Tybost

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



2 

 
 
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 aluminium lake (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 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. 
 



3 

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. 
 
Pregnancy 
Treatment with cobicistat and atazanavir or darunavir during pregnancy results in lower atazanavir or 
darunavir exposure.  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 4.4 and 4.6).  
Darunavir/ritonavir may be considered as an alternative regimen. 
 



4 

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 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). 



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 



6 

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 4.2 and 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. 
 
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-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). 
 



7 

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. 
 



8 

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: 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. 



9 

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 
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. 



10 

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 
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 
All corticosteroids excluding cutaneous products 
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. 
 
 

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. 



11 

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 
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: NC 
 
Ethinyloestradiol: 
AUC: ↓ 30% 
Cmax: ↔ 
Cmin: NC 

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: NC 
 
Ethinyloestradiol: 
AUC: ↔ 
Cmax: ↔ 
Cmin: NC 

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: 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. 



12 

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 
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. 

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). 



13 

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 
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: NC 
 
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: NC 
 
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: NC 
 
Cobicistat: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

Plasma concentrations of atorvastatin are 
increased when co-administered with 
atazanavir/cobicistat. 
 
Co-administration is not recommended.  



14 

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

Atorvastatin: 
AUC: ↑ 290% 
Cmax: ↑ 319% 
Cmin: NC 
 
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. 



15 

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 
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. 

ND = not determined 
NC = not calculated 
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 4.2 and 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 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 
 
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. 
 



16 

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 
 



17 

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 national reporting system 
listed in Appendix V. 
 
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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


18 

 
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 5). 
 
Table 5: 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 6). 
 
Table 6: 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. 



19 

 
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 7 and 8, respectively. 
 
Table 7: 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 

 



20 

Table 8: 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 9. 
 
Table 9: 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 



21 

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 safety and efficacy of cobicistat with atazanavir or darunavir were evaluated in an open-label 
phase 2/3 Study GS-US-216-0128 in 21 HIV-1 infected virologically suppressed paediatric patients 
between the ages of 12 and < 18 years with baseline estimated creatinine clearance ≥90 mL/min.  
Patients received cobicistat 150 mg once daily with either atazanavir 300 mg once daily (n = 14) or 
darunavir 800 mg once daily (n = 7), each administered with a background regimen containing two 
NRTIs. 
 
The mean age of patients was 14 years (range: 12 to 17); 62% were male; 38% were Asian, 33% were 
White, and 19% were Black.  At baseline, 20/21 subjects had plasma HIV-1 RNA < 50 copies/mL and 
1 subject had plasma HIV-1 RNA = 50 copies/mL. 
 
In patients treated with cobicistat + atazanavir, the median baseline CD4+ cell count and CD4+% was 
770 cells/mm3 (range: 486 to 1765) and 33% (range: 23% to 45%), respectively.  At Week 48, 93% 
(13/14) of patients retained HIV-1 RNA < 50 copies/mL and the median change from baseline in 
CD4+ cell count and CD4+% was -60 cells/mm3 and -0.3%, respectively.  In patients treated with 
cobicistat + darunavir, the median baseline CD4+ cell count and CD4+% was 1117 cells/mm3 
(range: 658 to 2416) and 45% (range: 28% to 56%), respectively.  At Week 48, 86% (6/7) of patients 
retained HIV-1 RNA < 50 copies/mL (1 subject had missing data) and the median change from 
baseline in CD4+ cell count and CD4+% was -342 cells/mm3 and -6%, respectively.  Overall, 3 of 21 
patients qualified for resistance analysis: 1 patient showed no resistance in protease or reverse 
transcriptase and 2 had missing data due to assay failure. 
 
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. 



22 

 
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 
 
In paediatric patients aged 12 to < 18 years who received cobicistat-boosted atazanavir (n = 14) or 
darunavir (n = 7) in Study GS-US-216-0128, exposures of atazanavir and cobicistat (AUCtau, Cmax, and 
Ctrough) were higher (24% to 180%) than in adults; however, the increases were not considered 
clinically significant as the safety profiles were similar in adult and paediatric patients.  Mean 
darunavir Ctrough was lower (61%) in the paediatric patients relative to adults but was not considered 
clinically significant based on exposure-response relationships.  The pharmacokinetics of cobicistat in 
paediatric subjects < 12 years of age or < 35 kg 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 cobicistat 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. 
 



23 

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. 
 
Pack sizes containing 1 bottle of 30 film-coated tablets or 3 bottles of 30 film-coated tablets. 



24 

 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
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 
Date of latest renewal: 26 July 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



26 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



29 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tybost 150 mg film-coated tablets 
cobicistat 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 150 mg of cobicistat. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sunset yellow FCF aluminium lake (E110), see leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 (3 bottles of 30) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



30 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/872/001 30 film-coated tablets 
EU/1/13/872/002 90 (3 bottles of 30) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Tybost [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  [Outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
[Outer packaging only] 
 



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



32 

Package leaflet: Information for the patient 
 

Tybost 150 mg film-coated tablets 
cobicistat 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet 
 
1. What Tybost is and what it is used for 
2. What you need to know before you take Tybost 
3. How to take Tybost 
4. Possible side effects 
5. How to store Tybost 
6. Contents of the pack and other information 
 
 
1. What Tybost is and what it is used for 
 
Tybost contains the active substance cobicistat. 
 
Tybost is used for the treatment of human immunodeficiency virus-1 (HIV-1) infection, the virus that 
causes acquired immune deficiency syndrome (AIDS).  It is used in HIV-1 infected adults and 
adolescents aged 12 years and older: 
• weighing at least 35 kg (when co-administered with atazanavir 300 mg) or 
• weighing at least 40 kg (when co-administered with darunavir 800 mg). 
 
Tybost acts as a booster (enhancer) of atazanavir or darunavir (both protease inhibitors) to improve 
their effect (see section 3 of this leaflet). 
 
Tybost does not directly treat your HIV, but boosts the levels of atazanavir and darunavir in the 
blood.  It does this by slowing down the breakdown of atazanavir and darunavir which will make them 
stay in the body for longer. 
 
 
2. What you need to know before you take Tybost 
 
Do not take Tybost 
 
• If you are allergic to cobicistat or any of the other ingredients of this medicine (listed in 

section 6 of this leaflet). 
 
• If you are taking medicines containing any of the following: 

- alfuzosin, used to treat an enlarged prostate gland 
- amiodarone, quinidine, used to correct irregular heartbeats 
- dabigatran, used to prevent and treat blood clots 
- carbamazepine, phenobarbital, phenytoin, used to prevent seizures 
- rifampicin, used to prevent and treat tuberculosis and other infections 
- dihydroergotamine, ergometrine, ergotamine, used to treat migraine headache 



33 

- St. John’s wort (Hypericum perforatum), a herbal remedy used for depression and 
anxiety 

- lovastatin, simvastatin, used to lower blood cholesterol 
- pimozide, lurasidone, used to treat abnormal thoughts or feelings 
- sildenafil, used to treat pulmonary arterial hypertension – a lung disease that makes 

breathing difficult 
- orally administered midazolam, triazolam, used to help you sleep and/or relieve anxiety 

 
 If any of these applies to you, you should not take Tybost and you should tell your doctor 

immediately. 
 
Warnings and precautions 
 
You must remain under the care of your doctor while taking Tybost. 
 
You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy.  Discuss with your doctor the precautions needed to avoid infecting other 
people.  This medicine does not directly treat your HIV infection.  You may still develop infections or 
other illnesses associated with HIV infection.  You must keep in regular contact with your doctor. 
 
Talk to your doctor before taking Tybost: 
 
• If you are taking another protease inhibitor.  Tybost taken with atazanavir or darunavir 

should not be used with another antiviral medicine that requires boosting. 
 
• Talk to your doctor or pharmacist if you have or have had kidney disease, or if tests have 

shown problems with your kidneys.  Your doctor will carefully consider whether to treat you 
with Tybost. 

 
• Talk to your doctor or pharmacist if you have or have had severe liver disease, or if tests 

have shown problems with your liver.  Your doctor will carefully consider whether to treat 
you with Tybost. 

 
 If any of these applies to you, talk to your doctor before taking Tybost. 
 
Children and adolescents 
 
Do not give this medicine to children under 12 years of age, or who weigh less than 35 kg (or 40 kg) 
as explained in section 3 of this leaflet.  The use of Tybost in children under 12 years of age or who 
weigh less than 35 kg has not yet been studied. 
 
Other medicines and Tybost 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  Tybost may interact with other substances.  As a result, the amounts of Tybost or other 
medicines in your blood may be affected.  This may stop your medicines from working properly, or 
may make any side effects worse.  In some cases, your doctor may need to adjust your dose or check 
the levels of medicine in your blood. 
 
There are some medicines that should never be taken with Tybost. 
These are mentioned above under the heading “Do not take Tybost-If you are taking medicines 
containing any one of the following”. 
 
Medicines used in treating HIV infection: 
You should not take Tybost with other medicines containing: 
• ritonavir 
• cobicistat 



34 

Talk to your doctor if you are taking 
• another protease inhibitor 
• efavirenz 
• etravirine 
• nevirapine 
• maraviroc 
 Tell your doctor if you are taking any of these HIV medicines. 
 
Other types of medicine: 
• ketoconazole, itraconazole, voriconazole, posaconazole and fluconazole, medicines used to 

treat fungal infections 
• clarithromycin and rifabutin, medicines used to treat bacterial infections including 

tuberculosis 
• dasatinib, nilotinib, vinblastine and vincristine, medicines used to treat cancer 
• corticosteroids including betamethasone, budesonide, fluticasone, mometasone, 

prednisone, triamcinolone.  These medicines are used to treat allergies, asthma, inflammatory 
bowel diseases, inflammatory conditions of the eyes, joints and muscles and other inflammatory 
conditions.  If alternatives cannot be used, its use should only take place after medical 
evaluation and under close monitoring by your doctor for corticosteroid side effects. 

• metformin, medicine used for the treatment of type 2 diabetes 
• oral or implanted hormonal contraceptives used to prevent pregnancy 
• amlodipine, digoxin, diltiazem, disopyramide, felodipine, flecainide, lidocaine, metoprolol, 

mexiletine, nicardipine, nifedipine, propafenone, timolol and verapamil, medicines used to 
treat heart problems 

• bosentan, a medicine used to treat pulmonary arterial hypertension 
• apixaban, edoxaban, rivaroxaban and warfarin, medicines used to prevent and treat blood 

clots 
• salmeterol, a medicine used to treat asthma 
• atorvastatin, fluvastatin, pitavastatin, pravastatin and rosuvastatin, medicines used to lower 

cholesterol 
• sildenafil and vardenafil, medicines used to treat impotence, and tadalafil, a medicine used to 

treat impotence and pulmonary hypertension 
• trazodone, a medicine used to treat depression 
• ciclosporin, sirolimus and tacrolimus, medicines used to control your body’s immune 

response after a transplant 
• buspirone, clorazepate, diazepam, estazolam, flurazepam, perphenazine, risperidone, 

thioridazine, zolpidem, medicines used to treat nervous system disorders 
• colchicine, a medicine used to treat gout 
 Tell your doctor if you are taking any of these medicines. 
 
 Tell your doctor if you are taking these or any other medicines.  Do not stop your treatment 

without contacting your doctor. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
• Tell your doctor immediately if you are pregnant, think you may be pregnant or are 

planning to have a baby.  Pregnant women should not take Tybost with atazanavir or 
darunavir.  The amounts of these medicines in your blood may decrease during pregnancy, 
which may stop them from working properly.   

 
• Do not breast-feed during treatment with Tybost.  It is not known if the active substance in 

this medicine can pass into human breast milk.  If you are a woman with HIV it is 



35 

recommended that you do not breast-feed to avoid passing the virus to the baby through your 
breast milk. 

 
Driving and using machines 
 
Some patients have reported dizziness when Tybost was taken with atazanavir or darunavir.  If you are 
affected while taking Tybost, do not drive and do not use any tools or machines. 
 
Tybost contains sunset yellow FCF aluminium lake (E110) 
 
Tell your doctor if you have an allergy to sunset yellow FCF aluminium lake (E110).  Tybost 
contains sunset yellow FCF aluminium lake which may cause allergic reactions. 
 
 
3. How to take Tybost 
 
Always take this medicine exactly as your doctor has told you.  Check with your doctor or pharmacist 
if you are not sure. 
 
Recommended dose for adults: 
 
• One tablet each day by mouth, with food.  Do not chew, crush or split the tablet. 
• Tybost must be taken with atazanavir (300 mg) or darunavir (800 mg). 
 
Recommended dose for adolescents 12 to less than 18 years of age: 
 
• One tablet each day by mouth, with food.  Do not chew, crush or split the tablet. 
• When taking Tybost with atazanavir (300 mg), adolescents must weigh at least 35 kg. 
• When taking Tybost with darunavir (800 mg), adolescents must weigh at least 40 kg. 
 
Always take the dose recommended by your doctor.  This is to make sure that your medicine is 
fully effective.  Do not change the dose unless your doctor tells you to. 
 
If you take more Tybost than you should 
 
If you accidentally take more than the recommended dose of Tybost you may be at increased risk of 
experiencing side effects with this medicine (see section 4 of this leaflet). 
 
Contact your doctor or nearest emergency department immediately for advice.  Keep the tablet bottle 
with you so that you can easily describe what you have taken. 
 
If you forget to take Tybost 
 
It is important not to miss a dose of Tybost. 
 
If you do miss a dose and notice: 
 
• within 12 hours of the time you usually take Tybost, you must take the tablet as soon as 

possible.  Always take the tablet with food.  Then take the next dose as usual in combination 
with atazanavir or darunavir. 

 
• 12 hours or more after the time you usually take Tybost, then do not take the missed dose.  

Wait and take the next dose, with food, at your usual time. 
 



36 

Do not stop taking Tybost 
 
Do not stop taking Tybost without talking to your doctor.  Stopping Tybost and atazanavir or 
darunavir may reduce the success of future treatments prescribed by your doctor. 
 
Always keep enough Tybost so you don’t run out.  When your supply of Tybost starts to run low, 
get more from your doctor or pharmacist. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  When 
treating HIV infection, it is not always possible to tell whether some of the unwanted effects are 
caused by Tybost or by other medicines that you are taking at the same time, or by the HIV disease 
itself.  The following side effects may occur when taking Tybost with atazanavir. 
 
Very common side effects 
(may affect more than 1 in 10 people) 
• feeling sick (nausea) 
• yellowing of the skin and/or eyes (jaundice) 
Common side effects 
(may affect up to 1 in 10 people) 
• high sugar levels in the blood (hyperglycaemia) 
• increased appetite, disturbed sense of taste, dry mouth 
• headache, dizziness 
• vomiting, diarrhoea, stomach pain, problems with digestion resulting in pain after meals 

(dyspepsia), feeling bloated, wind (flatulence) 
• increased levels of bilirubin in the blood (hyperbilirubinaemia) 
• rash 
• difficulty sleeping, abnormal dreams, drowsiness, tiredness (fatigue) 
Uncommon side effects 
(may affect up to 1 in 100 people) 
• blood in the urine (haematuria) 
• protein in the urine (proteinuria) 
• feeling depressed 
• itchiness 
• aching muscles, weakness 
• kidney stones 
• fever 
• sleep disorder 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 
effects not listed in this leaflet.  You can also report side effects directly via the national reporting 
system listed in Appendix V.  By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
For more information on the side effects of atazanavir or darunavir see the package leaflets for these 
medicines. 
 
 
5. How to store Tybost 
 
Keep this medicine out of the sight and reach of children. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


37 

 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Tybost contains 
 
The active substance is cobicistat.  Each film-coated tablet contains 150 mg cobicistat. 
 
The other ingredients are 
 
Tablet core 
Croscarmellose sodium, magnesium stearate, microcrystalline cellulose, silicon dioxide. 
 
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) (see section 2 
of this leaflet). 
 
What Tybost looks like and contents of the pack 
 
Tybost film-coated tablets are orange, round, biconvex tablets, debossed on one side with “GSI” and 
plain-faced on the other side of the tablet. 
 
Tybost comes in bottles of 30 tablets (with a silica gel sachet or canister that must be kept in the bottle 
to help protect your tablets).  The silica gel desiccant is contained in a separate sachet or canister and 
should not be swallowed. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
90 (3 bottles of 30) film-coated tablets.  Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 



38 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel.: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 



39 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu

http://www.ema.europa.eu/


40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATIONS 

 



41 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for cobicistat, the scientific 
conclusions of CHMP are as follows:  
 
During this reporting period, an article was published by Momper et al, Pharmacokinetics of 
Atazanavir Boosted with Cobicistat During Pregnancy and Postpartum, IDSA 2019 {Momper 2019}, 
describing the results from the IMPAACT P1026s study. In this study, the reported PK data showed 
lower exposures of cobicistat (COBI) and atazanavir (ATV) when cobicistat (COBI) was used as a 
booster with ATV during pregnancy specially in the second and third trimester compared to 
postpartum. This finding was consistent with previous studies which showed lower exposures of 
elvitegravir (EVG) and darunavir (DRV) after their use with COBI as a booster during pregnancy 
{Best 2017, Momper 2018}. 
 
The COBI CCDS was previously updated to include the statement that lower exposures of COBI have 
been reported during pregnancy and to closely monitor viral load in pregnant women (reported in a 
previous COBI PSUR [27 August 2017 -26 August 2018]).Consequently, the MAH has submitted a 
proposal to update the COBI SmPC and PL, which has been endorsed with minor changes.  
 
Of note, this proposal to update the product information of Tybost is consistent with the previously 
approved pregnancy update relating to the use of darunavir and cobicistat during pregnancy 
(procedure EMEA/H/C/002572/WS1401/0044), and with the recently approved pregnancy update to 
the EVOTAZ (atazanavir/cobicistat) product information (procedure EMEA/H/C/003904/II/0030). 
 
Therefore, and as proposed by the MAH, the SmPC and the PL of medicinal products containing 
cobicistat are updated to add a warning to not initiate atazanavir/cobicistat during pregnancy, and to 
switch to an alternative regimen for women who become pregnant during therapy with 
atazanavir/cobicistat. Consequently, the current recommendation that cobicistat and atazanavir should 
only be used during pregnancy if the potential benefit justifies the potential risk to the foetus and 
mother should be deleted. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
Grounds for the variation to the terms of the marketing authorisation(s) 
 
On the basis of the scientific conclusions for cobicistat the CHMP is of the opinion that the benefit-
risk balance of the medicinal product(s) containing cobicistat is unchanged subject to the proposed 
changes to the product information 
 
The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATIONS