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Tybost 150mg film coated tablet

Last Updated on eMC 10-May-2016 View changes  | Gilead Sciences Ltd Contact details

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Tybost 150 mg film-coated tablets

2. Qualitative and quantitative composition

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.

3. Pharmaceutical form

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.

4. Clinical particulars
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. 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 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

Dose of Tybost

Dose of HIV-1 protease inhibitor

150 mg once daily

Atazanavir 300 mg once daily

Darunavir 800 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 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.

4.3 Contraindications

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

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 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.

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.

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-glycoprotein (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 Tybost with medicinal products such as dihydroergotamine, ergotamine, ergometrine, orally administered midazolam, triazolam, amiodarone, quinidine, cisapride, pimozide, 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 Tybost 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 Tybost 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, boceprevir, fluticasone, and bosentan (see Table 2).

Co-administration of Tybost 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 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 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 2 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 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 2: 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 disoproxil fumarate

Co-administration of tenofovir disoproxil fumarate 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 fumarate.

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: ND

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 Tybost, 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.

HCV protease inhibitors

Telaprevir (750 mg three times daily)/Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)1

Telaprevir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Cobicistat:

AUC: ↔

Cmax: ↔

Cmin: ↑ 232%

No dose adjustment is required when Tybost is co-administered with telaprevir.

Boceprevir

Interaction not studied.

Atazanavir, darunavir or boceprevir plasma concentrations may decrease upon co-administration.

Co-administration with Tybost is not recommended.

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 Tybost 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 Tybost. 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

Inhaled/Nasal corticosteroids

Fluticasone

Interaction not studied.

Concomitant use of inhaled or nasal fluticasone and cobicistat may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations.

Use of inhaled or nasal fluticasone propionate and Tybost is not recommended unless the potential benefit to the patient outweighs the risks.

Alternative inhaled or nasal corticosteroids may be considered.

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: ↑ 12%

Cmin: ↑ 66%

Naloxone:

AUC: ↓ 28%

Cmax: ↓ 28%

No dose adjustment of Tybost is required.

ORAL CONTRACEPTIVES

Norgestimate/Ethinylestradiol

Interaction not studied.

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

No data are available to make recommendations on the use of atazanavir/cobicistat or darunavir/cobicistat with combined or progestagen-only oral or implanted contraceptives. Alternative forms of contraception should be used.

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: ND

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

Rivaroxaban

Interaction not studied.

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

Inhibition of CYP3A and intestinal P-gp may lead to increased plasma levels and pharmacodynamic effects of rivaroxaban which may lead to an increased bleeding risk.

Co-administration of rivaroxaban and Tybost is not recommended.

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.

Dabigatran

Interaction not studied.

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

Clinical monitoring is recommended when dabigatran is co-administered with P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.

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 Tybost 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

Atorvastatin

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 atorvastatin, pitavastatin, fluvastatin, pravastatin or rosuvastatin are expected to increase when co-administered with atazanavir/cobicistat or darunavir/cobicistat.

Co-administration of atorvastatin with Tybost is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful monitoring.

Caution should be exercised when co-administering Tybost 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)/Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)

Rosuvastatin:

AUC: ↑ 38%

Cmax: ↑ 89%

Cmin: ↑ 43%

Cobicistat:

AUC: ↔

Cmax: ↔

Cmin: ↔

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. Tybost should not be co-administered with colchicine to patients with renal or hepatic impairment.

1 This study was conducted using the fixed dose combination tablet elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil.

ND = not determined

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).

Tybost should not be used during pregnancy unless the clinical condition of the woman requires treatment with cobicistat co-administered with atazanavir or darunavir.

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 HIV infected women do not breast-feed their infants under any circumstances.

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

No studies on the effects of cobicistat on the ability to drive and use machines have been performed.

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 3).

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 3, below, by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100).

Table 3: Tabulated summary of adverse reactions to cobicistat-boosted atazanavir based on experience for 144 weeks from phase 3 study GS-US-216-0114

Frequency

Adverse reaction

Metabolism and nutritional 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

No data are available for children below 18 years of age. Tybost is not recommended in this population (see section 4.2).

Other special population(s)

Elderly

Cobicistat has not been studied in patients over the age of 65.

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 national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

4.9 Overdose

If overdose of Tybost occurs the patient must be monitored for evidence of toxicity. 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: All other therapeutic products, ATC code: V03AX03

Mechanism of action and pharmacodynamic effects

Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates (such as atazanavir or darunavir) that have limited oral bioavailability and a short half-life due to CYP3A-dependent metabolism.

The effect of cobicistat on atazanavir pharmacokinetics was demonstrated in the pharmacokinetic sub-study (n = 48) of the phase 3 study GS-US-216-0114 in which HIV-1 infected patients received atazanavir 300 mg + cobicistat 150 mg or atazanavir 300 mg + ritonavir 100 mg, both in combination with emtricitabine and tenofovir disoproxil fumarate fixed-dose combination. The steady-state pharmacokinetic parameters of atazanavir were comparable when boosted with cobicistat versus ritonavir (see Table 4).

Table 4: Pharmacokinetic parameters [mean ± SD (%CV)] of atazanavir in the pharmacokinetic sub-study of phase 3 study GS-US-216-0114

Atazanavir pharmacokinetics parameters

Atazanavir + cobicistata

(n = 22)

Atazanavir + ritonavira

(n = 26)

AUCtau (μg•h/ml)

46.13 ± 26.18 (56.8)

47.59 ± 24.39 (51.2)

Cmax (μg/ml)

3.91 ± 1.94 (49.6)

4.76 ± 1.94 (40.8)

Ctau (μg/ml)

0.80 ± 0.72 (90.3)

0.85 ± 0.72 (84.7)

a Plus background regimen of emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg fixed-dose combination

The pharmacokinetic enhancing effect of cobicistat on darunavir was evaluated in a phase 1 clinical study GS-US-216-0115 in 31 healthy subjects that were administered darunavir 800 mg in combination with cobicistat 150 mg or ritonavir 100 mg, all once daily, for 10 days. The steady-state pharmacokinetic parameters of darunavir were comparable when boosted with cobicistat versus ritonavir (see Table 5).

Table 5: Pharmacokinetic parameters [mean ± SD (%CV)] of darunavir 800 mg co-administered with cobicistat 150 mg or ritonavir 100 mg once daily

Darunavir pharmacokinetics parameters

Darunavir 800 mg + cobicistat 150 mg once daily

(n = 31)

Darunavir 800 mg + ritonavir 100 mg once daily

(n = 31)

AUCtau (μg•h/ml)

81.08 ± 25.15 (31.0)

79.99 ± 27.20 (34.0)

Cmax (μg/ml)

7.74 ± 1.69 (21.8)

7.46 ± 1.52 (20.3)

C0h (μg/ml)

2.40 ± 1.22 (50.7)

2.48 ± 0.85 (34.3)

Antiviral activity in vitro

Cobicistat has no detectable antiviral activity against HIV-1, HBV or HCV and does not antagonise the antiviral effect of HIV inhibitors.

Clinical experience

Antiviral efficacy data from randomised controlled studies is available for cobicistat-boosted atazanavir, but not for cobicistat-boosted darunavir (see sections 4.4 and 5.2).

In treatment-naïve HIV-1 infected patients

The safety and efficacy of cobicistat with atazanavir in HIV-1 infected patients were evaluated in the randomised, double-blind, active-controlled phase 3 study GS-US-216-0114 in HIV-1 infected patients with baseline estimated creatinine clearance above 70 ml/min who were treatment-naïve (n = 692).

Patients were randomised in a 1:1 ratio to receive either atazanavir 300 mg + cobicistat 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily, each administered with a fixed background regimen containing tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg administered as a fixed-dose combination tablet. Randomisation was stratified by screening HIV-1 RNA level (≤ 100,000 copies/ml or > 100,000 copies/ml). Virologic response rate was evaluated in both treatment arms and virologic response was defined as achieving an undetectable viral load (< 50 HIV-1 RNA copies/ml). Viruses were known to be susceptible to atazanavir, emtricitabine and tenofovir disoproxil fumarate at baseline.

Baseline characteristics and treatment outcomes at weeks 48 and 144 for study GS-US-216-0114 are presented in Tables 6 and 7, respectively.

Table 6: Demographic and baseline disease characteristics of antiretroviral treatment-naïve HIV-1 infected adult subjects in study GS-US-216-0114

 

Atazanavir + cobicistata

(n = 344)

Atazanavir + ritonavira

(n = 348)

Demographic characteristics

  

Median age, years (min-max)

36

(19-62)

37

(19-70)

Sex

  

Male

83.4%

82.5%

Female

16.6%

17.5%

Ethnicity

  

White

57.6%

61.8%

Black or African Heritage

18.9%

18.1%

Asian

12.8%

10.6%

Other

10.8%

9.5%

Baseline disease characteristics

  

Median baseline plasma HIV-1 RNA (range) log10 copies/ml

4.78

(3.22-6.43)

4.84

(3.21-6.44)

Percentage of subjects with viral load > 100,000 copies/ml

38.4%

41.1%

Median baseline CD4+ cell count (range), cells/mm3

348

(1-1,075)

341

(10-1,455)

Percentage of subjects with CD4+ cell count ≤ 200 cells/mm3

17.4%

16.4%

a Plus background regimen of emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg fixed-dose combination

Table 7: Virologic outcome of randomised treatment of study GS-US-216-0114 at weeks 48 and 144

 

Week 48a

Week 144b

 

Atazanavir + cobicistatf

(n = 344)

Atazanavir + ritonavirf

(n = 348)

Atazanavir + cobicistatf

(n = 344)

Atazanavir + ritonavirf

(n = 348)

Virologic success

HIV-1 RNA < 50 copies/ml

85%

87%

72%

74%

Treatment difference

-2.2% (95% CI = -7.4%, 3.0%)

-2.1% (95% CI = -8.7%, 4.5%)

Virologic failurec

6%

4%

8%

5%

No virologic data in week 48 or 144 window

9%

9%

20%

21%

Discontinued study drug due to AE or deathd

6%

7%

11%

11%

Discontinued study drug due to other reasons and last available HIV-1 RNA < 50 copies/mle

3%

2%

8%

10%

Missing data during window but on study drug

0%

0%

< 1%

< 1%

a Week 48 window is between day 309 and 378 (inclusive)

b Week 144 window is between day 967 and 1,050 (inclusive)

c Includes subjects who had ≥ 50 copies/ml in the week 48 or 144 windows; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, and at the time of discontinuation had a viral value of ≥ 50 copies/ml.

d Includes patients who discontinued due to adverse event (AE) or death at any time point from day 1 through the time window if this resulted in no virologic data on treatment during the specified window.

e Includes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up.

f Plus background regimen of emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg fixed-dose combination

Atazanavir + cobicistat + emtricitabine and tenofovir disoproxil fumarate fixed-dose combination was non-inferior in achieving HIV-1 RNA < 50 copies/ml when compared to atazanavir + ritonavir + emtricitabine and tenofovir disoproxil fumarate fixed-dose combination.

Changes in CD4+ cell counts through 48 and 144 weeks in study GS-US-216-0114 are presented in Table 8.

Table 8: Changes in CD4+ cell counts through weeks 48 and 144 in study GS-US-216-0114

 

Week 48

Week 144

 

Atazanavir + cobicistata

(n = 344)

Atazanavir + ritonavira

(n = 348)

Atazanavir + cobicistata

(n = 344)

Atazanavir + ritonavira

(n = 348)

Mean increase from baseline in CD4+ T-cell count (cells/mm3)b

213

219

310

332

a Plus background regimen of emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg fixed-dose combination

b Missing = excluded analysis

In an analysis of treatment-failure subjects in study GS-US-216-0114 through week 144, evaluable genotypic data from paired baseline and treatment-failure isolates were available for all 21 virologic failures in the cobicistat group. Among the 21 patients, 3 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitutions K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, genotypic data was available for all 19 virologic failures. Among the 19 patients, 1 developed the emtricitabine-associated resistance substitution M184V with no tenofovir- or primary protease inhibitor-associated resistance substitutions.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with cobicistat in one or more subsets of the paediatric population in treatment of HIV-1 infection (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following oral administration of cobicistat with food in HIV-1 infected subjects, peak plasma concentrations were observed 4 hours post-dose for cobicistat. The steady-state mean Cmax, AUCtau, and Ctrough (mean ± SD) following multiple doses of cobicistat in HIV-1 infected subjects (n = 68), respectively, were 1.2 ± 0.3 μg/ml, 10.9 ± 3.8 μg•h/ml, and 0.07 ± 0.07 μg/ml.

A food effect study was not conducted for Tybost. In clinical studies, cobicistat was co-administered with atazanavir or darunavir under fed conditions, in accordance with the Summary of Product Characteristics for these agents. It is recommended that Tybost be administered with food.

Distribution

Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drug concentration ratio was 2.

Biotransformation

Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does not undergo glucuronidation. Following oral administration of [14C]cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and faeces and do not contribute to the CYP3A inhibitory activity of cobicistat.

Elimination

Following oral administration of [14C]cobicistat, 86% and 8.2% of the dose were recovered in faeces and urine, respectively. The median terminal plasma half-life of cobicistat following administration of Tybost is approximately 3-4 hours.

Linearity/non-linearity

Cobicistat exposures are non-linear and greater than dose-proportional over the range of 50 mg to 400 mg, consistent with a mechanism-based CYP3A inhibitor.

Elderly

Pharmacokinetics of cobicistat have not been fully evaluated in the elderly (65 years of age and older).

Gender

No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat.

Ethnicity

No clinically relevant pharmacokinetic differences due to ethnicity have been identified for cobicistat.

Paediatric population

The pharmacokinetics of cobicistat in paediatric subjects have not been established.

Renal impairment

A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 ml/min). No meaningful differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects, consistent with low renal clearance of cobicistat.

Hepatic impairment

Cobicistat is primarily metabolised and eliminated by the liver. A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. No dose adjustment of Tybost is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

Hepatitis B and/or hepatitis C virus co-infection

Pharmacokinetics of cobicistat have not been fully evaluated in hepatitis B and/or C virus co-infected subjects.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. No teratogenic effects were observed in rats and rabbit developmental toxicity studies. In rats, ossification changes in the spinal column and sternebra of foetuses occurred at a dose that produced significant maternal toxicity.

Ex vivo rabbit studies and in vivo dog studies suggest that cobicistat has a low potential for QT prolongation, and may slightly prolong the PR interval and decrease left ventricular function at mean concentrations at least 10-fold higher than the human exposure at the recommended 150 mg daily dose.

A long term carcinogenicity study of cobicistat in rats revealed tumourigenic potential specific for this species that is regarded as of no relevance for humans. A long term carcinogenicity study in mice did not show any carcinogenic potential.

The active substance cobicistat is persistent in the environment.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Silicon dioxide

Croscarmellose sodium

Magnesium stearate

Microcrystalline cellulose

Film-coating

Sunset yellow FCF aluminium lake (E110)

Macrogol 3350 (E1521)

Polyvinyl alcohol (partially hydrolysed) (E1203)

Talc (E553B)

Titanium dioxide (E171)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 30 film-coated tablets and a silica gel desiccant.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and outer cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Gilead Sciences International Limited

Cambridge

CB21 6GT

United Kingdom

8. Marketing authorisation number(s)

EU/1/13/872/001

EU/1/13/872/002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 19 September 2013

10. Date of revision of the text

04/2016

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Company contact details

Gilead Sciences Ltd

Company image
Address

Gilead Medical Information (UK & Eire), 280 High Holborn, London, WC1V 7EE, UK

Medical Information Direct Line

+353 214 825 999 (Ireland)

Medical Information e-mail
Telephone

+44 (0)203 681 4500

Medical Information Direct Line

08000 113 700 (UK)

Customer Care direct line

+44 (0)203 681 4681

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Active ingredients

cobicistat

Legal categories

POM - Prescription Only Medicine

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