Tybost 150 mg film-coated tablets

Each film-coated tablet contains 150 mg of cobicistat.

Excipient(s) with known effect: Each tablet contains 59 micrograms sunset yellow FCF (E110).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Orange, round, biconvex, film-coated tablet of diameter 10.3 mm, debossed with “GSI” on one side of the tablet and plain-faced on the other side of the tablet.

Tybost is indicated as a pharmacokinetic enhancer of atazanavir 300 mg once daily or darunavir 800 mg once daily as part of antiretroviral combination therapy in human immunodeficiency virus-1 (HIV-1) infected adults. See sections 4.2, 4.4, 5.1 and 5.2.

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Tybost is used in combination with atazanavir or darunavir, therefore the atazanavir or darunavir Summary of Product Characteristics should be consulted.

Tybost must be co-administered with atazanavir or darunavir, taken orally, once daily with food.

The doses of Tybost and the co-administered protease inhibitor, atazanavir or darunavir, are presented in Table 1.

Table 1: Dosing regimens

If the patient misses a dose of Tybost within 12 hours of the time it is usually taken, the patient should take Tybost with food as soon as possible and resume their normal dosing schedule in combination with atazanavir or darunavir. If a patient misses a dose of Tybost by more than 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Special populations

Elderly

No data are available on which to make a dose recommendation for patients over the age of 65 years (see section 5.2).

Renal impairment

No dose adjustment of Tybost is required for patients with renal impairment, including those with severe renal impairment. Cobicistat has not been studied in patients receiving dialysis, and, therefore, no recommendation can be made for these patients.

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine. Tybost 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

No dose adjustment of Tybost is required in patients with mild (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B). Cobicistat has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, the use of Tybost is not recommended in these patients (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of cobicistat in children aged 0 to less than 18 years have not been established (see section 5.1). No data are available.

Method of administration

Tybost should be taken orally, once daily with food (see section 5.2). The film-coated tablet should not be chewed or crushed.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with the following medicinal products due to the potential for serious and/or life-threatening events or loss of therapeutic effect (see sections 4.4 and 4.5):

• alpha 1-adrenoreceptor antagonists: alfuzosin

• antiarrhythmics: amiodarone, quinidine

• anticonvulsants: carbamazepine, phenobarbital, phenytoin

• antimycobacterials: rifampicin

• ergot derivatives: dihydroergotamine, ergometrine, ergotamine

• gastrointestinal motility agents: cisapride

• herbal products: St. John's wort (Hypericum perforatum)

• HMG Co-A reductase inhibitors: lovastatin, simvastatin

• neuroleptics: pimozide

• PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial hypertension

• sedatives/hypnotics: orally administered midazolam, triazolam

Co-administration with other medicinal products

Cobicistat is a strong mechanism-based CYP3A inhibitor and is a CYP3A substrate.

Increased plasma concentrations of medicinal products that are metabolised by CYP3A (including atazanavir and darunavir) are observed on co-administration with cobicistat. Higher plasma concentrations of co-administered medicinal products can result in increased or prolonged therapeutic effects or adverse reactions. For medicinal products metabolised by CYP3A these higher plasma concentrations may potentially lead to severe, life-threatening or fatal events (see section 4.3).

Co-administration of Tybost with medicinal products that induce CYP3A is contraindicated or is not recommended (see sections 4.3 and 4.5) because decreased plasma concentrations of cobicistat could result in plasma levels that are insufficient to achieve adequate pharmacoenhancement of atazanavir or darunavir.

Co-administration of Tybost with medicinal products that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased cobicistat plasma concentrations (see section 4.5).

Cobicistat is a weak CYP2D6 inhibitor and is metabolised to a minor extent by CYP2D6. Co-administration with cobicistat can increase plasma concentrations of medicinal products that are metabolised by CYP2D6 (see sections 4.3 and 4.5).

Cobicistat inhibits the transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Co-administration of Tybost in patients receiving medicinal products that are substrates of these transporters may result in increased plasma concentrations of the co-administered medicinal products (see section 4.5).

Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. If switching pharmacoenhancer from ritonavir to cobicistat, caution is required during the first two weeks of treatment with Tybost, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer (see section 4.5).

Contraception requirements

No dosing recommendations can be made regarding the use of Tybost with oral contraceptives. Alternative forms of contraception should be considered (see section 4.5).

Co-administration of Tybost and antiretroviral medicinal products

Tybost must be co-administered with either atazanavir 300 mg once daily or with darunavir 800 mg once daily (see section 4.2). Safety and efficacy have not been established for use of Tybost with either atazanavir or darunavir when used in any other dosing regimen. Antiviral efficacy data from randomised controlled studies is available for cobicistat-boosted atazanavir, but not for cobicistat-boosted darunavir (see sections 5.1 and 5.2).

Tybost must not be used as a pharmacokinetic enhancer of any other HIV-1 protease inhibitor or any other antiretroviral medicinal product that requires boosting since dosing recommendations for such co-administration have not been established and may result in insufficient plasma level of the antiretroviral medicinal product(s) leading to loss of therapeutic effect and development of resistance (see section 4.2).

Tybost co-administered with atazanavir or darunavir should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 to reach the desired therapeutic plasma concentrations (i.e., another protease inhibitor or elvitegravir). Dosing recommendations for such combinations have not been established and co-administration may result in decreased plasma concentrations of atazanavir, darunavir and/or the other antiretroviral agents that require pharmacoenhancement leading to loss of antiviral activity and development of resistance.

Tybost should not be used concurrently with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

Tybost should not be used in combination with other medicinal products containing cobicistat (such as the fixed-dose combination tablet elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil).

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 Tybost 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.

Tybost 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.

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.

Liver disease

Cobicistat has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, the use of Tybost is not recommended in these patients (see sections 4.2 and 5.2).

Excipients

Tybost contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic reactions.