- ACRONYMS AND DEFINITIONS
- AASLD - American Association for the Study of Liver Diseases
- CP - Child-Pugh liver failure classification
- HBV - Hepatitis B virus
- HCV - Hepatitis C virus
- IDSA - Infectious Diseases Society of America
- N/A - Not available
- PegIFN - Pegylated interferon
- RBV - Ribavirin
- ULN - Upper limit of normal
- DRUGS IN CLASS
- Sofosbuvir is part of a new generation of antiviral medications that are highly effective against hepatitis C
- Sofosbuvir is available by itself, and it is also found in the combination pills Epclusa and Harvoni
- See Hepatitis C treatment for a list of other HCV drugs
- MECHANISM OF ACTION
- Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication.
- Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator
- FDA-APPROVED INDICATIONS
- Adults
- HCV genotype 1
- Treatment-naïve, no cirrhosis or Child-Pugh A: Sofosbuvir + RBV + PegIFN (no longer recommended)
- See Epclusa and Harvoni for other regimens that include sofosbuvir
- HCV genotype 2
- Treatment-naïve and treatment-experienced✝, no cirrhosis or Child-Pugh A: Sofosbuvir + RBV
- See Epclusa for other regimens that include sofosbuvir
- HCV genotype 3
- Treatment-naïve and treatment-experienced✝, no cirrhosis or Child-Pugh A: Sofosbuvir + RBV
- See Epclusa for another regimen that includes sofosbuvir
- HCV genotype 4
- Treatment-naïve, no cirrhosis or Child-Pugh A: Sofosbuvir + RBV + PegIFN (no longer recommended)
- See Epclusa and Harvoni for other regimens that include sofosbuvir
- Retreatment of HCV genotype 1, 2, 3, 4, 5, and 6 in patients who failed previous treatment with an NS5A inhibitor or sofosbuvir
- No cirrhosis or Child-Pugh A: See Vosevi
- ✝Treatment-experienced patients have failed an interferon based regimen with or without ribavirin
- Pediatric
- HCV genotype 2 or 3 infection in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis for use in combination with ribavirin
- HEPATITIS C TREATMENT
| HCV genotype 1 cure rates | ||
|---|---|---|
| Drug | No cirrhosis or CP A | CP B/C |
| Epclusa | > 90% | > 90% |
| Harvoni | > 90% | > 85% |
| Vosevi | > 90% | N/A |
| Sofosbuvir + daclatasvir✝ | > 90% | B > 90% C ∼ 50% |
| HCV genotype 2 cure rates | ||
|---|---|---|
| Drug | No cirrhosis or CP A | CP B/C |
| Epclusa | > 90% | > 90% |
| Vosevi | > 90% | N/A |
| Sofosbuvir + ribavirin | > 90% | > 80%✝ |
| HCV genotype 3 cure rates | ||
|---|---|---|
| Drug | No cirrhosis or CP A | CP B/C |
| Epclusa | > 90% | > 90% |
| Vosevi | > 90% | N/A |
| Sofosbuvir + daclatasvir | > 90% | ∼ 60% |
| Sofosbuvir + ribavirin | > 85% | See note✝ |
| HCV genotype 4 cure rates | ||
|---|---|---|
| Drug | No cirrhosis or CP A | CP B/C |
| Epclusa | > 90% | > 90% |
| Harvoni | > 90% | N/A |
| Vosevi | > 90% | N/A |
| HCV genotype 5 cure rates | ||
|---|---|---|
| Drug | No cirrhosis or CP A | CP B/C |
| Epclusa | > 90% | N/A |
| Harvoni | > 90% | N/A |
| Vosevi | > 90% | N/A |
| HCV genotype 6 cure rates | ||
|---|---|---|
| Drug | No cirrhosis or CP A | CP B/C |
| Epclusa | > 90% | N/A |
| Harvoni | > 90% | N/A |
| Vosevi | > 90% | N/A |
- SIDE EFFECTS
- Overview
- There are no well-documented, significant side effects that can be directly attributed to sofosbuvir
- The table below is presented in the sofosbuvir PI. It shows the incidence of side effects observed in trials where sofosbuvir was prescribed in combination with ribavirin. Many of these side effects are well-documented effects of ribavirin (ex. anemia).
- In the COSMOS trial where sofosbuvir was prescribed with simeprevir, only rash (13%), itching (9%), and photosensitivity (7%) were reported in greater than one patient in groups treated with sofosbuvir + simeprevir only
| Side Effect | Placebo (N=71) |
Sofosbuvir + RBV (N=650) |
|---|---|---|
| Fatigue | 24% | 38% |
| Headache | 20% | 24% |
| Nausea | 18% | 29% |
| Insomnia | 4% | 15% |
| Itching | 8% | 11% |
| Anemia | 0% | 10% |
| Rash | 8% | 8% |
| Loss of appetite | 10% | 6% |
| Flu-like illness | 3% | 3% |
| Fever | 0% | 4% |
| Diarrhea | 6% | 9% |
| Neutropenia | 0% | < 1% |
| Muscle ache | 0% | 6% |
| CK elevations (10 X ULN) |
- | 2% |
| Lipase elevations (3 X ULN) |
- | 2% |
- CONTRAINDICATIONS
- None known
- PRECAUTIONS
- Kidney disease
- CrCl ≥ 30ml/min: no dose adjustment necessary
- CrCl < 30ml/min: safety has not been established. No recommendation made.
- Liver disease
- No dose adjustment of sofosbuvir is required for patients with mild, moderate, or severe hepatic impairment
- Hepatitis B coinfection
- In October 2016, the FDA placed a boxed warning on all new hepatitis C drugs about the possible reactivation of hepatitis B infection in coinfected patients who are taking direct-acting antiviral hepatitis C drugs
- At the time of the warning, the FDA had identified 24 cases of hepatitis B reactivation in patients taking these drugs. Reactivation occurred in patients who were HBsAg positive and in those who were HBsAg negative and anti-HBc positive (see interpreting HBV screening results for more).
- The FDA recommends that providers check all patients for hepatitis B coinfection (HBsAg and anti-HBc) before starting therapy and that they monitor patients for reactivation during and after therapy
- See AASLD guidelines for HBV coinfected patients for more
- MONITORING THERAPY
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Sofosbuvir
- See Sovaldi PI for a complete list of drug interactions
- Amiodarone (Cordarone®) - Serious cases of bradycardia (slow heart rate) have been reported in patients taking amiodarone in combination with ledipasvir. Amiodarone should not be combined with sofosbuvir and other antivirals (e.g. simeprevir, ledipasvir).
- Clearance of HCV and liver function - Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. Examples of drugs that may need to be adjusted after liver function improves include diabetes medications, drugs with narrow therapeutic index, warfarin, immunosuppressants, and others.
- P-glycoprotein inducers
- Drugs that induce P-glycoprotein may decrease the effectiveness of sofosbuvir
- Sofosbuvir is contraindicated with potent intestinal P-glycoprotein inducers (ex. rifampin and St. John's Wort)
- NOTE: Sofosbuvir may be taken with P-glycoprotein inhibitors because levels of the predominant metabolite are not affected
- Examples of common P-glycoprotein inducers include:
- Carbamazepine (Tegretol®)
- Oxcarbazepine (Trileptal®) (decreases sofosbuvir levels probably through P-glycoprotein induction)
- Phenobarbital
- Phenytoin (Dilantin®)
- Rifabutin
- Rifampin
- St John's Wort
- Tipranavir (Aptivus®)
- Ritonavir (Norvir®)
- Warfarin (Coumadin®) - Fluctuations in INR levels may occur when sofosbuvir is taken with warfarin. Monitor INR levels closely.
- Metabolism and clearance
- Sofosbuvir does not undergo CYP450 metabolism
- The metabolic activation pathway of sofosbuvir involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
- P-glycoprotein - substrate
- BCRP - substrate
- DOSING
- Dosage forms
- Tablet
- 200 mg
- 400 mg
- Comes in bottle with 28 tablets. Dispense in original container.
- Oral pellets
- 150 mg packet
- 200 mg packet
- Comes in carton with 28 packets
- Pellets are sprinkled on food and swallowed whole
- Dosing
- Adults: 400 mg once daily. May take without regard to food.
- See Sovaldi PI [sec 2] for dosing recommendations in pediatric patients
| Sofosbuvir treatment regimens in adults | ||
|---|---|---|
| HCV GT | Patient population | Regimen |
| 1 |
|
Sofosbuvir + PegIFN + RBV for 12 weeks |
| 2 |
|
Sofosbuvir + RBV for 12 weeks |
|
||
| 3 |
|
Sofosbuvir + RBV for 24 weeks |
|
||
| 4 |
|
Sofosbuvir + PegIFN + RBV for 12 weeks |
|
||
- LONG TERM SAFETY
- Sofosbuvir was FDA-approved in 2013
- There is no long-term safety data for sofosbuvir, but it has been studied in a number of clinical trials and appears to be generally safe
- BIBLIOGRAPHY
- 1 - Sofosbuvir PI