Sofosbuvir


Concise Prescribing Info
Indications/Uses
Chronic hepatitis C.
Dosage/Direction for Use
Adult : PO Combined with antiviral treatment regimen in patients with chronic HCV genotype 1, 2, 3, or 4: 400 mg once daily. Treatment duration may vary depending on genotype and treatment regimen. Refer to detailed product guideline.
Dosage Details
Oral
Chronic hepatitis C
Adult: As combination therapy with antiviral treatment regimen in patients with chronic HCV genotype 1, 2, 3, or 4: 400 mg once daily. Treatment duration may vary depending on genotype and treatment regimen. Refer to detailed product guideline.
Child: As combination therapy with antiviral treatment regimen in patients with chronic HCV genotype 2 or 3: ≥12 years or weighing ≥35 kg: Same as adult dose.
Special Patient Group
Pharmacogenomics:

CPIC guidelines identify IL28B also known as IFNL3 as the strongest baseline predictor of responses for previously untreated patients with HCV genotype 1. Since sofosbuvir is indicated as combination therapy with ribavirin and peginterferon-α, IFNL3 genotype may be considered relevant.

IFNL3 variation is the most established pretreatment predictor of therapy response. The two identified IFNL3 polymorphisms are rs12979860 and rs8099917. The alleles of these polymorphism are associated with increase sustained virological response (SVR) in HCV genotype 1 patients, specifically allele CC for rs12979860 and allele TT for rs8099917.

The allele frequency of rs12979860 varies among different ethnic backgrounds. The rs12979860 favorable C allele is most frequently found in East Asians, followed by Caucasians and Hispanics and least common among individuals of African origin.

CPIC states the following assignment and recommendations of probable IFNL3 phenotypes based on genotypes:

Favorable response genotype (carrier of 2 favorable response alleles e.g. rs12979860 CC)
Patient may have higher SVR rate to peginterferon-α and ribavirin therapy. Approx 70% chance for SVR after 48 weeks of therapy. Consider implications before starting peginterferon-α and ribavirin treatment.

Unfavorable response genotype (carrier of at least 1 unfavorable response alleles e.g. rs12979860 CT or TT)
Patient may have lower SVR rate to peginterferon-α and ribavirin therapy. Approx 30% chance for SVR after 48 weeks of therapy. Consider implication before starting peginterferon- α and ribavirin treatment.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity. Pregnancy (when used in combination with ribavirin and peginterferon-α). Concomitant use with amiodarone and potent P-glycoprotein (P-gp) inducers.
Special Precautions
Patient with diabetes mellitus; co-infection with HIV; 1 or more factors associated with lower response rates to interferon-based therapies (e.g. advanced fibrosis/cirrhosis, high baseline viral concentration, black race, IL28B non-CC genotype, prior null response to peginterferon-α and ribavirin therapy). Patient awaiting liver transplantation and liver transplant recipients. Not intended for use as a monotherapy. Children. Hepatic impairment. Lactation.
Adverse Reactions
Blood and lymphatic system disorders: Anaemia, neutropenia.
Gastrointestinal disorders: Nausea, decreased appetite, diarrhoea, vomiting, abdominal discomfort, constipation, dyspepsia, dry mouth.
General disorders and administration site conditions: Fatigue, flu-like symptoms, fever, irritability.
Hepatobiliary disorders: Increased blood bilirubin.
Metabolism and nutrition disorders: Decreased appetite and weight.
Musculoskeletal and connective tissue disorders: Asthenia, myalgia, arthralgia, muscle spasms, chills.
Nervous system disorders: Headache, migraine, memory impairment.
Psychiatric disorders: Insomnia, depression, anxiety, agitation.
Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, dyspnoea, cough, dyspnoea exertional.
Skin and subcutaneous tissue disorders: Rash, pruritus, alopecia, dry skin.
Potentially Fatal: Hepatitis B virus reactivation.
PO: B, X (if used w/ ribavirin/peginterferon-α)
Patient Counseling Information
This drug may cause dizziness, blurred vision, and disturbance in attention, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor LFT, CBC, INR, calculated GFR, quantitative HCV viral load and HCV genotype at baseline within 12 weeks prior to starting the therapy. Monitor CBC, serum creatinine, calculated GFR during treatment; LFT (after 4 weeks of therapy and as necessary); quantitative HCV viral load (after 4 weeks of therapy then at 12 weeks after completion of treatment). Perform hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation of treatment. Monitor for clinical and laboratory signs of hepatitis flare or hepatitis B virus (HBV) reactivation in patients with serologic evidence of HBV infection during and post-treatment follow-up. Monitor changes in glucose tolerance and signs and symptoms of hypoglycaemia in diabetic patients.
Drug Interactions
May cause symptomatic hypoglycaemia when given with antidiabetic agents. May diminish anticoagulant effect of vitamin K antagonists (e.g. warfarin). May decrease concentration of sofosbuvir with modafinil, oxcarbazepine, rifapentine and HIV protease inhibitor (e.g. tipranavir/ritonavir) thereby reducing therapeutic effect.
Potentially Fatal: May cause severe symptomatic bradycardia and heart block when given with amiodarone. Significantly decreased plasma concentration with potent P-gp inducers (e.g. carbamazepine, phenytoin, phenobarbital).
Food Interaction
Decreased plasma concentration of sofosbuvir with St. John’s wort.
Action
Description: Sofosbuvir is a nucleotide analogue inhibitor, effective against hepatitis C virus (HCV) nonstructural 5B (NS5B) polymerase, which is necessary for viral replication. It is a direct-acting antiviral prodrug that has broad genotypic coverage and acts as chain terminator.
Pharmacokinetics:
Absorption: Time to peak plasma concentration: Approx 0.5-2 hours.
Distribution: Plasma protein binding: Approx 61-65%.
Metabolism: Extensively metabolised in the liver via sequential hydrolysis, phosphoramidate cleavage followed by phosphorylation to form pharmacologically active nucleoside analogue triphosphate GS-461203, and subsequent dephosphorylation to form nucleoside inactive metabolite GS-331007.
Excretion: Mainly via urine (approx 80%; 78% as GS-331007 metabolite, 3.5 % as unchanged drug); faeces (approx 14%); expired air (approx 2.5%). Elimination half-life: 0.4 hour.
Chemical Structure

Chemical Structure Image
Sofosbuvir

Source: National Center for Biotechnology Information. PubChem Database. Sovaldi, CID=45375808, https://pubchem.ncbi.nlm.nih.gov/compound/Sovaldi (accessed on Jan. 23, 2020)

Storage
Store below 30°C.
MIMS Class
ATC Classification
J05AP08 - sofosbuvir ; Belongs to the class of antivirals for treatment of HCV infections. Used in the treatment of hepatitis C viral infections.
References
Muir AJ, Gong L, Johnson SG, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for IFNL3 (IL28B) Genotype and PEG Interferon-α-Based Regimens. CPIC Guidelines. 2014 Feb;95(2):141-146. doi: 10.1038/clpt.2013.203. Accessed 15/10/2019

Anon. IL28B - Sofosbuvir (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/10/2019.

Anon. Sofosbuvir. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/10/2019.

Buckingham R (ed). Sofosbuvir. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 17/10/2019.

Clinical Annotation for rs12979860 (IFNL3, IFNL4); Ledispasvir or Sofosbuvir; Hepatitis C, Chronic (Level 3 Efficacy). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/10/2019.

Clinical Annotation for rs8099917(IFNL3, IFNL4); Ledispasvir or Sofosbuvir; Hepatitis C, Chronic (Level 3 Efficacy). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/10/2019.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for IFNL3 (IL28B) Genotype and PEG Interferon-Alpha-Based Regimens. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 15/10/2019.

Joint Formulary Committee. Sofosbuvir. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 17/10/2019.

Sovaldi Tablet, Film-Coated (Gilead Sciences, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 17/10/2019.

Disclaimer: This information is independently developed by MIMS based on Sofosbuvir from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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