4.1. Therapeutic indications

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 and adolescents aged 12 years and older:

• weighing at least 35 kg co-administered with atazanavir or

• weighing at least 40 kg co-administered with darunavir.

See sections 4.2, 4.4, 5.1 and 5.2.

4.2. Posology and method of administration

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

150 mg once daily

Atazanavir 300 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

≥ 40

150 mg once daily

Atazanavir 300 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.

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 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. Cobicistat 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, or adefovir) requires dose adjustment based on creatinine clearance. See sections 4.4, 4.8 and 5.2.

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). 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 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.

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.

4.3. Contraindications

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

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. Therefore, Tybost should not be co-administered with medicinal products that include, but are not limited to, the following (see sections 4.4 and 4.5):

• 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. Therefore, Tybost should not be co-administered with medicinal products that include, but are not limited to, the following (see sections 4.4 and 4.5):

• anticonvulsants: carbamazepine, phenobarbital, phenytoin

• antimycobacterials: rifampicin

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

Co-administration with dabigatran etexilate, a P-glycoprotein (P-gp) substrate, is contraindicated (see section 4.5).

4.4. Special warnings and precautions for use

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 serious and/or life-threatening events (see section 4.3). 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.

Co-administration of cobicistat 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 cobicistat 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-gp, BCRP, MATE1, OATP1B1 and OATP1B3. Co-administration of cobicistat 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 cobicistat, 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

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. 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 cobicistat 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).

Cobicistat 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). 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 in combination with other medicinal products containing cobicistat or with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

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 cobicistat 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 or adefovir). See sections 4.2, 4.8 and 5.2.

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil 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).

Pregnancy

Treatment with cobicistat and atazanavir or darunavir during the second and third trimesters of pregnancy has been shown to result in lower atazanavir or darunavir exposure compared to postpartum. Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in atazanavir or darunavir exposure may result in virological failure and an increased risk of mother-to-child transmission of HIV infection. Therefore, therapy with cobicistat and atazanavir or darunavir should not be initiated during pregnancy, and women who become pregnant during therapy with cobicistat and atazanavir or darunavir should be switched to an alternative regimen (see sections 4.6). Darunavir given with low dose ritonavir may be considered as an alternative regimen.

Excipients

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

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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. 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) (see section 4.4).

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 4.4).

Cobicistat inhibits the transporters P-gp, BCRP, MATE1, OATP1B1 and OATP1B3. Co-administration of Tybost with medicinal products that are substrates of these transporters can result in increased plasma concentrations of the co-administered medicinal products (see section 4.4).

Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19.

Cobicistat is not expected to induce CYP3A4 or P-gp (MDR1).

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 4.4).

Concomitant use contraindicated

Medicinal products that are extensively metabolised by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in exposure when co-administered with cobicistat. Co-administration of cobicistat with medicinal products such as dihydroergotamine, ergotamine, ergometrine, orally administered midazolam, triazolam, amiodarone, quinidine, pimozide, lurasidone, alfuzosin, simvastatin, lovastatin, and sildenafil which are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (see section 4.3).

Co-administration of cobicistat with medicinal products that are strong inducers of CYP3A (such as St. John's wort (Hypericum perforatum), rifampicin, carbamazepine, phenobarbital, phenytoin) may result in decreased plasma concentrations of cobicistat and consequently that of atazanavir or darunavir being boosted, leading to loss of therapeutic effect and possible development of resistance (see section 4.3).

Concomitant use not recommended

Co-administration of cobicistat with medicinal products that are moderate to weak inducers of CYP3A may result in decreased plasma concentration of cobicistat and consequently that of atazanavir or darunavir being boosted, leading to loss of therapeutic effect and possible development of resistance. Some examples include, but are not limited to, etravirine, efavirenz, nevirapine, and bosentan (see Table 3).

Co-administration of cobicistat with medicinal products that inhibit CYP3A may result in increased plasma concentration of cobicistat. Some examples include, but are not limited to, itraconazole, ketoconazole, and voriconazole (see Table 3).

Cobicistat 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). Dosing recommendations for such combinations have not been established and 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.

Other interactions

Interactions of cobicistat and potential co-administered medicinal products are listed in Table 3 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). These interactions are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious and/or life-threatening events or loss of efficacy.

For additional drug-drug interactions with atazanavir or darunavir, consult their respective Summary of Product Characteristics when using Tybost.

Table 3: Interactions between cobicistat and other medicinal products

Medicinal product by therapeutic areas

Effects on drug levels

Mean percent change in AUC, Cmax, Cmin

Recommendation concerning co-administration with cobicistat 150 mg and atazanavir or darunavir

ANTIRETROVIRALS

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Tenofovir disoproxil1

Co-administration of tenofovir disoproxil with cobicistat is expected to increase tenofovir plasma concentration.

Tenofovir:

AUC: ↑ 23%

Cmax: ↑ 55%

This increase is not considered to be clinically relevant and does not necessitate dose adjustment of tenofovir disoproxil.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz (600 mg single dose)

Co-administration of efavirenz and cobicistat is expected to decrease cobicistat plasma concentrations.

Efavirenz:

AUC: ↔

Cmax: ↓ 13%

Cmin: N/A

Atazanavir or darunavir plasma concentrations may decrease as a consequence of a reduction in cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Co-administration is not recommended (see section 4.4).

Etravirine

Interaction not studied.

Co-administration of etravirine and cobicistat is expected to decrease cobicistat plasma concentrations.

Atazanavir or darunavir plasma concentrations may decrease as a consequence of a reduction in cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Co-administration is not recommended (see section 4.4).

Nevirapine

Interaction not studied.

Co-administration of nevirapine and cobicistat is expected to decrease cobicistat plasma concentrations.

Nevirapine plasma concentrations may be increased when co-administered with cobicistat.

Atazanavir or darunavir plasma concentrations may decrease as a consequence of a reduction in cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Co-administration is not recommended (see section 4.4).

Rilpivirine

Interaction not studied.

Co-administration of rilpivirine and cobicistat is expected to increase the plasma concentration of rilpivirine.

Rilpivirine is not expected to affect the plasma concentration of cobicistat.

No dose adjustment of rilpivirine is required when atazanavir/cobicistat or darunavir/cobicistat are used concomitantly with rilpivirine.

CCR5 Antagonists

Maraviroc

Interaction not studied.

Maraviroc is a substrate of CYP3A and its plasma concentration increases when co-administered with potent CYP3A inhibitors.

When co-administering maraviroc and Tybost patients should receive maraviroc 150 mg twice daily. For further details, consult the Summary of Product Characteristics for maraviroc.

ANTI-INFECTIVES

Antifungals

Ketoconazole

Interaction not studied.

Concentrations of ketoconazole and/or cobicistat may increase with co-administration of cobicistat.

When administering ketoconazole with Tybost, the maximum daily dose of ketoconazole should not exceed 200 mg per day.

Caution is warranted and clinical monitoring is recommended during co-administration.

Itraconazole

Voriconazole

Posaconazole

Fluconazole

Concentrations of itraconazole, fluconazole and posaconazole may be increased when co-administered with cobicistat.

Concentrations of voriconazole may increase or decrease when co-administered with cobicistat.

Clinical monitoring is recommended upon co-administration with Tybost.

When administering with cobicistat, the maximum daily dose of itraconazole should not exceed 200 mg per day.

Voriconazole should not be used unless the possible benefit is considered to outweigh the risks associated with the unpredictable effect on plasma concentrations.

Antimycobacterials

Rifabutin (150 mg every other day)/Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)

Co-administration of rifabutin, a potent CYP3A inducer, may significantly decrease cobicistat plasma concentrations.

Cobicistat:

AUC: ↔

Cmax: ↔

Cmin: ↓ 66%

Rifabutin:

AUC: ↔

Cmax: ↔

Cmin: ↔

25-O-desacetyl-rifabutin:

AUC: ↑ 525%

Cmax: ↑ 384%

Cmin: ↑ 394%

Co-administration of cobicistat and rifabutin is not recommended. If the combination is needed, the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday). Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to desacetyl-rifabutin. Further dose reduction of rifabutin has not been studied. It should be kept in mind that a twice weekly dose of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifabutin resistance and a treatment failure.

Macrolide antibiotics

Clarithromycin

Interaction not studied.

Concentrations of clarithromycin may be increased upon co-administration with cobicistat.

Concentrations of clarithromycin may be increased upon co-administration of cobicistat. Alternative antibiotics should be considered for co-administration with atazanavir/cobicistat. Consult atazanavir Summary of Product Characteristics for dosing recommendations.

When clarithromycin is co-administered with darunavir/cobicistat, consult the darunavir Summary of Product Characteristics for dosing recommendations.

ANTI-NEOPLASTICS

Dasatinib

Nilotinib

Vinblastine

Vincristine

Interaction not studied.

Concentrations of these medicinal products may be increased when co-administered with cobicistat.

Concentrations of these medicinal products may be increased when co-administered with Tybost resulting in the potential for increased adverse events usually associated with these anticancer medicinal products.

GLUCOCORTICOIDS

Corticosteroids

Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone).

Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co--administered with cobicistat, resulting in reduced serum cortisol concentrations.

Concomitant use of cobicistat and corticosteroids that are metabolised by CYP3A (e.g. fluticasone propionate or other inhaled or nasal corticosteroids) may increase the risk of development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Co-administration with CYP3A-metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects. Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone for intranasal or inhalational use should be considered, particularly for long-term use.

For coadministration of cutaneously-administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for conditions or uses that augment its systemic absorption.

ORAL ANTI-DIABETICS

Metformin

Interaction not studied.

Cobicistat reversibly inhibits MATE1, and concentrations of metformin may be increased when co-administered with cobicistat.

Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking Tybost.

NARCOTIC ANALGESICS

Methadone

Methadone:

AUC: ↔

Cmax: ↔

Cmin: ↔

No dose adjustment of methadone is required.

Buprenorphine/Naloxone

Buprenorphine:

AUC: ↑ 35%

Cmax: ↔

Cmin: ↑ 66%

Naloxone:

AUC: ↓ 28%

Cmax: ↓ 28%

No dose adjustment of cobicistat is required.

ORAL CONTRACEPTIVES

Drospirenone/Ethinyloestradiol (3 mg/0.02 mg single dose)/ Darunavir (800 mg once daily)/Cobicistat (150 mg once daily)

Drospirenone:

AUC: ↑ 58%

Cmax: ↔

Cmin: N/A

Ethinyloestradiol:

AUC: ↓ 30%

Cmax: ↔

Cmin: N/A

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 co-administration of drospirenone/ethinyloestradiol with darunavir/cobicistat. If drospirenone/ethinyloestradiol is co-administered with darunavir/cobicistat clinical monitoring is recommended due to the potential for hyperkalemia.

Drospirenone/Ethinyloestradiol (3 mg/0.02 mg single dose)/Atazanavir (300 mg once daily)/Cobicistat (150 mg once daily)

Drospirenone:

AUC: ↑ 130%

Cmax: ↔

Cmin: N/A

Ethinyloestradiol:

AUC: ↔

Cmax: ↔

Cmin: N/A

Plasma concentrations of drospirenone are increased following co-administration of drospirenone/ethinyloestradiol with atazanavir/cobicistat. If drospirenone/ethinyloestradiol is co-administered with atazanavir/cobicistat clinical monitoring is recommended due to the potential for hyperkalemia.

Norgestimate/Ethinyloestradiol

Interaction not studied.

Concentrations of norgestimate may be affected on co-administration with cobicistat.

Data are not available to make recommendations on the use of darunavir/cobicistat or atazanavir/cobicistat with other oral contraceptives than drospirenone/ethinyloestradiol.

Alternative forms of contraception should be considered.

ANTIARRHYTHMICS

Disopyramide

Flecainide

Systemic lidocaine

Mexiletine

Propafenone

Interaction not studied.

Concentrations of these antiarrhythmic medicinal products may be increased when co-administered with cobicistat.

Caution is warranted and clinical monitoring is recommended upon co-administration of these antiarrhythmic medicinal products with Tybost.

Digoxin (0.5 mg single dose)/Cobicistat (150 mg multiple doses)

Plasma concentrations of digoxin may be increased when co-administered with cobicistat.

Digoxin:

AUC: ↔

Cmax: ↑ 41%

Cmin: N/A

The peak concentration of digoxin is increased when co-administered with Tybost. The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effects.

ANTI-HYPERTENSIVES

Metoprolol

Timolol

Interaction not studied.

Concentrations of beta-blockers may be increased when co-administered with cobicistat.

Clinical monitoring is recommended and a dose reduction may be necessary when these beta-blockers are co-administered with Tybost.

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Verapamil

Interaction not studied.

Concentrations of calcium channel blockers may be increased when co-administered with cobicistat.

Clinical monitoring of therapeutic effect and adverse events is recommended when these medicinal products are co-administered with Tybost.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan

Interaction not studied.

Co-administration of bosentan with cobicistat may lead to decreased cobicistat plasma concentrations.

Atazanavir or darunavir plasma concentrations may decrease as a consequence of a reduction in cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Co-administration is not recommended (see section 4.4).

ANTICOAGULANTS

Dabigatran

Interaction not studied.

Co-administration with Tybost may increase dabigatran plasma concentrations with similar effects as seen with other strong P-gp inhibitors.

Co-administration of cobicistat with dabigatran is contraindicated.

Apixaban

Rivaroxaban

Edoxaban

Interaction not studied.

Co-administration with cobicistat may result in increased plasma concentrations of the DOAC, which may lead to an increased bleeding risk.

Co-administration of apixaban, rivaroxaban or edoxaban is not recommended with Tybost.

Warfarin

Interaction not studied.

Concentrations of warfarin may be affected upon co-administration with cobicistat.

It is recommended that the international normalised ratio (INR) be monitored upon co-administration with Tybost.

ANTIPLATELETS

Clopidogrel

Interaction not studied.

Co-administration of clopidogrel with cobicistat is expected to decrease clopidogrel active metabolite plasma concentrations, which may reduce the antiplatelet activity of clopidogrel.

Co-administration of clopidogrel with cobicistat is not recommended.

Prasugrel

Interaction not studied.

Cobicistat is not expected to have a clinically relevant effect on plasma concentrations of the active metabolite of prasugrel.

No dose adjustment of prasugrel is required.

ANTICONVULSANTS

Carbamazepine (200 mg twice daily)/Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)

Co-administration of carbamazepine, a potent CYP3A inducer, may significantly decrease cobicistat plasma concentrations.

Cobicistat:

AUC: ↓ 84%

Cmax: ↓ 72%

Cmin: ↓ 90%

Carbamazepine:

AUC: ↑ 43%

Cmax: ↑ 40%

Cmin: ↑ 51%

Carbamazepine-10,11-epoxide:

AUC: ↓ 35%

Cmax: ↓ 27%

Cmin: ↓ 41%

Carbamazepine, a potent CYP3A inducer, decreases cobicistat plasma concentrations and that of atazanavir or darunavir, which may result in loss of therapeutic effect and development of resistance. Co-administration of cobicistat with carbamazepine is contraindicated (see section 4.3).

INHALED BETA AGONISTS

Salmeterol

Interaction not studied.

Co-administration of salmeterol with cobicistat may result in increased plasma concentrations of salmeterol.

Increased plasma concentrations of salmeterol are associated with the potential for serious and/or life-threatening reactions.

Co-administration of salmeterol and Tybost is not recommended (see section 4.4).

HMG Co-A REDUCTASE INHIBITORS

Fluvastatin

Pitavastatin

Pravastatin

Interaction not studied.

Plasma concentrations of HMG Co-A reductase inhibitors may be increased when co-administered with cobicistat.

Plasma concentrations of, pitavastatin, fluvastatin or pravastatin are expected to increase when co-administered with atazanavir/cobicistat or darunavir/cobicistat.

Caution should be exercised when co-administering cobicistat with pitavastatin.

Consult the Summary of Product Characteristics of atazanavir or darunavir for further information on use in combination with these medicinal products.

Rosuvastatin (10 mg single dose)/Atazanavir (300 mg once daily)/Cobicistat (150 mg once daily)

Rosuvastatin:

AUC: ↑ 242%

Cmax: ↑ 958%

Cmin: N/A

Cobicistat:

AUC: ↔

Cmax: ↔

Cmin: ↔

Plasma concentrations of rosuvastatin are increased when co-administered with atazanavir/cobicistat.

When co-administration is necessary, do not exceed 10 mg rosuvastatin daily and clinical monitoring for safety (e.g. myopathy) is recommended.

Rosuvastatin (10 mg single dose)/Darunavir (800 mg once daily)/Cobicistat (150 mg once daily)

Rosuvastatin:

AUC: ↑ 93%

Cmax: ↑ 277%

Cmin: N/A

Cobicistat:

AUC: ↔

Cmax: ↔

Cmin: ↔

Plasma concentrations of rosuvastatin are increased when co-administered with darunavir/cobicistat.

It is recommended to start with the lowest recommended dose of rosuvastatin and titrate based on clinical response while monitoring for safety (e.g. myopathy).

Atorvastatin (10 mg single dose)/Atazanavir (300 mg)/Cobicistat (150 mg once daily)

Atorvastatin:

AUC: ↑ 822%

Cmax: ↑ 1785%

Cmin: N/A

Cobicistat:

AUC: ↔

Cmax: ↔

Cmin: ↔

Plasma concentrations of atorvastatin are increased when co-administered with atazanavir/cobicistat.

Co-administration is not recommended.

Atorvastatin (10 mg single dose)/Darunavir (800 mg)/Cobicistat (150 mg once daily)

Atorvastatin:

AUC: ↑ 290%

Cmax: ↑ 319%

Cmin: N/A

Cobicistat:

AUC: ↔

Cmax: ↔

Cmin: ↔

Plasma concentrations of atorvastatin are increased when co-administered with darunavir/cobicistat.

When co-administration is necessary, it is recommended to start with a dose of atorvastatin 10 mg and titrate based on clinical response while monitoring for safety (e.g. myopathy).

PHOSPHODIESTERASE TYPE-5 (PDE-5) INHIBITORS

Sildenafil

Tadalafil

Vardenafil

Interaction not studied.

PDE-5 inhibitors are primarily metabolised by CYP3A. Co-administration with cobicistat may result in increased sildenafil, tadalafil and vardenafil plasma concentrations, which may result in PDE-5 inhibitor-associated adverse reactions.

Co-administration of Tybost with sildenafil for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).

Caution should be exercised, including consideration of dose reduction, when co-administering Tybost with tadalafil for the treatment of pulmonary arterial hypertension.

For the treatment of erectile dysfunction, it is recommended that a single dose of sildenafil no more than 25 mg in 48 hours, vardenafil no more than 2.5 mg in 72 hours, or tadalafil no more than 10 mg in 72 hours be co-administered with Tybost.

ANTIDEPRESSANTS

Selective Serotonin Reuptake Inhibitors (SSRIs)

Trazodone

Interaction not studied.

Plasma concentrations of trazodone may be increased when co-administered with cobicistat.

Dose titration may be required for most medicinal products of the SSRI class, when co-administered with Tybost.

IMMUNOSUPPRESSANTS

Ciclosporin

Sirolimus

Tacrolimus

Interaction not studied.

Concentrations of these immunosuppressants may be increased when co-administered with cobicistat.

Therapeutic monitoring is recommended upon co-administration with Tybost.

NEUROLEPTICS

Perphenazine

Risperidone

Thioridazine

Interaction not studied.

Co-administration of neuroleptics with cobicistat may result in increased plasma concentrations of neuroleptics.

For these neuroleptics, consider reducing the dose of the neuroleptic upon co-administration with Tybost.

SEDATIVES/HYPNOTICS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Zolpidem

Interaction not studied.

Concentrations of these sedatives/hypnotics may be increased when co-administered with cobicistat.

For these sedatives/hypnotics, dose reduction may be necessary and concentration monitoring is recommended.

ANTI-GOUT

Colchicine

Interaction not studied.

Colchicine plasma concentrations may be increased when co-administered with cobicistat.

Dose reductions of colchicine may be required. Cobicistat should not be co-administered with colchicine to patients with renal or hepatic impairment.

N/A = not applicable

DOAC = direct oral anticoagulant

1 Study was conducted with tenofovir disoproxil fumarate

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited clinical data with cobicistat in pregnant women.

Animal studies do not indicate direct or indirect harmful effects of cobicistat with respect to reproductive toxicity (see section 5.3).

Treatment with cobicistat and atazanavir or darunavir during pregnancy results in lower atazanavir or darunavir exposure which may be associated with an increased risk of virological failure and an increased risk of mother-to-child transmission of HIV infection. Therapy with cobicistat and atazanavir or darunavir should not be initiated during pregnancy, and women who become pregnant during therapy with cobicistat and atazanavir or darunavir should be switched to an alternative regimen (see sections 4.4).

Breast-feeding

It is unknown whether cobicistat/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of cobicistat/metabolites in milk. A risk to the newborns/infants cannot be excluded. Therefore, Tybost should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants.

Fertility

No human data on the effect of cobicistat on fertility are available. Animal studies do not indicate harmful effects of cobicistat on fertility.

4.7. Effects on ability to drive and use machines

Tybost has no or negligible influence on the ability to drive and use machines. However, patients should be informed that dizziness has been reported during treatment with cobicistat-containing regimens.

4.8. Undesirable effects

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. An increase from baseline in serum creatinine solely due to cobicistat's inhibitory effect generally does not exceed 0.4 mg/dl.

In Study GS-US-216-0114, decreases in estimated creatinine clearance occurred early in treatment with cobicistat, after which they stabilised. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was -15.1 ± 16.5 ml/min in the cobicistat-boosted atazanavir plus emtricitabine and tenofovir disoproxil fumarate fixed-dose combination group and -8.0 ± 16.8 ml/min in the ritonavir-boosted atazanavir plus emtricitabine and tenofovir disoproxil fumarate fixed-dose combination group.

Effects on the liver

In Study GS-US-216-0114, hyperbilirubinaemia (> 1 x ULN) was common: 97.7% in the cobicistat-boosted atazanavir plus emtricitabine and tenofovir disoproxil fumarate fixed-dose combination group, and 97.4% in the ritonavir-boosted atazanavir plus emtricitabine and tenofovir disoproxil fumarate fixed-dose combination group through 144 weeks of treatment. However, a higher percentage of subjects in the cobicistat-boosted group had increases in total bilirubin > 2 x ULN than those in the ritonavir-boosted group (88.0% versus 80.9%). The rates of study drug discontinuation due to bilirubin-related adverse events were low and similar in both groups (4.9% in the cobicistat-boosted group and 4.0% in the ritonavir-boosted group). An increase of > 3 x ULN in alanine aminotransferase or aspartate aminotransferase was recorded in 12.8% of subjects in the cobicistat-boosted group and 9.0% in the ritonavir-boosted group.

Paediatric population

The safety of cobicistat was evaluated in 21 HIV-1 infected virologically suppressed paediatric patients between the ages of 12 to < 18 years through 48 weeks in an open-label clinical study (GS-US-216-0128) of cobicistat-boosted atazanavir (n = 14) or darunavir (n = 7) plus two NRTIs. In this study, the safety profile of cobicistat was similar to that in adults.

Other special population(s)

Patients with renal impairment

The safety of Tybost in 73 HIV-1 infected treatment-experienced patients with mild to moderate renal impairment (eGFR by Cockcroft-Gault method 50-89 ml/min) who switched pharmacokinetic enhancer from ritonavir to cobicistat was evaluated in an open-label clinical Study (GS-US-236-0118) of cobicistat-boosted atazanavir or darunavir plus two NRTIs. At week 96 the mean change in serum creatinine was 0.07 ± 0.15 mg/dl and the mean change in eGFR by Cockcroft-Gault method was -6.2 ± 9.07 ml/min. The effect of cobicistat on serum creatinine and eGFR in patients switching from ritonavir to cobicistat in Study GS-US-236-0118 was consistent with the effect in treatment-naïve patients in Study GS-US-216-0114.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8). Treatment of overdose with cobicistat consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

There is no specific antidote for overdose with cobicistat. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.