s treated with Exviera and ombitasvir/paritaprevir/ritonavir and ribavirin in phase 3 clinical trials, although some adverse reactions were increased in frequency. 10 subjects (29.4%) had at least one post baseline haemoglobin value of less than 10 g/dL. 10 of 34 subjects (29.4%) dose modified ribavirin due to decrease in haemoglobin and 2.9% (1/34) had an interruption of ribavirin. Ribavirin dose modification did not impact SVR rates. 5 subjects required erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No subject received a blood transfusion.
HIV/HCV co-infected patients
The overall safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Transient elevations in total bilirubin >3 x ULN (mostly indirect) occurred in 17 (27.0%) subjects; 15 of these subjects were receiving atazanavir. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases.
Paediatric population
The safety of Exviera in children and adolescents aged < 18 years has not yet been established. No data are available.
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 Yellow Card Scheme:
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
The highest documented single dose of dasabuvir administered to healthy volunteers was 2 g. No study drug-related adverse reactions or clinically significant laboratory abnormalities were observed. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use; direct-acting antivirals, ATC code: not yet assigned
Mechanism of action
Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome.
Co-administration of dasabuvir with ombitasvir/paritaprevir/ritonavir combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle. Refer to the Summary of Product Characteristics of ombitasvir/paritaprevir/ritonavir for its pharmacological properties.
Activity in cell culture and biochemical studies
The EC50 of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays was 7.7 and 1.8 nM, respectively. The replicon activity of dasabuvir was attenuated 12- to 13-fold in the presence of 40% human plasma. The mean EC50 of dasabuvir against replicons containing NS5B from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.77 nM (range 0.4 to 2.1 nM; n=11) and 0.46 nM (range 0.2 to 2 nM; n=10), respectively. In biochemical assays, dasabuvir inhibited a panel of genotype 1a and 1b polymerases with a mean IC50 value of 4.2 nM (range 2.2 to 10.7 nM; n=7).
The M1 metabolite of dasabuvir had EC50 values of 39 and 8 nM against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays, respectivel |
