SOVALDI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SOVALDI (SOVALDI).
Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, which is essential for viral replication. It is converted to the active triphosphate form (GS-461203) that competes with natural nucleotides and causes chain termination upon incorporation into viral RNA.
| Metabolism | Sofosbuvir is a prodrug that undergoes extensive hepatic metabolism to form the active triphosphate. It is metabolized by cathepsin A (CatA) and carboxylesterase 1 (CES1), followed by phosphorylation by nucleoside kinases. The inactive metabolite GS-331007 is eliminated renally. |
| Excretion | Primarily fecal (77% of absorbed dose as metabolites, 3.5% as unchanged drug) with minor renal elimination (3.5% total, mainly metabolites). Biliary excretion contributes to fecal elimination. |
| Half-life | Terminal half-life of sofosbuvir is approximately 0.4-0.5 hours; the predominant circulating metabolite GS-331007 has a terminal half-life of 27 hours. This long half-life supports once-daily dosing. |
| Protein binding | Sofosbuvir is 61-65% bound to human plasma proteins; the metabolite GS-331007 has minimal protein binding (<1%). |
| Volume of Distribution | Sofosbuvir: approximately 0.25 L/kg (based on 80 kg individual, Vd ~20 L), suggesting limited extravascular distribution. GS-331007: Vd is not clinically relevant as it is inactive. |
| Bioavailability | Oral bioavailability of sofosbuvir is not precisely determined but is adequate for therapeutic effect; absorption is enhanced by food (high-fat meal increases AUC by ~1.8-fold). |
| Onset of Action | Oral: Rapid viral suppression observed within 1 week; maximal effect at 4 weeks of therapy. |
| Duration of Action | Sustained virologic response (SVR) is achieved after 12 weeks of therapy. Duration of action is defined by SVR, which is cure in most patients. |
| Action Class | Direct acting hepatitis C agent |
| Brand Substitutes | MY Hep 400mg Tablet, Resof 400mg Tablet, Hepcinat Tablet, Sofokem 400mg Tablet, Zosovir 400mg Tablet |
400 mg orally once daily with or without food.
| Dosage form | PELLETS |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. For severe renal impairment (eGFR <30 mL/min/1.73 m2) or end-stage renal disease requiring hemodialysis, no prospective data; may use with caution but insufficient data to recommend dose adjustment. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not recommended for use in patients with severe hepatic impairment (Child-Pugh C) due to significantly increased exposure and potential toxicity; contraindicated. |
| Pediatric use | Approved for patients aged 3 years and older: weight <17 kg: 150 mg orally once daily; weight 17 to <35 kg: 200 mg orally once daily; weight ≥35 kg: 400 mg orally once daily; administer with food. |
| Geriatric use | No specific dose adjustment required for elderly patients; dosing based on hepatic and renal function with consideration of age-related decline in renal function. Monitor for adverse events as elderly may have higher risk of comorbidities and concomitant medications. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SOVALDI (SOVALDI).
| Breastfeeding | It is not known whether sofosbuvir or its metabolites are excreted in human breast milk. In lactating rats, sofosbuvir was detected in milk at concentrations similar to maternal plasma. The M/P ratio in rats was approximately 1.0. The pharmacokinetics in nursing infants have not been evaluated. Because of the potential for adverse reactions in breastfed infants, and because ribavirin (if coadministered) is contraindicated during lactation, breastfeeding is not recommended during treatment with Sovaldi. The CDC recommends that women with chronic HCV can breastfeed, as HCV is not transmitted through breast milk; however, the safety of sofosbuvir during lactation has not been established. |
| Teratogenic Risk |
■ FDA Black Box Warning
NOT APPROVED BY FDA FOR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION. WAIT, SOVALDI IS APPROVED. CORRECTION: No black box warning for Sovaldi (sofosbuvir) as a single agent. However, when used in combination with other antivirals, there is a risk of hepatitis B virus (HBV) reactivation. The FDA has issued a boxed warning regarding HBV reactivation for direct-acting antivirals, including sofosbuvir-containing regimens.
| Serious Effects |
["Hypersensitivity to sofosbuvir or any component of the formulation","Coadministration with potent P-glycoprotein (P-gp) inducers (e.g., rifampin, St. John's wort) which may significantly reduce sofosbuvir efficacy"]
| Precautions | ["Risk of hepatitis B virus reactivation in patients coinfected with HBV and HCV, which can lead to fulminant hepatitis and death.","Symptomatic bradycardia when used with amiodarone, especially in patients also taking beta-blockers or with underlying cardiac comorbidities.","Reduced efficacy in patients with genotype 3 HCV infection when used without ribavirin.","Use with caution in patients with severe renal impairment (eGFR <30 mL/min) or end-stage renal disease due to increased exposure of the metabolite GS-331007."] |
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| Sovaldi (sofosbuvir) is classified as FDA Pregnancy Category B. Animal studies have shown no evidence of teratogenicity at exposures up to 10 times the human therapeutic dose. However, human data are limited. In animal reproduction studies, no fetal harm was observed in rats and rabbits at exposures 10 and 5 times the human exposure, respectively. No dose-limiting maternal or fetal toxicity was noted in rats or rabbits. The risk of teratogenicity in humans is considered low, but because of limited human data, use during pregnancy should only be if clearly needed. Ribavirin, which is commonly used in combination with sofosbuvir for chronic hepatitis C, is contraindicated in pregnancy due to its known teratogenic and embryocidal effects (Pregnancy Category X). Therefore, concomitant use of ribavirin imposes significant fetal risk, especially during the first trimester. |
| Fetal Monitoring | Monitor HCV RNA levels at baseline and periodically during therapy to assess virologic response. If used with ribavirin, pregnancy testing must be performed monthly in women of childbearing potential and continued for 6 months after therapy. Monitor CBC (hemoglobin, WBC, platelets) and liver function tests (ALT, AST, bilirubin) at baseline and monthly. Also monitor renal function (serum creatinine, eGFR) at baseline and as clinically indicated, as dose reduction may be needed in severe renal impairment (eGFR <30 mL/min/1.73 m²). For patients on ribavirin, monitor for hemolytic anemia and signs of lactic acidosis. Perform pregnancy tests monthly during combination therapy with ribavirin and for 6 months after treatment. In pregnant patients, fetal ultrasound may be considered to assess for anomalies, especially if ribavirin was inadvertently used. |
| Fertility Effects | In animal studies, sofosbuvir had no adverse effects on male or female fertility at exposures up to 10 times the human therapeutic dose. In rats, there were no effects on mating, fertility, or early embryonic development. There are no human data on fertility effects. However, ribavirin, commonly used in combination, has been shown to cause reversible infertility in men and is contraindicated in women of childbearing potential and male partners of pregnant women. Therefore, fertility effects may be related to ribavirin coadministration rather than sofosbuvir alone. |