ALT elevations

During clinical trials with dasabuvir and ombitasvir/paritaprevir/ritonavir with or without ribavirin, transient elevations of ALT to greater than 5 times the upper limit of normal occurred in approximately 1% of subjects (35 of 3,039). ALT elevations were asymptomatic and generally occurred during the first 4 weeks of treatment, without concomitant elevations of bilirubin, and declined within approximately two weeks of onset with continued dosing of dasabuvir and ombitasvir/paritaprevir/ritonavir with or without ribavirin.

These ALT elevations were significantly more frequent in the subgroup of subjects who were using ethinylestradiol -containing medicinal products such as combined oral contraceptives or contraceptive vaginal rings (6 of 25 subjects); (see section 4.3). In contrast, the rate of ALT elevations in subjects using other types of estrogens as typically used in hormonal replacement therapy (i.e., oral and topical estradiol and conjugated estrogens) was similar to the rate observed in subjects who were not using estrogen-containing products (approximately 1% in each group).

Patients who are taking ethinylestradiol -containing medicinal products (i.e. most combined oral contraceptives or contraceptive vaginal rings) must switch to an alternative method of contraception (e.g., progestin only contraception or non-hormonal methods) prior to initiating Exviera with ombitasvir/paritaprevir/ritonavir therapy (see sections 4.3 and 4.5).

Although ALT elevations associated with dasabuvir and ombitasvir/paritaprevir/ritonavir have been asymptomatic, patients should be instructed to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discoloured faeces, and to consult a doctor without delay if such symptoms occur. Routine monitoring of liver enzymes is not necessary. Early discontinuation may result in drug resistance, but implications for future therapy are not known.

Use with statins

Rosuvastatin

Dasabuvir with ombitasvir/paritaprevir/ritonavir is expected to increase the exposure to rosuvastatin more than 3-fold. If rosuvastatin treatment is required during the treatment period, the maximum daily dose of rosuvastatin should be 5 mg (see section 4.5, Table 2).

Pitavastatin and fluvastatin

The interactions with pitavastatin and fluvastatin have not been investigated. Theoretically, dasabuvir with ombitasvir/paritaprevir/ritonavir is expected to increase the exposure to pitavastatin and fluvastatin. A temporary suspension of pitavastatin/fluvastatin is recommended for the duration of treatment with ombitasvir/paritaprevir/ritonavir. If statin treatment is required during the treatment period, a switch to a reduced dose of pravastatin/rosuvastatin is possible (see section 4.5, Table 2).

Treatment of patients with HIV co-infection

Exviera is recommended in combination with paritaprevir/ombitasvir/ritonavir, and ritonavir may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected patients without suppressive antiretroviral therapy should not be treated with dasabuvir.

Drug interactions need to be carefully taken into account in the setting of HIV co-infection (for details see section 4.5, Table 2).

Atazanavir can be used in c