icant. Exviera has not been studied in patients on dialysis (see section 4.2).
Hepatic impairment
Pharmacokinetics of the combination of dasabuvir 400 mg, with ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg were eva luated in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, relative to subjects with normal hepatic function.
In subjects with mild, moderate and severe hepatic impairment, dasabuvir AUC values were 17% higher, 16% lower and 325% higher, respectively. The AUC values of dasabuvir M1 metabolite were unchanged, 57% lower, and 77% higher, respectively. Plasma protein binding of dasabuvir and its M1 metabolite were not meaningfully different in subjects with hepatic impairment compared to normal control subjects.
The changes in dasabuvir exposures in subjects with mild and moderate hepatic impairment are not considered clinically significant. The safety and efficacy of Exviera and ombitasvir/paritaprevir/ritonavir have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B) (see section 4.2).
Paediatric population
The pharmacokinetics of Exviera with ombitasvir/paritaprevir/ritonavir in paediatric patients has not been investigated (see section 4.2).
Dasabuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.
Dasabuvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (2 g/kg/day), resulting in dasabuvir AUC exposures approximately 39-fold higher than those in humans at the recommended dose of 500 mg (250 mg twice daily).
The carcinogenicity study of dasabuvir in rats is ongoing.
Dasabuvir had no effects on embryo-foetal viability or on fertility in rodents and were not teratogenic in two species. No adverse effects on behaviour, reproduction or development of offspring were reported. The highest dasabuvir dose tested produced exposures equal to 33 to 48-fold (rat) or 12-fold (rabbit) the exposures in humans at the maximum recommended clinical dose.
Dasabuvir was the predominant component observed in the milk of lactating rats, without effect on nursing pups. Elimination half-life in rat milk was slightly shorter than in plasma, AUC was about 2 fold of that in plasma. Since dasabuvir is a BCRP substrate, distribution to the milk may change if this transporter is inhibited or induced by co-administration of other medicinal products. Dasabuvir-derived material was minimally transferred through the placenta in pregnant rats.
Tablet core
Microcrystalline cellulose (E460(i))
Lactose monohydrate
Copovidone
Croscarmellose sodium
Colloidal anhydrous silica (E551)
Magnesium stearate (E470b)
Film-coating
Polyvinyl alcohol (E1203)
Titanium dioxide (E171)
Polyethylene glycol 3350
Talc (E553b)
Iron oxide yellow (E172)
Iron oxide red (E172)
Iron oxide black (E172)
