this medication will not prevent you from passing hepatitis C to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HCV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

If you take sofosbuvir and you also take a heart rhythm medicine called amiodarone: This combination of medicines can cause dangerous side effects on your heart. Get medical help right away if you take these medicines and you have:

• very slow heartbeats, chest pain, shortness of breath;

• confusion, weakness, extreme tiredness; or

• a light-headed feeling, like you might pass out.

Call your doctor at once if you have:

• low red blood cells (anemia)--pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating.

Common side effects may include:

• headache, feeling tired;

• anemia;

• nausea; or

• sleep problems (insomnia);

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Antiviral;1 nucleotide analog HCV NS5B polymerase inhibitor.1

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, or 4 infection in adults, including those with HIV coinfection and those with hepatocellular carcinoma awaiting liver transplantation.1 119

Treatment of chronic HCV infection caused by genotype 5† or 6†;1 2 119 only limited data available.1 2 119

Must be used in conjunction with other antivirals;1 119 do not use alone.1 119

Used in multiple-drug regimen that includes sofosbuvir and ribavirin (with or without peginterferon alfa),1 2 3 4 5 11 multiple-drug regimen that includes sofosbuvir and simeprevir,12 119 183 or multiple-drug regimen that includes sofosbuvir and daclatasvir (with or without ribavirin).8 9 10 119 178

Used in conjunction with ledipasvir;119 181 fixed combination containing ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) commercially available.181

Used in conjunction with velpatasvir;176 fixed combination containing sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) commercially available.176

Specific multiple-drug treatment regimen and duration of treatment with sofosbuvir and other antivirals depend on HCV genotype and patient population.1

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Substrate of P-glycoprotein (P-gp) transport system;1 predominant metabolite (GS-331007) not a P-gp substrate.1 Sofosbuvir and GS-331007 do not inhibit P-gp.1

Substrate of breast cancer resistance protein (BCRP);1 GS-331007 is not a BCRP substrate.1 Sofosbuvir and GS-331007 do not inhibit BCRP.1

Drugs Affecting P-glycoprotein Transport System

P-gp inducers: Possible decreased sofosbuvir plasma concentrations leading to reduced therapeutic effect.1

Drugs Affecting Breast Cancer Resistance Protein

BCRP inhibitors: Possible increased sofosbuvir plasma concentrations without increase in plasma concentrations of GS-331007.1

Specific Drugs

Absorption

Bioavailability

Following oral administration, peak plasma concentrations of sofosbuvir and predominant metabolite (GS-331007) occur approximately 0.5–2 and 2–4 hours, respectively, after a dose.1

Sofosbuvir and GS-331007 account for approximately 4 and 90% of systemic exposure, respectively, after a single 400-mg dose.1

Food

High-fat meal does not substantially affect sofosbuvir or GS-331007 peak plasma concentrations or AUC relative to fasting state.1

Special Populations

Compared with healthy individuals receiving sofosbuvir alone, sofosbuvir AUC is 39% higher and GS-331007 AUC is 39% lower in HCV-infected individuals.1

In patients with moderate or severe hepatic impairment (Child-Pugh class B or C), sofosbuvir AUC is 126 or 143% higher, respectively, compared with patients with normal hepatic function; GS-331007 AUC is 18 or 9% higher, respectively.1 Population pharmacokinetics analysis in HCV-infected patients indicates that cirrhosis does not substantially affect sofosbuvir or GS-331007 exposure.1

In patients with mild, moderate, or severe renal impairment, sofosbuvir AUC is 61, 107, or 171% higher, respectively, compared with patients with normal renal function;1 GS-331007 AUC is 55, 88, or 451% higher, respectively.1

Population pharmacokinetic analysis indicates age (range 19–75 years), race, and gender do not have clinically important effects on sofosbuvir pharmacokinetics.1

Distribution

Plasma Protein Binding

Sofosbuvir: Approximately 61–65%.1

GS-331007: Minimal protein binding.1

Elimination

Metabolism

Sofosbuvir is a prodrug.1 Undergoes intracellular metabolic activation in the liver (hydrolysis by human cathepsin A [CatA] or carboxylesterase 1 [CES1], phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 [HINT1], and phosphorylation by pyrimidine nucleotide biosynthesis pathway).1 7 Results in formation of pharmacologically active metabolite, GS-461203.1

Desphosphorylation subsequently occurs leading to formation of GS-331007 (the predominant circulating metabolite) which has no anti-HCV activity.1

Elimination Route

Eliminated in urine (80%, mainly as GS-331007), in feces (14%), and in expired air (2.5%).1

Half-life

Sofosbuvir: 0.4 hours.1

GS-331007: 27 hours.1

Special Populations

Hemodialysis (4-hour session) removes approximately 18% of dose.1

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Refer to adult dosing.

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

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, severe depression, suicidal ideation

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).

Animal studies have failed to reveal evidence of fetal harm. There are no controlled data in human pregnancy. Monotherapy is not recommended. Pregnancy must be avoided in female patients and female partners of male patients using a ribavirin-containing regimen. All animal species exposed to ribavirin have shown significant teratogenic and/or embryocidal effects. Females of reproductive potential and their male partners should not receive ribavirin unless they are using effective contraception during therapy and for 6 months after therapy. AU TGA pregnancy category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage. AU TGA pregnancy category X: Drugs which have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Use of a ribavirin-containing regimen is contraindicated in pregnant women and in the male partners of women who are pregnant; sofosbuvir should not be used as monotherapy. -According to some authorities: As a precaution, it is preferable to avoid use of sofosbuvir during pregnancy. For regimens containing ribavirin or peginterferon alfa: -AU TGA pregnancy category: X For sofosbuvir: -AU TGA pregnancy category: B1 -US FDA pregnancy category: Not assigned. Risk summary: No data available on use of this drug in pregnant women to inform a drug-related risk. Comments: -The manufacturer product information for ribavirin and peginterferon alfa should be consulted regarding use during pregnancy and use in females and males of reproductive potential. -Effective contraception is required during ribavirin therapy and for 6 months after the last dose; local protocol should be consulted regarding contraception timing.