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    NS5B RNA Polymerase Inhibitor Antivirals for Hepatitis C

    BOXED WARNING

    Hepatitis B exacerbation

    Use of direct-acting antivirals (DAA), such as sofosbuvir, to treat hepatitis C virus (HCV) infection in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and hepatitis B exacerbation. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Hepatitis B reactivation has also occurred in patients receiving certain immunosuppressive or chemotherapeutic medications; the risk of HBV reactivation associated with DAA treatment may be increased in these patients. HBV reactivation is characterized as an abrupt increase in viral replication manifesting as a rapid increase in serum HBV DNA concentration. In patients with resolved HBV infection, the reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis (i.e., increases in aminotransferase concentrations) and, in severe cases, increases in bilirubin concentrations, liver failure, and death can occur. To decrease the risk of reactivating an HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring the hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). For those patients whose screening reveals serologic evidence of HBV infection, a baseline HBV DNA concentration should be obtained prior to starting sofosbuvir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If a sofosbuvir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection as clinically indicated.

    DEA CLASS

    Rx

    DESCRIPTION

    Hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor
    For chronic hepatitis C infection, genotypes 1, 2, 3, and 4, in adult patients and genotypes 2 and 3 in pediatric patients 3 years and older, including those with hepatocellular carcinoma awaiting liver transplant, and HCV/HIV coinfection
    Black Box Warning regarding reactivation of hepatitis B virus (HBV) infection in HCV/HBV coinfected patients; screen all patients for HBV before initiating treatment.

    COMMON BRAND NAMES

    Sovaldi

    HOW SUPPLIED

    Sovaldi Oral Gran: 150mg, 200mg
    Sovaldi Oral Tab: 200mg, 400mg

    DOSAGE & INDICATIONS

    For the treatment of chronic hepatitis C infection.
    NOTE: Sofosbuvir MUST be administered in combination with other antiviral agents; monotherapy is not recommended. If other antiviral agents are discontinued for any reason, then sofosbuvir must also be discontinued.
    For the treatment of chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis or with compensated (Child-Pugh A) cirrhosis.
    Oral dosage
    Treatment-naive Adults able to receive interferon products

    400 mg PO once daily in combination with peginterferon alfa and ribavirin for 12 weeks; includes HIV coinfected patients.

    Treatment-naive Adults unable to receive interferon products

    400 mg PO once daily with ribavirin for 24 weeks; however, this regimen may be less effective.

    Treatment-experienced Adults who previously failed treatment with glecaprevir; pibrentasvir†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks.

    Treatment-experienced Adults who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir or glecaprevir; pibrentasvir plus sofosbuvir)†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks. Increase the treatment duration to 24 weeks for patients with previous failure on glecaprevir; pibrentasvir plus sofosbuvir.

    For the treatment of chronic hepatitis C virus (HCV) genotype 2 infection without cirrhosis or with compensated (Child-Pugh A) cirrhosis.
    Oral dosage
    Treatment-naive and experienced (i.e., prior interferon-based regimens) Adults

    400 mg PO once daily in combination with ribavirin for 12 weeks; includes HIV coinfected patients.

    Treatment-experienced Adults who previously failed treatment with glecaprevir; pibrentasvir†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks.

    Treatment-experienced Adults who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir or glecaprevir; pibrentasvir plus sofosbuvir)†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks. Increase the treatment duration to 24 weeks for patients with previous failure on glecaprevir; pibrentasvir plus sofosbuvir.

    Children and Adolescents 3 to 17 years weighing 35 kg or more

    400 mg PO once daily in combination with ribavirin for 12 weeks; includes HIV coinfected patients.

    Children and Adolescents 3 to 17 years weighing 17 to 34 kg

    200 mg PO once daily in combination with ribavirin for 12 weeks; includes HIV coinfected patients.

    Children 3 to 12 years weighing less than 17 kg

    150 mg PO once daily (oral pellets) in combination with ribavirin for 12 weeks; includes HIV coinfected patients.

    For the treatment of chronic hepatitis C virus (HCV) genotype 3 infection without cirrhosis or with compensated (Child-Pugh A) cirrhosis.
    Oral dosage
    Treatment-naive and experienced (i.e., prior interferon-based regimens) Adults

    400 mg PO once daily in combination with ribavirin for 24 weeks; includes HIV coinfected patients.

    Treatment-experienced Adults who previously failed treatment with glecaprevir; pibrentasvir†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks.

    Treatment-experienced Adults without cirrhosis who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir or glecaprevir; pibrentasvir plus sofosbuvir)†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks. Increase the treatment duration to 24 weeks for patients with previous failure on glecaprevir; pibrentasvir plus sofosbuvir.

    Treatment-experienced Adults with compensated cirrhosis who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir or glecaprevir; pibrentasvir plus sofosbuvir)†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 24 weeks.

    Children and Adolescents 3 to 17 years weighing 35 kg or more

    400 mg PO once daily in combination with ribavirin for 24 weeks; includes HIV coinfected patients.

    Children and Adolescents 3 to 17 years weighing 17 to 34 kg

    200 mg PO once daily in combination with ribavirin for 24 weeks; includes HIV coinfected patients.

    Children 3 to 12 years weighing less than 17 kg

    150 mg PO once daily (oral pellets) in combination with ribavirin for 24 weeks; includes HIV coinfected patients.

    For the treatment of chronic hepatitis C virus (HCV) genotypes 1, 2, 3, or 4 infection in adult patients with hepatocellular carcinoma awaiting liver transplant.
    NOTE: The manufacturer has not established safe and effective use in patients with decompensated cirrhosis.
    Oral dosage
    Adults

    400 mg PO once daily in combination with ribavirin for up to 48 weeks or until liver transplant, whichever occurs first, to prevent post-transplant HCV infection.[56528]

    For the treatment of chronic hepatitis C virus (HCV) genotype 4 infection in patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis.
    Oral dosage
    Treatment-naive Adults

    400 mg PO once daily in combination with peginterferon alfa and ribavirin for 12 weeks; includes HIV coinfected patients.

    Treatment-experienced Adults who previously failed treatment with glecaprevir; pibrentasvir†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks.

    Treatment-experienced Adults who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir or glecaprevir; pibrentasvir plus sofosbuvir)†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks. Increase the treatment duration to 24 weeks for patients with previous failure on glecaprevir; pibrentasvir plus sofosbuvir.

    For the treatment of chronic hepatitis C virus (HCV) genotypes 5 or 6 infection in patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis†.
    Oral dosage
    Treatment-experienced Adults who previously failed treatment with glecaprevir; pibrentasvir†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks.

    Treatment-experienced Adults who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir or glecaprevir; pibrentasvir plus sofosbuvir)†

    Guidelines recommend sofosbuvir 400 mg PO once daily in combination with glecaprevir; pibrentasvir and weight-based ribavirin for 16 weeks. Increase the treatment duration to 24 weeks for patients with previous failure on glecaprevir; pibrentasvir plus sofosbuvir.

    For the treatment of chronic hepatitis C virus (HCV) genotypes 2 or 3 infection in pediatric patients with hepatocellular carcinoma awaiting liver transplant.
    NOTE: The manufacturer has not established safe and effective use in patients with decompensated cirrhosis.
    Oral dosage
    Children and Adolescents 3 to 17 years weighing 35 kg or more

    400 mg PO once daily in combination with ribavirin for up to 48 weeks or until liver transplant, whichever occurs first, to prevent post-transplant HCV infection.

    Children and Adolescents 3 to 17 years weighing 17 to 34 kg

    200 mg PO once daily in combination with ribavirin for up to 48 weeks or until liver transplant, whichever occurs first, to prevent post-transplant HCV infection.

    Children 3 to 12 years weighing less than 17 kg

    150 mg PO once daily (oral pellets) in combination with ribavirin for up to 48 weeks or until liver transplant, whichever occurs first, to prevent post-transplant HCV infection.

    MAXIMUM DOSAGE

    Adults

    400 mg/day PO.

    Geriatric

    400 mg/day PO.

    Adolescents

    weighing 35 kg or more: 400 mg/day PO.
    weighing 17 to 34 kg: 200 mg/day PO.

    Children

    3 to 12 years weighing 35 kg or more: 400 mg/day PO.
    3 to 12 years weighing 17 to 34 kg: 200 mg/day PO.
    3 to 12 years weighing less than 17 kg: 150 mg/day PO.
    1 to 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Safety and efficacy have not been established in patients with decompensated liver disease.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed for mild or moderate renal impairment. Safety and efficacy have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or end stage renal disease requiring hemodialysis.

    ADMINISTRATION

     
    NOTE: Sofosbuvir MUST be administered in combination with other antiviral agents; monotherapy is not recommended. If other antiviral agents are discontinued for any reason, then sofosbuvir must also be discontinued.

    Oral Administration

    May be administered with or without food.

    Oral Solid Formulations

    Oral pellets
    Inspect the packaging for damage. Do not use if the carton tamper-evident seal or the pellet packet seal is broken or damaged.
    Do not open packets until ready for use; shake the pellets packet gently to settle the pellets.
    If pellets are taken with food:
    Add 1 or more spoonfuls of non-acidic soft food (i.e., pudding, chocolate syrup, mashed potato, ice cream) to a bowl at or below room temperature.
    Sprinkle the entire contents of the prescribed number of pellet packets onto the food in the bowl.
    Gently mix with a spoon.
    Ingest pellets within 30 minutes of mixing with food and swallow entire contents without chewing to avoid a bitter taste. Do not store any leftover oral pellets mixed with food for use at a later time.
    If pellets are taken without food:
    Pour the entire contents of the pellet packet directly in the mouth and swallow without chewing to avoid a bitter taste.
    If needed, water may be taken after swallowing the pellets.
    Repeat the process if more than 1 pellet packet is prescribed.
    Discard any unused portion.[56528]

    STORAGE

    Sovaldi:
    - Store below 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Missing doses of direct-acting antiviral (DAA) therapy, such as sofosbuvir, is relatively common; however, outcome data in patients with incomplete adherence is limited and the threshold at which a lack of adherence to treatment results in a reduced systemic viral response (SVR) is unknown. Based on adherence and outcome data from the SIMPLIFY study, HCV guidelines consider a treatment interruption of less than 7 days unlikely to impact the SVR. Longer durations of missed doses, however, may affect the response to treatment. In these cases, the patient should be managed in consultation with an expert. Question all patients with incomplete adherence about contributing factors and counsel them regarding the importance of adherence to treatment.

    Pregnancy

    There are no well controlled studies evaluating the use of sofosbuvir during human pregnancy. In animal studies involving rats and rabbits, no adverse effects on fetal development were observed with sofosbuvir. However, in certain patient populations, sofosbuvir must be administered with ribavirin, which is contraindicated during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all the animal species tested. To monitor maternal-fetal outcomes of pregnancies in female patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patients who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    Breast-feeding

    It is unknown whether sofosbuvir or its metabolites are excreted in human milk, affect milk production, or have an adverse effect on nursing infants. Simeprevir may be considered as an alternative; however, its excretion into human breast milk is also unknown. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    In certain patient populations, sofosbuvir is administered with ribavirin, which is contraindicated in females who may become pregnant or in men whose female partners are pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Ribavirin therapy may also cause male-mediated teratogenicity. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all the animal species tested. Counsel patients about the reproductive risk and contraception requirements during ribavirin treatment. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking ribavirin or within 6 months after discontinuation of treatment, the healthcare provider should be informed right away. Patients who are not willing to practice strict contraception should not receive sofosbuvir and ribavirin. Females must also undergo pregnancy testing immediately prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patients who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    Renal failure, renal impairment

    Safety and efficacy of sofosbuvir have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or end stage renal failure. Compared to individuals with normal renal function, patients with mild, moderate, and severe renal impairment display increased exposure to the parent drug sofosbuvir (61%, 107%, and 171% higher, respectively) and the major metabolite, GS-331007, (55%, 88%, and 451% higher, respectively). Exposure to sofosbuvir and GS-331007 in patients with end stage renal failure, as compared to those with normal renal function, is 28% and 1,280% higher, respectively, when dosed 1 hour before hemodialysis and 60% and 2,070% higher, respectively, when dosed 1 hour after hemodialysis.

    Hepatic disease

    The manufacturer has not established the safety and efficacy of sofosbuvir in patients with decompensated hepatic disease or decompensated cirrhosis.

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all adult and adolescent patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. Additionally, perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive adult and adolescent patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with hepatitis C and HIV coinfection who have no contraindications to treatment. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Hepatitis B exacerbation

    Use of direct-acting antivirals (DAA), such as sofosbuvir, to treat hepatitis C virus (HCV) infection in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and hepatitis B exacerbation. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Hepatitis B reactivation has also occurred in patients receiving certain immunosuppressive or chemotherapeutic medications; the risk of HBV reactivation associated with DAA treatment may be increased in these patients. HBV reactivation is characterized as an abrupt increase in viral replication manifesting as a rapid increase in serum HBV DNA concentration. In patients with resolved HBV infection, the reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis (i.e., increases in aminotransferase concentrations) and, in severe cases, increases in bilirubin concentrations, liver failure, and death can occur. To decrease the risk of reactivating an HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring the hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). For those patients whose screening reveals serologic evidence of HBV infection, a baseline HBV DNA concentration should be obtained prior to starting sofosbuvir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If a sofosbuvir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection as clinically indicated.

    Anticoagulant therapy

    Caution is advised when prescribing sofosbuvir to patients receiving concurrent anticoagulant therapy, specifically warfarin. Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.

    Diabetes mellitus, hyperglycemia, hypoglycemia

    A safety review of direct-acting antivirals (DAAs) was conducted and it was determined that there is an association between these medications and episodes of dysglycemia (both hypoglycemia and hyperglycemia). At the time of the safety review, 36 case reports describing a possible link between the use of DAAs and dysglycemia were identified. Of the 36 reports, 24 were related to hyperglycemia or new-onset diabetes (including 1 death), 8 were related to hypoglycemia or improved diabetes, and 4 were reported as other (1 abnormal blood glucose, 2 loss of blood glucose control, 1 both hyperglycemia and hypoglycemia). A further evaluation concluded that 27 of the case reports (including the 1 fatality) were possibly linked to the use of a DAA, 3 were not likely associated with DAA use, and the rest could not be assessed due to insufficient data. Closely monitor blood glucose concentrations during treatment with sofosbuvir. For patients with diabetes mellitus who are receiving concurrent treatment with antidiabetic agents, dose adjustments of the antidiabetic agents may be needed in order to prevent the occurrence of hypoglycemia.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    anemia / Delayed / 6.0-21.0
    neutropenia / Delayed / 0-17.0
    hyperbilirubinemia / Delayed / 3.0-3.0
    depression / Delayed / 0-1.0

    Mild

    fatigue / Early / 38.0-59.0
    headache / Early / 24.0-36.0
    nausea / Early / 13.0-34.0
    pruritus / Rapid / 11.0-27.0
    insomnia / Early / 15.0-25.0
    asthenia / Delayed / 5.0-21.0
    weakness / Early / 5.0-21.0
    fever / Early / 4.0-18.0
    anorexia / Delayed / 6.0-18.0
    rash / Early / 8.0-18.0
    chills / Rapid / 2.0-17.0
    myalgia / Early / 6.0-14.0
    irritability / Delayed / 10.0-13.0
    diarrhea / Early / 9.0-12.0

    DRUG INTERACTIONS

    Acalabrutinib: (Moderate) Coadministration of acalabrutinib and sofosbuvir may increase the exposure and the risk of toxicity of sofosbuvir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sofosbuvir is a BCRP transporter substrate.
    Acarbose: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Acetohexamide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Albiglutide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Alogliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Alogliptin; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Alogliptin; Pioglitazone: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Amiodarone: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
    Antidiabetic Agents: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Apalutamide: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp) and BCRP, such as apalutamide. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Atazanavir; Cobicistat: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenobarbital. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Canagliflozin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Canagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Carbamazepine: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as carbamazepine. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Carvedilol: (Minor) Coadministration of sofosbuvir and carvedilol may result in elevated sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp); carvedilol is a P-gp inhibitor. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect.
    Chlorpropamide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Cobicistat: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
    Conivaptan: (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
    Dapagliflozin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Dapagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Dapagliflozin; Saxagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Darunavir; Cobicistat: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together (Moderate) Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together.
    Dulaglutide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
    Empagliflozin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Empagliflozin; Linagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Empagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Ertugliflozin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Ertugliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Ertugliflozin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Exenatide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Fosamprenavir: (Moderate) Caution is advised when administering sofosbuvir with fosamprenavir, as concurrent use may result in reduced sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is a P-gp inducer.
    Fosphenytoin: (Major) Avoid coadministration of sofosbuvir with fosphenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Glimepiride: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Glimepiride; Rosiglitazone: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Glipizide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Glipizide; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Glyburide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Glyburide; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Aspart: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Aspart; Insulin Aspart Protamine: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Degludec; Liraglutide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Detemir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Glargine: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Glargine; Lixisenatide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Glulisine: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Lispro: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin Lispro; Insulin Lispro Protamine: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Insulin, Inhaled: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
    Isophane Insulin (NPH): (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Itraconazole: (Minor) Itraconazole and sofosbuvir may be given together with caution. Taking these drugs together may increase plasma concentrations of sofosbuvir, without increasing GS-331007 plasma concentrations. Sofosbuvir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor; itraconazole is a P-gp and BCRP inhibitor.
    Lente Insulin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Linagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Linagliptin; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Liraglutide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Lixisenatide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Lumacaftor; Ivacaftor: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of sofosbuvir and lumacaftor; ivacaftor may alter sofosbuvir exposure; caution and close monitoring are advised if these drugs are used together. Sofosbuvir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. FDA-approved labeling for sofosbuvir recommends to avoid coadministration with potent P-gp inducers.
    Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Metformin; Repaglinide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Metformin; Rosiglitazone: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Metformin; Saxagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Metformin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Miglitol: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Nateglinide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Osimertinib: (Moderate) Monitor for an increase in sofosbuvir-related adverse reactions if coadministration with osimertinib is necessary. Sofosbuvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Oxcarbazepine: (Major) Avoid coadministration of sofosbuvir with oxcarbazepine. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Phenobarbital: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenobarbital. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenobarbital. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Phenytoin: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Pioglitazone: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Pioglitazone; Glimepiride: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Pioglitazone; Metformin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Pramlintide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Primidone: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein, such as primidone. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Regular Insulin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Regular Insulin; Isophane Insulin (NPH): (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Repaglinide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Rifabutin: (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Rifampin: (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
    Rifapentine: (Major) Avoid coadministration of sofosbuvir with rifapentine. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Rolapitant: (Moderate) Use caution if sofosbuvir and rolapitant are used concurrently, and monitor for sofosbuvir-related adverse effects. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Rosiglitazone: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Saxagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Semaglutide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Simeprevir: (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects.
    Simvastatin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Sitagliptin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate with inducers of P-gp, such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Tacrolimus: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as sofosbuvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations.
    Tafamidis: (Minor) Caution is advised with the coadministration of tafamidis and sofosbuvir as coadminstration may increase the plasma concentrations of sofosbuvir and increase the risk of adverse effects. Sofosbuvir is a substrate of the breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
    Tedizolid: (Moderate) If possible, stop use of sofosbuvir temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for sofosbuvir-associated adverse events. Sofosbuvir plasma concentrations may be increased when administered concurrently with oral tedizolid. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
    Tipranavir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor.
    Tolazamide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Tolbutamide: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Ultralente Insulin: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Warfarin: (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including sofosbuvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no well controlled studies evaluating the use of sofosbuvir during human pregnancy. In animal studies involving rats and rabbits, no adverse effects on fetal development were observed with sofosbuvir. However, in certain patient populations, sofosbuvir must be administered with ribavirin, which is contraindicated during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all the animal species tested. To monitor maternal-fetal outcomes of pregnancies in female patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patients who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    In certain patient populations, sofosbuvir is administered with ribavirin, which is contraindicated in females who may become pregnant or in men whose female partners are pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Ribavirin therapy may also cause male-mediated teratogenicity. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all the animal species tested. Counsel patients about the reproductive risk and contraception requirements during ribavirin treatment. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking ribavirin or within 6 months after discontinuation of treatment, the healthcare provider should be informed right away. Patients who are not willing to practice strict contraception should not receive sofosbuvir and ribavirin. Females must also undergo pregnancy testing immediately prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patients who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    MECHANISM OF ACTION

    Sofosbuvir is a nucleotide prodrug that prevents hepatitis C viral (HCV) replication by inhibiting the activity of HCV NS5B RNA polymerase. It undergoes intracellular metabolism to form GS-461203, a pharmacologically active uridine analog triphosphate. Hepatitis C virus NS5B RNA polymerase incorporates this metabolite into the viral RNA, where it acts as a chain terminator. GS-461203 does not inhibit human DNA or RNA polymerase, nor does it block mitochondrial RNA polymerase.
     
    In cell cultures, recombinant NS5B polymerase expressing a S282T substitution displayed a 2- to 18-fold decrease in susceptibility to sofosbuvir. This substitution was not detected at baseline or in failure isolates from Phase 3 clinical trials; however, it was detected in 1 patient who received sofosbuvir monotherapy for the treatment of HCV genotype 2 infection. The isolate from this patient displayed a 13.5-fold decrease in susceptibility to sofosbuvir. While susceptibility is reduced with the S282T substitution, these viruses remain susceptible to NS5A inhibitors and ribavirin. Cross resistance is not expected between sofosbuvir and ribavirin, NS3/4A protease inhibitors, NS5B non-nucleoside inhibitors, or NS5A inhibitors.

    PHARMACOKINETICS

    Sofosbuvir is administered orally. After administration, approximately 61% to 65% is bound to plasma protein. In the liver, sofosbuvir is converted from the nucleotide prodrug to the pharmacologically active nucleoside analog triphosphate, GS-461203. This conversion occurs via hydrolysis of the carboxy ester moiety by human cathepsin A (CatA) or carboxylesterase 1 (CES1), phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT 1), and phosphorylation by pyrimidine nucleotide biosynthesis pathway. GS-461203 is then further metabolized by dephosphorylation to form GS-331007, a metabolite that lacks anti-HCV activity and cannot be rephosphorylated. GS-331007 is the predominant circulating metabolite and represents more than 90% of drug related material, while the parent drug accounts for approximately 4%. Elimination occurs primarily through the kidneys with approximately 80% of the dose recovered in the urine (78% as GS-331007, 3.5% as sofosbuvir). Other routes of elimination include the feces (14%) and expired air (2.5%). The median terminal elimination half-lives of sofosbuvir and GS-331007 are 0.4 and 27 hours, respectively.[56528]
     
    Affected drug transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)
    Sofosbuvir is a substrate of the drug transporters P-gp and BCRP. Inducers and inhibitors of these transporters may alter the plasma concentration of sofosbuvir. The major metabolite, GS-331007, is not a substrate of either P-gp or BCRP. Drugs that induce P-gp may reduce the therapeutic effect of sofosbuvir; however, the FDA-labeling suggests that inhibitors of P-gp and BCRP may be coadministered with sofosbuvir. In clinical trials, no clinically significant interaction was noted when sofosbuvir was administered with darunavir and ritonavir (P-gp inhibitors) or cyclosporine (a P-gp and BCRP inhibitor).[32432] [34375] [51834] [56528]

    Oral Route

    After oral administration, the time to reach maximum plasma concentrations (Tmax) is 0.5 to 2 hours for the parent drug sofosbuvir and 2 to 4 hours for the major metabolite GS-331007. The geometric mean steady state concentrations (AUC) for sofosbuvir and GS-331007 in patients infected with hepatitis C are 969 ng x hour/mL and 6,790 ng x hour/mL, respectively. When compared to data from healthy subjects, these concentrations are 60% higher for sofosbuvir and 39% lower for GS-331007. Food does not alter the pharmacokinetic parameters of sofosbuvir or GS-331007.[56528]