Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor approved for the treatment of chronic hepatitis C virus (HCV) infection in adults (genotypes 1, 2, 3, and 4) and pediatric patients 3 years and older (genotypes 2 and 3) without cirrhosis or with compensated hepatic disease. The drug is also approved to treat HCV infection in patients with hepatocellular carcinoma who are awaiting liver transplant and in patients who are coinfected with HIV. In some patients, treatment with sofosbuvir may preclude the need for concomitant interferon therapy; however, monotherapy is NOT recommended. The product labeling contains a Black Box Warning regarding reactivation of hepatitis B virus (HBV) infection in HCV/HBV coinfected patients who receive sofosbuvir without concurrent HBV therapy. All potential recipients of sofosbuvir should be tested for evidence of current or prior HBV infection before initiating treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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.
Route-Specific Administration
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.
Safety of sofosbuvir was assessed in Phase 3 clinical trials in which the drug was administered in combination with either ribavirin or peginterferon alfa and ribavirin; similar adverse reactions and frequencies were reported with both treatment regimens. For more information regarding adverse reactions to either ribavirin or peginterferon, see the Ribavirin or Peginterferon alfa monographs.
Fatigue (38% to 59%), headache (24% to 36%), insomnia (15% to 25%), and asthenia or weakness (5% to 21%) were among the most frequent adverse events associated with the use of sofosbuvir, ribavirin and sofosbuvir, peginterferon alfa, ribavirin during clinical trials. Other adverse events experienced by recipients of the 2- and 3-drug treatment regimens were pyrexia or fever (4% to 18%), chills (2% to 17%), influenza-like symptoms (3% to 16%), myalgia (6% to 14%), and irritability (10% to 13%).
Gastrointestinal adverse events reported by recipients of sofosbuvir, ribavirin, and sofosbuvir, peginterferon alfa, ribavirin during clinical trials included nausea (13% to 34%), anorexia or decreased appetite (6% to 18%), and diarrhea (9% to 12%).
Pruritus and rash were observed in 11% to 27% and 8% to 18% of drug recipients, respectively, during sofosbuvir, ribavirin, and sofosbuvir, peginterferon alfa, ribavirin clinical trials. Skin rash, sometimes with blisters or angioedema-like swelling, has been reported with sofosbuvir in postmarketing surveillance.
Hematologic adverse events experienced by recipients of sofosbuvir, ribavirin and sofosbuvir, peginterferon alfa, ribavirin during clinical trials included anemia (6% to 21%) and neutropenia (17% or less). Pancytopenia (less than 1%) was also observed; however, it was deemed to occur primarily in patients receiving concurrent peginterferon therapy. An evaluation of hematologic parameters found patients treated with the 2- and 3-drug treatment regimens experienced decreases in hemoglobin concentrations (less than 10 g/dL, 6% to 23%; less than 8.5 g/dL, 1% to 2%), neutrophil concentrations (0.5 to 0.74 x109/L, 15% or less; less than 0.5 x109/L, 5% or less), and platelet concentrations (25 to 49 x109/L, 1% or less). Other laboratory abnormalities included hyperbilirubinemia (more than 2.5-times upper limit of normal (ULN), 3%), isolated asymptomatic increases in creatine kinase (at least 10-times ULN, 1% to 2%), and increased lipase concentrations (more than 3-times ULN, 2% or less). Elevated bilirubin concentrations were not associated with increased transaminases, peaked within the first 2 weeks of treatment, and subsequently declined to baseline levels by post-treatment week 4.
Severe depression, including suicide and suicidal ideation, were observed in less than 1% of patients receiving treatment with sofosbuvir, ribavirin and sofosbuvir, peginterferon alfa, ribavirin during clinical trials. These adverse events occurred primarily in patients with a pre-existing history of psychiatric illness.
Hepatitis B exacerbation (including fulminant hepatitis, hepatic failure requiring liver transplant, and death) has been reported in patients coinfected with hepatitis B and C receiving treatment with direct-acting antivirals (DAA), such as sofosbuvir. The exact mechanism is unknown; however, a commonly reported sequence of events includes initiation of a DAA-based HCV regimen, rapid drop in HCV RNA to undetectable levels within 1 to 2 weeks of liver enzyme normalization, followed by a rise in HBV DNA (with or without increased transaminases) between treatment weeks 4 and 8.
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.
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.
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.
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.
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.
The manufacturer has not established the safety and efficacy of sofosbuvir in patients with decompensated hepatic disease or decompensated cirrhosis.
HIV treatment guidelines recommend all adult and adolescent patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). Additionally, perform HCV screening in any child whose mother is known to have HCV infection. For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experienced with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. 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 HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
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.
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.
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.
Initiation of therapy for HCV infection:
-HCV screening (i.e., HCV-antibody for initial screening, HCV-RNA for confirmation of active infection) recommended for:
-All persons 18 years and older (a 1-time, routine, opt-out test)
-All persons younger than 18 years with any of the below activities, exposures, or conditions and circumstances associated with an increased risk of HCV infection (a 1-time test)
-Each pregnancy (testing as part of routine prenatal care)
-All persons with any of the below activities, exposures, or conditions and circumstances associated with an increased risk of HCV infection (periodic repeat testing)
-All persons who inject drugs (annual testing)
-Men with HIV who have unprotected sex with men, and men who have sex with men taking HIV pre-exposure prophylaxis (annual testing)
-HCV risk-associated activities, exposures, or conditions and circumstances include:-Activities: injection drug use (current or ever, including those who injected only once); intranasal illicit drug use; use of glass crack pipes; engagement in chem sex (i.e., combining sex with nonprescription drugs to facilitate or enhance sexual encounter); men who have sex with men.
-Exposures: persons on long-term hemodialysis (ever); persons with percutaneous or parenteral exposures in an unregulated setting; healthcare, emergency medical, and public safety workers after needlestick, sharps, or mucosal exposure to HCV-infected blood; children born to mothers with HCV; persons who were ever incarcerated; certain recipients of a prior transfusion or organ transplant (i.e., received blood from a donor who later tested positive for HCV; received a blood transfusion or blood component, or underwent an organ transplant before July 1992; received clotting factor concentrates produced before 1987).
-Conditions and Circumstances: HIV or HBV infection; sexually active persons about to start pre-exposure prophylaxis for HIV; chronic hepatic disease or chronic hepatitis, including unexplained elevated ALT concentrations; solid organ donors and recipients.
-Treatment is recommended for all patients with acute or chronic HCV infection, except those with short life expectancy that cannot be remediated by HCV therapy, liver transplantation or other direct therapy.
-Laboratory tests recommended prior to initiating antiviral therapy: quantitative HCV-RNA test to document baseline viral load; HCV genotype and subtype test (if starting a non-pangenotypic direct-acting antiviral [DAA]); HBsAg test for active HBV coinfection, and anti-HBs and anti-HBc test for prior HBV coinfection (if starting DAA); test for HIV coinfection (if starting DAA).
Place in therapy for HCV infection:
-Recommended therapy for:-treatment-experienced (i.e., glecaprevir; pibrentasvir failures) adult patients with genotypes 1, 2, 3, 4, 5, 6 with or without compensated cirrhosis (must be given with glecaprevir; pibrentasvir and ribavirin).
-treatment-experienced (i.e., multiple DAA failures) adult patients with genotypes 1, 2, 3, 4, 5, 6 with or without compensated cirrhosis (must be given with glecaprevir; pibrentasvir and ribavirin).
-Sofosbuvir is also co-formulated with other direct-acting antivirals; see specific combinations for place in therapy.
-Pediatric guidelines are also available.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: hepatitis C virus
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
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 genotypes 1 or 4 infection in treatment-naive persons without cirrhosis or with compensated (Child-Pugh A) cirrhosis who are interferon eligible:
Oral dosage:
Adults: 400 mg PO once daily for 12 weeks in combination with peginterferon alfa and ribavirin.
-for the treatment of chronic hepatitis C virus genotype 1 infection in treatment-naive persons without cirrhosis or with compensated (Child-Pugh A) cirrhosis who are interferon ineligible:
Oral dosage:
Adults: 400 mg PO once daily for 24 weeks in combination with ribavirin; however, this regimen may be less effective.
-for the treatment of chronic hepatitis C virus genotype 2 infection in treatment-naive and experienced (prior interferon-based regimens) persons without cirrhosis or with compensated (Child-Pugh A) cirrhosis:
Oral dosage:
Adults: 400 mg PO once daily for 12 weeks in combination with ribavirin.
Children and Adolescents 3 to 17 years weighing 35 kg or more: 400 mg PO once daily for 12 weeks in combination with ribavirin.
Children and Adolescents 3 to 17 years weighing 17 to 34 kg: 200 mg PO once daily for 12 weeks in combination with ribavirin.
Children 3 to 12 years weighing less than 17 kg: 150 mg PO once daily for 12 weeks in combination with ribavirin.
-for the treatment of chronic hepatitis C virus genotype 3 infection in treatment-naive and experienced (prior interferon-based regimens) persons without cirrhosis or with compensated (Child-Pugh A) cirrhosis:
Oral dosage:
Adults: 400 mg PO once daily for 24 weeks in combination with ribavirin.
Children and Adolescents 3 to 17 years weighing 35 kg or more: 400 mg PO once daily for 24 weeks in combination with ribavirin.
Children and Adolescents 3 to 17 years weighing 17 to 34 kg: 200 mg PO once daily for 24 weeks in combination with ribavirin.
Children 3 to 12 years weighing less than 17 kg: 150 mg PO once daily for 24 weeks in combination with ribavirin.
-for the treatment of chronic hepatitis C virus genotypes 1,2, 3, 4, 5, or 6 infection in persons with previous treatment with glecaprevir; pibrentasvir* without cirrhosis or with compensated cirrhosis:
Oral dosage:
Adults: 400 mg PO once daily for 16 weeks in combination with glecaprevir; pibrentasvir and ribavirin.
-for the treatment of chronic hepatitis C genotype genotypes 1, 2, 4, 5, or 6 infection in persons who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir) without cirrhosis or with compensated cirrhosis*:
Oral dosage:
Adults: 400 mg PO once daily for 16 weeks in combination with glecaprevir; pibrentasvir and ribavirin.
-for the treatment of chronic hepatitis C genotype 3 infection in persons who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir) without cirrhosis*:
Oral dosage:
Adults: 400 mg PO once daily for 16 weeks in combination with glecaprevir; pibrentasvir and ribavirin.
-for the treatment of chronic hepatitis C genotype 3 infection in persons who have multiple DAA failures (including sofosbuvir; velpatasvir; voxilaprevir) with compensated cirrhosis*:
Oral dosage:
Adults: 400 mg PO once daily for 24 weeks in combination with glecaprevir; pibrentasvir and ribavirin.
-for the treatment of chronic hepatitis C genotype genotypes 1, 2, 3, 4, 5, or 6 infection in persons who have multiple DAA failures (including glecaprevir; pibrentasvir plus sofosbuvir) without cirrhosis or with compensated cirrhosis:
Oral dosage:
Adults: 400 mg PO once daily for 24 weeks in combination with glecaprevir; pibrentasvir and ribavirin.
-for the treatment of chronic hepatitis C virus genotypes 1, 2, 3, or 4 infection in adult patients or HCV virus genotypes 2 or 3 infection in pediatric patients with hepatocellular carcinoma awaiting liver transplant:
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.
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 Limits:
-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.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
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.
Bexagliflozin: (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: (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.
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.
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.
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.
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.
Meropenem: (Major) Coadministration of sofosbuvir with meropenem is not recommended. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate and meropenem is a P-gp inducer.
Meropenem; Vaborbactam: (Major) Coadministration of sofosbuvir with meropenem is not recommended. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate and meropenem is a P-gp inducer.
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; 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.
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.
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.
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.
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.
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.
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).
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
Compared to individuals with normal hepatic function, patients with moderate and severe hepatic impairment display increased exposure to the parent drug sofosbuvir (126% and 143% higher, respectively) and the major metabolite, GS-331007, (18% and 9% higher, respectively).
Renal Impairment
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. A 4 hour hemodialysis session removes approximately 18% of the administered dose.
Pediatrics
Children and Adolescents 3 to 17 years
In a pharmacokinetic study (n = 64) in pediatric patients 3 to 17 years, the exposure of sofosbuvir was similar to what has been observed in adult patients. The mean AUC and Cmax of sofosbuvir was 851 ng x hour/mL and 418 ng/mL, respectively, after a dose of 150 mg PO once daily in those weighing less than 17 kg; 891 ng x hour/mL and 438 ng/mL, respectively, after a dose of 200 mg PO once daily in those weighing 17 to 34 kg; and 1,060 ng x hour/mL and 472 ng/mL, respectively, after a dose of 400 mg PO once daily in patients weighing 35 kg or more. The pharmacokinetics of sofosbuvir have not been established in pediatric patients younger than 3 years.