Exviera

Treatment with dasabuvir should be initiated and monitored by a physician experienced in the management of chronic hepatitis C. Posology The recommended dose is 250 mg of dasabuvir (one tablet) twice daily (morning and evening). Dasabuvir must not be administered as monotherapy.

1). Refer to the Summary of Product Characteristics of the medicinal products that are used in combination with dasabuvir. The recommended co-administered medicinal product(s) and treatment duration for dasabuvir combination therapy are provided in Table 1.

Medicinal product no longer authorised 3 Table 1. ) *Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. ** When assessing severity of liver disease using non-invasive methods, a combination of blood biomarkers or the combination of liver stiffness measurement and a blood test improves accuracy and should be undertaken prior to 8 week treatment in all patients with moderate fibrosis.

Missed doses In case a dose of dasabuvir is missed, the prescribed dose can be taken within 6 hours. If more than 6 hours have passed since dasabuvir is usually taken, the missed dose should NOT be taken and the patient should take the next dose per the usual dosing schedule.

Patients should be instructed not to take a double dose. Special populations HIV-1 Co-infection The dosing recommendations in Table 1 should be followed. 5. 1 for additional information. Liver transplant recipients Dasabuvir and ombitasvir/paritaprevir/ritonavir in combination with ribavirin is recommended for 24 weeks in liver transplant recipients.

Lower ribavirin dose at initiation may be appropriate. 1). 5. 2). 2). For patients that require ribavirin, refer to the ribavirin Summary of Product Characteristics for information regarding use in patients with renal impairment. Medicinal product no longer authorised 4 Hepatic impairment No dose adjustment of dasabuvir is required in patients with mild hepatic impairment (Child-Pugh A).

2). Paediatric population The safety and efficacy of dasabuvir in children less than 18 years of age have not been established. No data are available. Method of administration The film-coated tablets are for oral use. e. patients should not chew, break or dissolve the tablet).

8. 13) Medicinal product no longer authorised 18 Medicinal Product/ Possible Mechanism of Interaction GIVE N WITH EFFECT Cmax AUC Ctrough Clinical Comments (administere d in the evening) Mechanism: Increase in paritaprevir exposures may be due to inhibition of OATP1B1/B 3 and CYP3A by atazanavir and CYP3A inhibition by the additional dose of ritonavir.

54) same time as ombitasvir/paritaprevir/ ritonavir + dasabuvir (ritonavir dose in ombitasvir/paritaprevir/ ritonavir will provide darunavir pharmacokinetic enhancement). e. 4. Darunavir combined with ombitasvir/paritaprevir/ ritonavir + dasabuvir is not recommended in patients with extensive PI resistance.

No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ ritonavir. 42) Lopinavir/ritonavir 400/100 mg twice daily Medicinal product no longer authorised 20 Medicinal Product/ Possible Mechanism of Interaction GIVE N WITH EFFECT Cmax AUC Ctrough Clinical Comments 400/100 mg twice daily1 Mechanism: Increase in paritaprevir exposures may be due to inhibition of CYP3A/efflu x transporters by lopinavir and higher dose of ritonavir.

80) or 800/200 mg once daily is contraindicated with dasabuvir and ombitasvir/paritaprevir/r itonavir due to increase in paritaprevir exposures (see Summary of Product Characteristics of ombitasvir/paritaprevir/r itonavir). 55) HIV ANTIVIRALS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Rilpivirine2 25 mg once daily administered in the morning, with food Mechanism: CYP3A inhibition by ritonavir.

21) Co-administration of dasabuvir and ombitasvir/paritaprevir/ ritonavir with rilpivirine once daily should only be considered in patients without known QT- prolongation, and without other QT- prolongation co- administered medicinal products.

4. No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ ritonavir. 07) Efavirenz/ emtricitabine / tenofovir disoproxil fumarate 600/300/200 mg once daily dasabu vir + ombitas vir/parit aprevir/ ritonavi r Co-administration of efavirenz (enzyme inducer) based regimens with paritaprevir /ritonavir + dasabuvir resulted in ALT elevations and therefore, early discontinuation of the study.

1). Risk of hepatic decompensation and hepatic failure in patients with cirrhosis Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported post-marketing in patients treated with dasabuvir with ombitasvir/paritaprevir/ritonavir with and without ribavirin.

Most patients with these severe outcomes had evidence of advanced or decompensated cirrhosis prior to initiating therapy. Although causality is difficult to establish due to background advanced liver disease, a potential risk cannot be excluded.

2). For patients with cirrhosis:  Monitoring should be performed for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal haemorrhage).  Hepatic laboratory testing including direct bilirubin levels should be performed at baseline, during the first 4 weeks of starting treatment and as clinically indicated thereafter.

 Treatment should be discontinued in patients who develop evidence of hepatic decompensation. 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.

3). , oral and topical oestradiol and conjugated oestrogens) was similar to the rate observed in subjects who were not using oestrogen-containing products (approximately 1% in each group). e. 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.

1. 2). 5). Co-administration of dasabuvir with medicinal products that are strong or moderate enzyme inducers is expected to decrease dasabuvir plasma concentrations and reduce its therapeutic effect (see section