TYBOST

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 taken orally, once daily with food. The doses of Tybost and the co-administered protease inhibitor, atazanavir or darunavir, are presented in Tables 1 and 2.

Table 1:

Dosing regimens in adults Dose of Tybost Dose of HIV-1 protease inhibitor Atazanavir 300 mg once daily 150 mg once daily Darunavir 800 mg once daily Table 2: Dosing regimens in adolescents aged 12 years and older, weighing ≥ 35 kg Body Weight (kg) Dose of Tybost Dose of HIV-1 protease inhibitor Atazanavir 300 mg once daily ≥ 40 150 mg once daily Darunavir 800 mg once daily 35 to < 40 150 mg once daily Atazanavir 300 mg once daily 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. 2). Renal impairment No dose adjustment of cobicistat 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.

g. emtricitabine, lamivudine, tenofovir disoproxil, or adefovir) requires dose adjustment based on creatinine clearance. 2. Hepatic impairment No dose adjustment of cobicistat 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). 2). Paediatric population The safety and efficacy of cobicistat co-administered with atazanavir in children aged 0 to less than 12 years, or weighing less than 35 kg have not been established.

The safety and efficacy of cobicistat co-administered with darunavir in children aged 0 to less than 12 years, or weighing less than 40 kg have not been established. No data are available. 2). The film-coated tablet should not be chewed or crushed.

Summary of the safety profile Adverse reactions for cobicistat-boosted atazanavir were consistent with the safety profile of ritonavir-boosted atazanavir. The most frequently reported adverse reactions to cobicistat-boosted atazanavir were associated with elevated bilirubin levels (see Table 4).

Tabulated summary of adverse reactions The safety of cobicistat is based on 144-week data from a phase 3, randomised, active- controlled clinical Study (GS-US-216-0114), in which 692 treatment-naïve patients received at least one dose of cobicistat-boosted atazanavir (n = 344) or ritonavir- boosted atazanavir (n = 348) administered with emtricitabine and tenofovir disoproxil fumarate fixed-dose combination.

Of these 692 patients, 613 (300 atazanavir/cobicistat and 313 atazanavir/ritonavir) and 496 (250 atazanavir/cobicistat and 246 atazanavir/ritonavir) received at least 48 and 144 weeks of treatment, respectively. Adverse reactions to cobicistat-boosted atazanavir during 144 weeks of clinical trial experience from Study GS-US-216-0114 are listed in Table 4, below, by body system organ class and frequency.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from the available data).

Table 4:

Tabulated summary of adverse reactions to cobicistat-boosted atazanavir based on experience of 144 weeks from phase 3 Study GS-US-216-0114 Frequency Adverse reaction Metabolism and nutrition disorders: Common: hyperglycaemia, increased appetite Psychiatric disorders: Common: insomnia, abnormal dreams Uncommon: depression, sleep disorder Nervous system disorders: Common: headache, dizziness, somnolence, dysgeusia Eye disorders: Very common: ocular icterus Gastrointestinal disorders: Very common: nausea Common: vomiting, diarrhoea, dyspepsia, abdominal pain, abdominal distension, flatulence, dry mouth Hepatobiliary disorders: Very common: jaundice Common: hyperbilirubinaemia Skin and subcutaneous tissue disorders: Common: rash Uncommon: pruritus Musculoskeletal and connective tissue disorders: Uncommon: myalgia Renal and urinary disorders: Uncommon: nephrolithiasis, haematuria, proteinuria General disorders and administration site conditions: Common: fatigue Uncommon: pyrexia, asthenia Description of selected adverse reactions Renal impairment Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine.

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. 3). Co-administration of cobicistat with medicinal products that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of therapeutic effect.

5) because decreased plasma concentrations of cobicistat could result in plasma levels that are insufficient to achieve adequate pharmacoenhancement of atazanavir or darunavir. 5). Cobicistat is a weak CYP2D6 inhibitor and is metabolised to a minor extent by CYP2D6.

5). Cobicistat inhibits the transporters P-gp, BCRP, MATE1, OATP1B1 and OATP1B3. 5). Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. 5). Contraception requirements Plasma concentrations of ethinyloestradiol are decreased following co-administration of drospirenone/ethinyloestradiol with darunavir/cobicistat.

Alternative or additional contraceptive measures are recommended when oestrogen-based contraceptives are co-administered with darunavir/cobicistat. Plasma concentrations of drospirenone are increased following administration of drospirenone/ethinyloestradiol with atazanavir/cobicistat or with darunavir/cobicistat.

If drospirenone/ethinyloestradiol is co-administered with atazanavir/cobicistat or darunavir/cobicistat clinical monitoring is recommended due to the potential for hyperkalemia. Data are not available to make recommendations on the use of atazanavir/cobicistat or darunavir/cobicistat with other oral contraceptives.

1. Co-administration is contraindicated with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. 5): • alpha 1-adrenoreceptor antagonists: alfuzosin • antiarrhythmics: amiodarone, quinidine • ergot derivatives: dihydroergotamine, ergometrine, ergotamine • HMG Co-A reductase inhibitors: lovastatin, simvastatin • neuroleptics/antipsychotics: pimozide, lurasidone • PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial hypertension • sedatives/hypnotics: orally administered midazolam, triazolam Co-administration is contraindicated with medicinal products that are strong inducers of CYP3A due to the potential for loss of therapeutic effect.

5): • anticonvulsants: carbamazepine, phenobarbital, phenytoin • antimycobacterials: rifampicin • herbal products: St. 5).