vir/ritonavir, with or without ribavirin, and the adverse event is at least a reasonable possibility. The majority of adverse reactions presented in Table 3 were of grade 1 severity in Exviera- and ombitasvir/paritaprevir/ritonavir-containing regimens.
The adverse reactions are listed below by system organ class and frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000).
Table 3. Adverse reactions identified with Exviera in combination with ombitasvir/paritaprevir/ritonavir or ombitasvir/paritaprevir/ritonavir and ribavirin
*Data set includes all genotype 1-infected subjects in Phase 2 and 3 trials including subjects with cirrhosis. Note: For laboratory abnormalities refer to Table 4.
Description of selected adverse reactions
Laboratory abnormalities
Changes in selected laboratory parameters are described in Table 4. A side-by-side tabulation is provided to simplify presentation; direct comparisons should not be made across trials that differ in trial designs.
Table 4. Selected treatment emergent laboratory abnormalities
Serum ALT elevations
In a pooled analysis of clinical trials with Exviera and ombitasvir/paritaprevir/ritonavir with and without ribavirin, 1% of subjects experienced serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. As the incidence of such elevations was 26% among women taking a concomitant ethinylestradiol-containing medicine, such medicinal products are contraindicated with Exviera and ombitasvir/paritaprevir/ritonavir. No increase in incidence of ALT elevations was observed with other types of systemic estrogens commonly used for hormone replacement therapy (e.g., estradiol and conjugated estrogens). ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with ongoing therapy. Two patients discontinued Exviera and ombitasvir/paritaprevir/ritonavir due to elevated ALT, including one on ethinylestradiol. Three interrupted Exviera and ombitasvir/paritaprevir/ritonavir for one to seven days, including one on ethinylestradiol. The majority of these ALT elevations were transient and assessed as related to Exviera and ombitasvir/paritaprevir/ritonavir. Elevations in ALT were generally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT (see section 4.4).
Serum bilirubin elevations
Transient elevations in serum bilirubin (predominantly indirect) were observed in subjects receiving Exviera and ombitasvir/paritaprevir/ritonavir with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced haemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with aminotransferase elevations. The frequency of indirect bilirubin elevations was lower among subjects who did not receive ribavirin.
Liver transplant recipients
The overall safety profile in HCV-infected transplant recipients who were administered Exviera and ombitasvir/paritaprevir/ritonavir and ribavirin (in addition to their immunosuppressant medicinal products) was similar to subject |
