EVOTAZ 300 mg/150 mg film-coated tablets
Each film-coated tablet contains atazanavir sulphate corresponding to 300 mg atazanavir and 150 mg of cobicistat.
For the full list of excipients, see section 6.1.
Film-coated tablet
Pink, oval, biconvex, film-coated tablet of approximate dimensions of 19 mm x 10.4 mm, debossed with "3641" on one side and plain on the other side.
EVOTAZ is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults without known mutations associated with resistance to atazanavir (see sections 4.4 and 5.1).
Therapy should be initiated by a physician experienced in the management of HIV infection.
Posology
Adults
The recommended dose of EVOTAZ is one tablet once daily taken orally with food (see section 5.2).
Advice on missed doses
If EVOTAZ is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of EVOTAZ with food as soon as possible. If this is noticed later than 12 hours of the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.
Special populations
Renal impairment
Based on the very limited renal elimination of cobicistat and atazanavir, no special precautions or dose adjustments of EVOTAZ are required for patients with renal impairment.
EVOTAZ is not recommended for patients undergoing haemodialysis (see sections 4.4 and 5.2).
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. EVOTAZ should not be initiated in patients with creatinine clearance less than 70 ml/min if any co-administered agent (e.g. emtricitabine, lamivudine, tenofovir disoproxil fumarate or adefovir) requires dose adjustment based on creatinine clearance (see sections 4.4, 4.8 and 5.2).
Hepatic impairment
There are no pharmacokinetic data regarding the use of EVOTAZ in patients with hepatic impairment.
Atazanavir and cobicistat are metabolised by the hepatic system. Atazanavir should be used with caution in patients with mild (Child-Pugh Class A) hepatic impairment. However, atazanavir must not be used in patients with moderate (Child-Pugh Class B) to severe (Child-Pugh Class C) hepatic impairment. No dose adjustment of cobicistat is required in patients with mild or moderate hepatic impairment. Cobicistat has not been studied in patients with severe hepatic impairment and is not recommended in these patients.
EVOTAZ should be used with caution in patients with mild hepatic impairment. EVOTAZ must not be used in patients with moderate to severe hepatic impairment (see section 4.3).
Paediatric population
EVOTAZ should not be used in children less than 3 months of age because of safety concerns especially taking into account the potential risk of kernicterus associated with the atazanavir component.
The safety and efficacy of EVOTAZ in children less than 18 years of age have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.
Method of administration
EVOTAZ is to be taken orally with food (see section 5.2). The film-coated tablet should be swallowed whole and must not be chewed, broken, cut or crushed.
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Co-administration with the following medicinal products that are strong inducers of the CYP3A4 isoform of cytochrome P450 due to the potential for loss of therapeutic effect (see section 4.5):
• carbamazepine, phenobarbital, phenytoin (antiepileptics)
• St John's wort (Hypericum perforatum) (herbal product)
• rifampicin (antimycobacterial)
Co-administration with the following medicinal products due to the potential for serious and/or life-threatening adverse reactions (see section 4.5):
• colchicine, when used in patients with renal and/or hepatic impairment (antigout) (see section 4.5)
• sildenafil - when used for the treatment of pulmonary arterial hypertension (see sections 4.4 and 4.5 for co-administration for the treatment of erectile dysfunction), avanafil (PDE5 inhibitors)
• simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5)
• substrates of CYP3A4 or the UGT1A1 isoform of UDP-glucuronyltransferase and have narrow therapeutic windows:
• alfuzosin (alpha-1-adrenoreceptor antagonist)
• amiodarone, bepridil, dronedarone, quinidine, systemic lidocaine (antiarrhythmics/antianginals)
• astemizole, terfenadine (antihistamines)
• cisapride (gastrointestinal motility agent)
• ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
• pimozide, quetiapine (antipsychotics/neuroleptics) (see section 4.5)
• ticagrelor (platelet aggregation inhibitor)
• triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on parenterally administered midazolam, see section 4.5). Moderate to severe hepatic impairment.
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
The choice of EVOTAZ in adult patients should be based on individual viral resistance testing and the patient's treatment history (see section 5.1).
Patients with co-existing conditions
Hepatic impairment
The use of EVOTAZ is contraindicated in patients with moderate to severe hepatic impairment. EVOTAZ should be used with caution in patients with mild hepatic impairment (see sections 4.2, 4.3 and 5.2).
Atazanavir
Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 5.2). The safety and efficacy of atazanavir have not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions (see section 4.8). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.
Patients with previous liver dysfunction or patients with chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Cobicistat
Cobicistat has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Renal impairment
EVOTAZ is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).
Effects on estimated creatinine clearance
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This effect on serum creatinine, leading to a decrease in the estimated creatine clearance, should be taken into consideration when EVOTAZ is administered to patients in whom the estimated creatinine clearance is used to guide aspects of their clinical management, including adjusting doses of co-administered medicinal products. For more information consult the cobicistat Summary of Product Characteristics.
EVOTAZ should not be initiated in patients with creatinine clearance less than 70 ml/min if one or more co-administered agent requires dose adjustment based on creatinine clearance (e.g. emtricitabine, lamivudine, tenofovir disoproxil fumarate or adefovir; see sections 4.2, 4.8 and 5.2).
As atazanavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).
There are currently inadequate data to determine whether co-administration of tenofovir disoproxil fumarate and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil fumarate without cobicistat.
QT prolongat
