Treatment with Exviera should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.
Posology
The recommended dose of dasabuvir is 250 mg (one tablet) twice daily (morning and evening).
Exviera must not be administered as monotherapy. Exviera should be used in combination with other medicinal products for the treatment of HCV (see section 5.1). Refer to the Summary of Product Characteristics of the medicinal products that are used in combination with Exviera.
The recommended co-administered medicinal product(s) and treatment duration for Exviera combination therapy are provided in table 1.
Table 1. Recommended co-administered medicinal product(s) and treatment duration for Exviera by patient population
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Patient population
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Treatment*
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Duration
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Genotype 1b, without cirrhosis or with compensated cirrhosis
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Exviera + ombitasvir/paritaprevir/ritonavir
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12 weeks
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Genotype 1a, without cirrhosis
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Exviera + ombitasvir/paritaprevir/ritonavir + ribavirin*
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12 weeks
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Genotype 1a, with compensated cirrhosis
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Exviera + ombitasvir/paritaprevir/ritonavir + ribavirin*
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24 weeks (see section 5.1.)
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*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.
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Missed doses
In case a dose of Exviera is missed, the prescribed dose can be taken within 6 hours. If more than 6 hours have passed since Exviera 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
Follow the dosing recommendations in Table 1. For dosing recommendations with HIV antiviral agents, refer to sections 4.4 and 4.5. See sections 4.8 and 5.1 for additional information.
Liver transplant recipients
Exviera 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. In the post-liver transplant study, ribavirin dosing was individualized and most subjects received 600 to 800 mg per day (see section 5.1). For dosing recommendations with calcineurin inhibitors refer to section 4.5.
Elderly
No dose adjustment of Exviera is warranted in elderly patients (see section 5.2).
Renal impairment
No dose adjustment of Exviera is required for patients with mild, moderate, or severe renal impairment (see section 5.2).
Hepatic impairment
No dose adjustment of Exviera is required in patients with mild hepatic impairment (Child-Pugh A). Exviera is not recommended in patients with moderate hepatic impairment (Child-Pugh B)(see sections 4.4 and 4.8). Exviera should not be used in patients with severe hepatic impairment (Child-Pugh C) (see section 5.2).
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. Patients should be instructed to swallow the tablets whole (i.e. patients should not chew, break or dissolve the tablet). To maximise absorption, Exviera tablets should be taken with food, without regard to fat and calorie content (see section 5.2).
General
Exviera is not recommended for administration as monotherapy and must be used in combination with other medicinal products for the treatment of hepatitis C infection (see section 4.2 and 5.1).
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 postmarketing in patients treated with Exviera 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.
Exviera is not recommended in patients with moderate hepatic impairment (Child-Pugh B). Exviera should not be used in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.8 and 5.2).
For patients with cirrhosis:
• Monitor 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.
• Discontinue treatment 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.
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 in patients that do not have cirrhosis (for cirrhotics, see above). Early discontinuation may result in drug resistance, but implications for future therapy are not known.
Pregnancy and concomitant use with ribavirin
Also see section 4.6.
Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when Exviera is taken in combination with ribavirin, see section 4.6 and refer to the Summary of Product Characteristics for ribavirin for additional information.
Genotype-specific activity
Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1.
The efficacy of dasabuvir has not been established in patients with HCV genotypes other than genotype 1; Exviera should not be used for the treatment of patients infected with other genotypes than 1.
Co-administration with other direct-acting antivirals against HCV
Exviera safety and efficacy have been established in combination with ombitasvir/ paritaprevir /ritonavir with or without ribavirin. Co-administration of Exviera with other antivirals has not been studied and, therefore, cannot be recommended.
Retreatment
The efficacy of dasabuvir in patients previously exposed to dasabuvir, or to medicinal products anticipated to be cross-resistant, has not been demonstrated.
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 combination with dasabuvir with ombitasvir/paritaprevir/ritonavir if administered at the same time. To be noted, atazanavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of the ombitasvir/paritaprevir/ritonavir fixed dose combination. The combination carries an increased risk for hyperbilirubinemia (including ocular icterus), in particular when ribavirin is part of the hepatitis C regimen.
Darunavir, dosed 800 mg once daily, if administered at the same time as ombitasvir/paritaprevir/ritonavir, can be used in the absence of extensive PI resistance (darunavir exposure lowered). To be noted, darunavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of the ombitasvir/paritaprevir/ritonavir fixed dose combination.
For the use of HIV protease inhibitors other than atazanavir and darunavir refer to the Summary of Product Characteristics of ombitasvir/ paritaprevir /ritonavir.
Raltegravir exposure is substantially increased (2-fold). The combination was not linked to any particular safety issues in a limited set of patients treated for 12-24 weeks.
Rilpivirine exposure is substantially increased (3-fold) when rilpivirine is given in combination with dasabuvir with ombitasvir/paritaprevir/ritonavir, with a consequent potential for QT-prolongation. If an HIV protease inhibitor is added (atazanavir, darunavir), rilpivirine exposure may increase even further and is therefore not recommended. Rilpivirine should be used cautiously, in the setting of repeated ECG monitoring.
NNRTIs other than rilpivirine (efavirenz, etravirine, and nevirapine) are contraindicated (see section 4.3).
HCV/HBV (Hepatitis B Virus) co-infection
The safety and efficacy of dasabuvir have not been established in patients with HCV/HBV co-infection.
Paediatric population
The safety and efficacy of dasabuvir in children below 18 years have not been established. No data are available.
Lactose
Exviera contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medic
