Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR -1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt
 
4.9 Overdose
 The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mg administered to 59 healthy subjects. In that study, there were no untoward effects observed at this dose level, and adverse reactions were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are unknown.

No specific antidote is available for overdose with Sovaldi. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sovaldi consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Haemodialysis can efficiently remove (53% extraction ratio) the predominant circulating metabolite GS-331007. A 4-hour haemodialysis session removed 18% of the administered dose.

5. Pharmacological properties
  
5.1 Pharmacodynamic properties
 Pharmacotherapeutic group: Direct-acting antiviral; ATC code: not yet assigned

Mechanism of action

Sofosbuvir is a pan-genotypic 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. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC50) value ranging from 0.7 to 2.6 μM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Antiviral activity

In HCV replicon assays, the effective concentration (EC50) values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 μM, respectively, and EC50 values of sofosbuvir against chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a were 0.014 to 0.015 μM. The mean ± SD EC50 of sofosbuvir against chimeric replicons e