Evotaz

1 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



 

2 
 

 
1. NAME OF THE MEDICINAL PRODUCT 
 
EVOTAZ 300 mg/150 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains atazanavir sulphate corresponding to 300 mg atazanavir and 150 mg 
of cobicistat. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet  
 
Pink, oval, biconvex, film-coated tablet of approximate dimensions of 19 mm x 10.4 mm, debossed 
with "3641" on one side and plain on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
EVOTAZ is indicated in combination with other antiretroviral medicinal products for the treatment of 
HIV-1 infected adults without known mutations associated with resistance to atazanavir (see 
sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of HIV infection. 
 
Posology 
 
The recommended dose of EVOTAZ is one tablet once daily taken orally with food (see section 5.2). 
 
Advice on missed doses 
If EVOTAZ is missed within 12 hours of the time it is usually taken, patients should be instructed to 
take the prescribed dose of EVOTAZ with food as soon as possible. If this is noticed later than 
12 hours of the time it is usually taken, the missed dose should not be taken and the patient should 
resume the usual dosing schedule. 
 
Special populations 
 
Renal impairment 
Based on the very limited renal elimination of cobicistat and atazanavir, no special precautions or dose 
adjustments of EVOTAZ are required for patients with renal impairment. 
 
EVOTAZ is not recommended for patients undergoing haemodialysis (see sections 4.4 and 5.2).  
 
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular 
secretion of creatinine without affecting actual renal glomerular function. EVOTAZ should not be 
initiated in patients with creatinine clearance less than 70 ml/min if any co-administered medicinal 



 

3 
 

product (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 
There are no pharmacokinetic data regarding the use of EVOTAZ in patients with hepatic impairment. 
 
Atazanavir and cobicistat are metabolised by the hepatic system. Atazanavir should be used with 
caution in patients with mild (Child-Pugh Class A) hepatic impairment. However, atazanavir must not 
be used in patients with moderate (Child-Pugh Class B) to severe (Child-Pugh Class C) hepatic 
impairment. No dose adjustment of cobicistat is required in patients with mild or moderate hepatic 
impairment. Cobicistat has not been studied in patients with severe hepatic impairment and is not 
recommended in these patients.  
 
EVOTAZ should be used with caution in patients with mild hepatic impairment. EVOTAZ must not 
be used in patients with moderate to severe hepatic impairment (see section 4.3). 
 
Paediatric population 
EVOTAZ should not be used in children less than 3 months of age because of safety concerns 
especially taking into account the potential risk of kernicterus associated with the atazanavir 
component. 
 
The safety and efficacy of EVOTAZ in children less than 18 years of age have not been established. 
Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a 
posology can be made. 
 
Pregnancy and postpartum 
Treatment with EVOTAZ during pregnancy results in low atazanavir exposure. Therefore, therapy 
with EVOTAZ should not be initiated during pregnancy, and women who become pregnant during 
therapy with EVOTAZ should be switched to an alternative regimen (see sections 4.4 and 4.6). 
 
Method of administration 
 
EVOTAZ is to be taken orally with food (see section 5.2). The film-coated tablet should be swallowed 
whole and must not be chewed, broken, cut or crushed. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
Co-administration with the following medicinal products that are strong inducers of the CYP3A4 
isoform of cytochrome P450 due to the potential for loss of therapeutic effect (see section 4.5):  
 carbamazepine, phenobarbital, phenytoin (antiepileptics) 
 St John's wort (Hypericum perforatum) (herbal product)  
 rifampicin (antimycobacterial) 
 
Co-administration with the following medicinal products due to the potential for serious and/or life-
threatening adverse reactions (see section 4.5):  
 colchicine, when used in patients with renal and/or hepatic impairment (antigout) (see 

section 4.5) 
 sildenafil - when used for the treatment of pulmonary arterial hypertension (see sections 4.4 

and 4.5 for co-administration for the treatment of erectile dysfunction), avanafil (PDE5 
inhibitors)  

 dabigatran (anticoagulant) 
 simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5)  
 lomitapide (lipid-modifying agent) 



 

4 
 

 grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used to 
treat chronic hepatitis C infection) (see section 4.5) 

 glecaprevir/pibrentasvir fixed dose combination (see section 4.5) 
 substrates of CYP3A4 or the UGT1A1 isoform of UDP-glucuronyltransferase and have narrow 

therapeutic windows: 
 alfuzosin (alpha-1-adrenoreceptor antagonist)  
 amiodarone, bepridil, dronedarone, quinidine, systemic lidocaine 

(antiarrhythmics/antianginals)  
 astemizole, terfenadine (antihistamines) 
 cisapride (gastrointestinal motility agent)  
 ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine) 
 pimozide, quetiapine, lurasidone (antipsychotics/neuroleptics) (see section 4.5)  
 ticagrelor (platelet aggregation inhibitor)  
 triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on 

parenterally administered midazolam, see section 4.5).  
 
Moderate to severe hepatic impairment. 
 
4.4 Special warnings and precautions for use 
 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission 
should be taken in accordance with national guidelines. 
 
The choice of EVOTAZ in adult patients should be based on individual viral resistance testing and the 
patient’s treatment history (see section 5.1). 
 
Pregnancy 
Treatment with atazanavir/cobicistat 300/150 mg during the second and third trimester has been 
shown to result in low atazanavir exposure. Cobicistat levels decrease and may not provide sufficient 
boosting. The substantial reduction in atazanavir exposure may result in virological failure and an 
increased risk of mother to child transmission of HIV infection. Therefore, therapy with EVOTAZ 
should not be initiated during pregnancy, and women who become pregnant during therapy with 
EVOTAZ should be switched to an alternative regimen (see sections 4.2 and 4.6). 
 
Patients with co-existing conditions 
 
Hepatic impairment 
The use of EVOTAZ is contraindicated in patients with moderate to severe hepatic impairment. 
EVOTAZ should be used with caution in patients with mild hepatic impairment (see sections 4.2, 4.3 
and 5.2). 
 
Atazanavir 
Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in 
patients with hepatic impairment (see sections 4.2 and 5.2). The safety and efficacy of atazanavir have 
not been established in patients with significant underlying liver disorders. Patients with chronic 
hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe 
and potentially fatal hepatic adverse reactions (see section 4.8). In case of concomitant antiviral 
therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for 
these medicinal products. 
 
Patients with previous liver dysfunction or patients with chronic active hepatitis have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy and should be 
monitored according to standard practice. If there is evidence of worsening liver disease in such 
patients, interruption or discontinuation of treatment must be considered. 



 

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Cobicistat 
Cobicistat has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). 
 
Renal impairment  
EVOTAZ is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2). 
 
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 EVOTAZ 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. For more information consult the cobicistat 
Summary of Product Characteristics. 
 
EVOTAZ should not be initiated in patients with creatinine clearance less than 70 ml/min if one or 
more co-administered medicinal product requires dose adjustment based on creatinine clearance (e.g. 
emtricitabine, lamivudine, tenofovir disoproxil or adefovir; see sections 4.2, 4.8 and 5.2). 
 
As atazanavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be 
significantly removed by haemodialysis or peritoneal dialysis (see sections 4.2 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. 
 
QT prolongation 
Dose related asymptomatic prolongations in PR interval with atazanavir, a component of EVOTAZ 
have been observed in clinical studies. Caution should be used with medicinal products known to 
induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher 
atrioventricular or complex bundle-branch block), EVOTAZ should be used with caution and only if 
the benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing 
EVOTAZ in association with medicinal products which have the potential to increase the QT interval 
and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte 
imbalances (see sections 4.8 and 5.3). 
 
Haemophiliac patients 
There have been reports of increased bleeding, including spontaneous skin haematomas and 
haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In some 
patients additional factor VIII was given. In more than half of the reported cases, treatment with 
protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal 
relationship has been suggested, although the mechanism of action has not been elucidated. 
Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding. 
 
Weight and metabolic parameters 
 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to the disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate. 
 
In clinical studies, atazanavir has been shown to induce dyslipidaemia to a lesser extent than 
comparators.  
 



 

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Hyperbilirubinaemia 
 
Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl 
transferase (UGT) have occurred in patients receiving atazanavir (see section 4.8). Hepatic 
transaminase elevations that occur with elevated bilirubin in patients receiving EVOTAZ should be 
evaluated for alternative aetiologies. Alternative antiretroviral therapy to EVOTAZ may be considered 
if jaundice or scleral icterus is unacceptable to a patient. 
 
Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of 
UGT. Combinations of EVOTAZ and indinavir have not been studied and co-administration of these 
medicinal products is not recommended (see section 4.5). 
 
Cholelithiasis 
 
Cholelithiasis has been reported in patients receiving atazanavir (see section 4.8). Some patients 
required hospitalisation for additional management and some had complications. If signs or symptoms 
of cholelithiasis occurs, temporary interruption or discontinuation of treatment may be considered. 
 
Chronic kidney disease 
 
Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has 
been reported during post-marketing surveillance. A large prospective observational study has shown 
an association between an increased incidence of chronic kidney disease and cumulative exposure to 
atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This 
association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the 
renal function of patients should be maintained throughout the treatment duration (see section 4.8).  
 
Nephrolithiasis 
 
Nephrolithiasis has been reported in patients receiving atazanavir (see section 4.8). Some patients 
required hospitalisation for additional management and some had complications. In some cases, 
nephrolithiasis has been associated with acute renal failure or renal insufficiency. If signs or symptoms 
of nephrolithiasis occurs, temporary interruption or discontinuation of treatment may be considered. 
 
Immune reactivation syndrome 
 
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, 
such reactions have been observed within the first few weeks or months of initiation of CART. 
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, 
and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and 
treatment instituted when necessary. Autoimmune disorders (such as Graves' disease and autoimmune 
hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported 
time to onset is more variable and these events can occur many months after initiation of treatment. 
 
Osteonecrosis 
 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination 
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience 
joint aches and pain, joint stiffness or difficulty in movement. 
 
Rash and associated syndromes 



 

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Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks 
of starting therapy with atazanavir, a component of EVOTAZ. 
 
Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with 
eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving 
atazanavir. Patients should be advised of the signs and symptoms and monitored closely for skin 
reactions. EVOTAZ or any other medicinal product containing atazanavir should be discontinued if 
severe rash develops. 
 
The best results in managing these events come from early diagnosis and immediate interruption of 
any suspect medicines. If the patient has developed SJS or DRESS associated with the use of 
EVOTAZ, EVOTAZ may not be restarted. 
 
Co-administration with antiretroviral medicinal products 
 
EVOTAZ is indicated for use with other antiretrovirals for the treatment of HIV-1 infection. EVOTAZ 
should not be used in combination with products containing the same active components including 
atazanavir, cobicistat or with fixed-dose products that contain cobicistat. EVOTAZ should not be used 
in combination with another antiretroviral that requires pharmacokinetic enhancement (i.e., another 
protease inhibitor or elvitegravir) since dosing recommendations for such combinations have not been 
established and may result in decreased plasma concentrations of atazanavir and/or the other 
antiretroviral leading to loss of therapeutic effect and development of resistance. Co-administration of 
EVOTAZ with other protease inhibitors is not recommended. Because atazanavir is a component of 
EVOTAZ, co-administration of EVOTAZ with nevirapine or efavirenz is not recommended (see 
section 4.5). 
 
EVOTAZ should not be used in combination with ritonavir or medicinal products containing ritonavir 
due to similar pharmacological effects of cobicistat and ritonavir on CYP3A (see section 4.5). 
 
Interactions with other medicinal products  
 
Atazanavir is metabolised principally by CYP3A4. Cobicistat is a strong mechanism-based CYP3A 
inhibitor and is a CYP3A substrate. Co-administration of EVOTAZ and medicinal products that 
induce CYP3A4 is contraindicated or not recommended (see sections 4.3 and 4.5) because, in addition 
to decreased plasma concentrations of atazanavir due to induction of CYP3A4, decreased plasma 
concentrations of cobicistat could result in cobicistat plasma levels that are insufficient to achieve 
adequate pharmacoenhancement of atazanavir. 
 
Increased plasma concentrations of medicinal products that are metabolised by CYP3A (including 
atazanavir) 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 sections 4.3 and 4.5). 
 
Co-administration of EVOTAZ with medicinal products that inhibit CYP3A may decrease the 
clearance of atazanavir and cobicistat, resulting in increased atazanavir and cobicistat plasma 
concentrations (see section 4.5). 
 
Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
UGT1A1. If switching from atazanavir boosted with ritonavir to EVOTAZ, caution is required during 
the first two weeks of treatment with EVOTAZ, 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). 
  



 

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Cobicistat is a weak CYP2D6 inhibitor and is metabolised to a minor extent by CYP2D6. 
Co-administration with EVOTAZ can increase plasma concentrations of medicinal products that are 
metabolised by CYP2D6 (see sections 4.3 and 4.5). 
 
Because atazanavir is a component of EVOTAZ, the combination of EVOTAZ with atorvastatin is not 
recommended (see section 4.5). 
 
PDE5 inhibitors used for the treatment of erectile dysfunction 
Particular caution should be used when prescribing PDE5-inhibitors (sildenafil, tadalafil, vardenafil, or 
avanafil) for the treatment of erectile dysfunction in patients receiving EVOTAZ. Co-administration of 
EVOTAZ with these medicinal products is expected to substantially increase their concentrations and 
may result in PDE5-associated adverse reactions such as hypotension, visual changes and priapism 
(see section 4.5). 
 
Co-administration of voriconazole and EVOTAZ is not recommended unless an assessment of the 
benefit/risk justifies the use of voriconazole (see section 4.5). 
 
Concomitant use of EVOTAZ and fluticasone or other glucocorticoids that are metabolized by 
CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic 
corticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5). 
 
Co-administration of EVOTAZ with warfarin has the potential to produce serious and/or 
life-threatening bleeding due to increased warfarin plasma concentrations, and it is recommended that 
the INR (International Normalized Ratio) be monitored (see section 4.5). 
 
Co-administration of EVOTAZ with proton pump inhibitors (PPIs) is not recommended due to the 
decreased solubility of atazanavir as intra-gastric pH increase with PPIs (see section 4.5).  
 
Contraception requirements 
Plasma concentrations of drospirenone are increased following 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. 
 
Data are not available to make recommendations regarding the use of EVOTAZ with other oral 
contraceptives. Alternative forms of contraception (non-hormonal) should be considered (see 
section 4.5). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Drug interaction trials were not conducted for EVOTAZ. As EVOTAZ contains atazanavir and 
cobicistat, any interactions that have been identified with these active substances individually may 
occur with EVOTAZ. 
 
Complex or unknown mechanisms of drug interaction preclude extrapolation of ritonavir drug 
interactions to certain cobicistat drug interactions. The recommendations given for concomitant use of 
atazanavir and other medicinal products may, therefore, differ depending on whether atazanavir is 
boosted with ritonavir or cobicistat. In particular, atazanavir boosted with cobicistat is more sensitive 
for CYP3A induction (see section 4.3 and the interaction table). Caution is also required during the 
first time of treatment if switching the pharmacoenhancer from ritonavir to cobicistat (see section 4.4). 
 
Medicinal products that affect atazanavir/cobicistat exposure  
 
Atazanavir is metabolised in the liver through CYP3A4. 
Cobicistat is a CYP3A substrate and is metabolised to a minor extent by CYP2D6. 



 

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Concomitant use contraindicated 
Co-administration of EVOTAZ with medicinal products that are strong inducers of CYP3A (such as 
carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John’s wort [Hypericum perforatum]) 
may result in decreased plasma concentrations of atazanavir and/or cobicistat, leading to loss of 
therapeutic effect and possible development of resistance to atazanavir (see section 4.3 and Table 1).  
 
Concomitant use not recommended 
Co-administration of EVOTAZ with medicinal products containing ritonavir or cobicistat, which are 
strong inhibitors of CYP3A, may result in additional boosting and increased plasma concentration of 
atazanavir. 
 
Co-administration of EVOTAZ with medicinal products that inhibit CYP3A may result in increased 
plasma concentration of atazanavir and/or cobicistat. Some examples include, but are not limited to, 
itraconazole, ketoconazole and voriconazole (see Table 1). 
 
Co-administration of EVOTAZ with medicinal products that are moderate to weak inducers of 
CYP3A may result in decreased plasma concentration of atazanavir and/or cobicistat, leading to loss 
of therapeutic effect and possible development of resistance to atazanavir. Some examples include, but 
are not limited to etravirine, nevirapine, efavirenz, fluticasone and bosentan (see Table 1). 
 
Medicinal products that may be affected by atazanavir/cobicistat 
 
Atazanavir is an inhibitor of CYP3A4 and UGT1A1. Atazanavir is a weak to moderate inhibitor of 
CYP2C8. Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the 
biotransformation of some medicinal products metabolised by CYP3A4.  
 
Cobicistat is a strong mechanism-based CYP3A inhibitor and a weak CYP2D6 inhibitor. Cobicistat 
inhibits the transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. 
Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19.  
Cobicistat is not expected to induce CYP3A4 or P-gp. Unlike ritonavir, cobicistat is not an inducer of 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. 
 
Concomitant use contraindicated 
Co-administration of medicinal products that are substrates of CYP3A and have narrow therapeutic 
indeces and for which elevated plasma concentrations are associated with serious and/or 
life-threatening events are contraindicated with EVOTAZ. These medicinal products include 
alfuzosin, amiodarone, astemizole, bepridil, cisapride, colchicine, dronedarone, ergot deriviatives (e.g. 
dihydroergotamine, ergometrine, ergotamine, methylergonovine), lomitapide, lovastatin, orally 
administered midazolam, pimozide, quetiapine, quinidine, lurasidone, simvastatin, sildenafil (when 
used to treat pulmonary arterial hypertension), avanafil, systemic lidocaine, ticagrelor, terfenadine and 
triazolam. 
 
Co-administration of EVOTAZ with grazoprevir-containing products, including elbasvir/grazoprevir 
fixed dose combination (used to treat chronic hepatitis C infection) is contraindicated because of the 
increase in grazoprevir and elbasvir plasma concentrations and potential for the increase in risk of 
ALT elevations associated with the increase in grazoprevir concentrations (see section 4.3 and 
Table 1). Co-administration of EVOTAZ with glecaprevir/pibrentasvir fixed dose combination is 
contraindicated because of the potential increase in the risk of ALT elevations due to a significant 
increase in glecaprevir and pibrentasvir plasma concentrations (see section 4.3). 
 
Increased plasma concentrations of medicinal products that are metabolised by CYP3A, CYP2C8, 
CYP2D6 and/or UGT1A1 are expected when co-administered with EVOTAZ. Co-administration of 
EVOTAZ in patients receiving medicinal products that are substrates of the transporters P-gp, BCRP, 
MATE1, OATP1B1 and OATP1B3 may result in increased plasma concentrations of the 



 

10 
 

co-administered medicinal products (see section 4.4). Co-administration with dabigatran, a substrate of 
P-gp, is contraindicated. Clinically significant interactions between EVOTAZ and substrates of 
CYP1A2, CYP2B6, CYP2C9 or CYP2C19 are not expected. 
 
Interaction table 
 
Interactions between EVOTAZ and other medicinal products are listed in Table 1 below (increase is 
indicated as “↑”, decrease as “↓”, no change as “↔”). The recommendations shown in Table 1 are 
based on either drug interaction trials of unboosted atazanavir, atazanavir boosted with ritonavir, 
cobicistat or predicted interactions due to the expected magnitude of the interaction and potential for 
serious adverse reactions or loss of therapeutic effect of EVOTAZ. If available, 90% confidence 
intervals (CI) are shown in parentheses. The studies presented in Table 1 were conducted in healthy 
subjects unless otherwise noted. 
 
Table 1: Interactions between EVOTAZ and other medicinal products 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

ANTI-HCV AGENTS 

Grazoprevir 200 mg once daily 
(atazanavir 300 mg / ritonavir 
100 mg once daily) 

Atazanavir AUC ↑43% (↑30% 
↑57%) 
Atazanavir Cmax ↑12% (↑1% 
↑24%) 
Atazanavir Cmin ↑23% (↑13% 
↑134%) 
 
Grazoprevir AUC: ↑958% (↑678% 
↑1339%) 
Grazoprevir Cmax: ↑524% (↑342% 
↑781%) 
Grazoprevir Cmin: ↑1064% (↑696% 
↑1602%) 
 
Grazoprevir concentrations were 
greatly increased when 
co-administered with 
atazanavir/ritonavir. 

Co-administration of EVOTAZ 
and elbasvir/grazoprevir is 
contraindicated because of the 
expected increase in grazoprevir 
plasma concentrations and the 
associated potential increase in the 
risk of ALT elevations 
(see section 4.3). 

Elbasvir 50 mg once daily 
(atazanavir 300 mg / ritonavir 
100 mg once daily 

Atazanavir AUC ↑7% (↓2% 
↑17%) 
Atazanavir Cmax ↑2% (↓4% ↑8%) 
Atazanavir Cmin ↑15% (↑2% 
↑29%) 
 
Elbasvir AUC: ↑376% (↑307% 
↑456%) 
Elbasvir Cmax: ↑315% (↑246% 
↑397%) 
Elbasvir Cmin: ↑545% (↑451% 
↑654%) 
 
Elbasvir concentrations were 
increased when co-administered 
with atazanavir/ritonavir 



 

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Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Sofosbuvir 400 mg/velpatasvir, 
100 mg/voxilaprevir 100 mg 
single dose* 
(atazanavir 300 mg with ritonavir 
100 mg once daily) 

Sofosbuvir AUC : ↑40% (↑25% 
↑57%) 
Sofosbuvir Cmax :↑29% (↑9% 
↑52%) 
 
Velpatasvir AUC: ↑93% (↑58% 
↑136%) 
Velpatasvir Cmax : ↑29% (↑7% 
↑56%) 
 
Voxilaprevir AUC : ↑331% 
(↑276% ↑393%) 
Voxilaprevir Cmax : ↑342% (↑265% 
↑435%) 
 

*Lack of pharmacokinetics 
interaction bounds 70-143%  
 
Effect on atazanavir and ritonavir 
exposure has not been studied.  
Expected: 
↔ Atazanavir 
↔ Ritonavir 
 
The mechanism of interaction 
between atazanavir/ritonavir and 
sofosbuvir/velpatasvir/voxilaprevir 
is inhibition of OATP1B, Pgp, and 
CYP3A. 

Co-administration of EVOTAZ 
with voxilaprevir-containing 
products is expected to increase 
the concentration of voxilaprevir. 
Co-administration of EVOTAZ 
with voxilaprevir-containing 
regimens is not recommended. 



 

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Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Glecaprevir 300 
mg/pibrentasvir 120 mg once 
daily 
(atazanavir 300 mg with ritonavir 
100 mg once daily*) 

Glecaprevir AUC : ↑553% 
(↑424% ↑714%)    
Glecaprevir Cmax : ↑306% (↑215% 
↑423%) 
Glecaprevir Cmin : ↑1330% (↑885% 
↑1970%) 
 
Pibrentasvir AUC : ↑64% (↑48% 
↑82%)   
Pibrentasvir Cmax : ↑29% (↑15% 
↑45%) 
Pibrentasvir Cmin: ↑129% (↑95% 
↑168%) 
 
Atazanavir AUC : ↑11% (↑3% 
↑19%) 
Atazanavir Cmax : ↔ 0% (↓ 
10% ↑10%) 
Atazanavir Cmin: ↑16% (↑7% 
↑25%) 
 
* Effect of atazanavir and ritonavir 
on the first dose of glecaprevir and 
pibrentasvir is reported. 

Contraindicated because of the 
potential increase in the risk of 
ALT elevations due to a 
significant increase in glecaprevir 
and pibrentasvir plasma 
concentrations (see section 4.3) 

ANTI-RETROVIRALS 

Protease inhibitors: EVOTAZ in combination with other protease inhibitors is not recommended because 
co-administration may not provide adequate protease inhibitor exposure. 
Indinavir Indinavir is associated with 

indirect unconjugated 
hyperbilirubinaemia due to 
inhibition of UGT. 

Co-administration of EVOTAZ 
and indinavir is not recommended 
(see section 4.4). 

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) 

Lamivudine 150 mg twice daily 
+ zidovudine 300 mg twice daily 
(atazanavir 400 mg once daily) 

No significant effect on 
lamivudine and zidovudine 
concentrations was observed when 
co-administered with atazanavir. 

Based on these data and because 
cobicistat is not expected to have a 
significant impact on the 
pharmacokinetics of NRTIs, the 
co-administration of EVOTAZ 
with these medicinal products is 
not expected to significantly alter 
the exposure of the 
co-administered medicinal 
products. 



 

13 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Didanosine (buffered tablets) 
200 mg/stavudine 40 mg, both 
single dose 
(atazanavir 400 mg single dose) 

Atazanavir, simultaneous 
administration with ddI+d4T 
(fasted) 
Atazanavir AUC ↓87% (↓92% 
↓79%) 
Atazanavir Cmax ↓89% (↓94% 
↓82%) 
Atazanavir Cmin ↓84% (↓90% 
↓73%) 
 
Atazanavir, dosed 1 hr after 
ddI+d4T (fasted) 
Atazanavir AUC ↔3% (↓36% 
↑67%) 
Atazanavir Cmax ↑12% (↓33% 
↑18%) 
Atazanavir Cmin ↔3% (↓39% 
↑73%) 
 
Atazanavir concentrations were 
greatly decreased when 
co-administered with didanosine 
(buffered tablets) and stavudine.  
 
The mechanism of interaction is a 
reduced solubility of atazanavir 
with increasing pH related to the 
presence of anti-acid agent in 
didanosine buffered tablets. 
 
No significant effect on didanosine 
and stavudine concentrations was 
observed. 

Didanosine should be taken in the 
fasted state 2 hours after EVOTAZ 
taken with food. The 
co-administration of EVOTAZ 
with stavudine is not expected to 
significantly alter the exposure of 
stavudine. 

Didanosine (enteric coated 
capsules) 400 mg single dose 
(atazanavir 400 mg once daily) 

Didanosine (with food) 
Didanosine AUC ↓34% (↓40% 
↓26%) 
Didanosine Cmax ↓36% (↓45% 
↓26%) 
Didanosine Cmin ↑13% (↓9% 
↑41%) 
 
No significant effect on atazanavir 
concentrations was observed when 
administered with enteric-coated 
didanosine, but administration 
with food decreased didanosine 
concentrations. 



 

14 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Tenofovir disoproxil fumarate 
(tenofovir DF) 300 mg 
once daily 
(atazanavir 400 mg once daily) 
 
300 mg tenofovir disoproxil 
fumarate is equivalent to  
245 mg tenofovir disoproxil. 

Atazanavir AUC ↓25% (↓30% 
↓19%)  
Atazanavir Cmax ↓21% (↓27% 
↓14%)  
Atazanavir Cmin ↓40% (↓48% 
↓32%)  
 
Tenofovir:  
AUC: ↑24% (↑21% ↑28%) 
Cmax: ↑14% (↑8% ↑20%) 
Cmin: ↑22% (↑15% ↑30%) 
 
Co-administration of tenofovir DF 
with cobicistat is expected to 
increase tenofovir plasma 
concentrations. 
 
Tenofovir: 
AUC: ↑23% 
Cmin: ↑55% 
 
The mechanism of interaction 
between atazanavir and tenofovir 
DF is unknown. 

Tenofovir  DF may decrease the 
AUC and Cmin of atazanavir. When 
co-administered with tenofovir 
DF, it is recommended that 
EVOTAZ and tenofovir DF 
300 mg be given together with 
food. Atazanavir increases 
tenofovir concentrations. Higher 
concentrations could potentiate 
tenofovir-associated adverse 
reactions, including renal 
disorders. Patients receiving 
tenofovir disoproxil should be 
monitored for tenofovir-associated 
adverse reactions. 

Tenofovir alafenamide 10 mg 
once daily/emtricitabine 200 mg 
once daily 
(atazanavir 300 mg once daily 
with cobicistat 150 mg once daily) 

Tenofovir alafenamide 
AUC ↑75% (↑55% ↑98%) 
Cmax ↑80% (↑48% ↑118%) 
 
Tenofovir: 
AUC ↑247% (↑229% ↑267%) 
Cmax ↑216% (↑200% ↑233%) 
Cmin ↑273% (↑254% ↑293%) 
 
Cobicistat: 
AUC ↑5% (↔0% ↑9%) 
Cmax ↓4% (↓8% ↔0%) 
Cmin ↑35% (↑21% ↑51%) 
 
Co-administration of tenofovir 
alafenamide with cobicistat is 
expected to increase tenofovir 
alafenamide and tenofovir plasma 
concentrations. 
 
Atazanavir: 
AUC ↑6% (↑1% ↑11%) 
Cmax ↓2% (↓4% ↑2%) 
Cmin ↑18% (↑6% ↑31%) 
 

When co-administering tenofovir 
alafenamide/emtricitabine and 
EVOTAZ, the recommended dose 
of tenofovir 
alafenamide/emtricitabine is 
10/200 mg once daily.  
 

Tenofovir alafenamide 10 mg 
once daily 
(atazanavir 300 mg once daily 
with cobicistat 150 mg once daily) 

Co-administration of EVOTAZ 
and tenofovir alafenamide 25 mg 
for treatment of HBV infection is 
not recommended 



 

15 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 

Efavirenz 600 mg once daily 
(atazanavir 400 mg once daily) 
 
 

Atazanavir 
Atazanavir AUC ↓74% (↓78% 
↓68%) 
Atazanavir Cmax ↓59% (↓77% 
↓49%) 
Atazanavir Cmin ↓93% (↓95% 
↓90%) 
 

EVOTAZ is not recommended for 
co-administration with efavirenz. 
Efavirenz decreases atazanavir 
concentrations and is expected to 
decrease cobicistat plasma 
concentrations. This may result in 
loss of therapeutic effect of 
EVOTAZ and development of 
resistance to atazanavir (see 
section 4.4). 

Efavirenz 600 mg single dose 
(cobicistat 150 mg once daily) 

Efavirenz:  
AUC: ↔7% (↓11% ↓3%) 
Cmax: ↓13% (↓20% ↓6%) 
Cmin: Not determined  
 
The mechanism of interaction 
between efavirenz and atazanavir, 
or efavirenz and cobicistat is 
CYP3A4 induction by efavirenz. 

Etravirine Co-administration of etravirine 
and EVOTAZ is expected to 
decrease atazanavir and cobicistat 
plasma concentrations.  
 
The mechanism of interaction is 
CYP3A4 induction by etravirine. 

EVOTAZ is not recommended for 
co-administration with etravirine 
because it may result in the loss of 
therapeutic effect and development 
of resistance to atazanavir. 

Nevirapine 200 mg twice daily 
(atazanavir 300 mg once daily 
with ritonavir 100 mg once daily) 
 
Study conducted in HIV infected 
patients 
 

Nevirapine AUC ↑25% (↑17% 
↑34%) 
Nevirapine Cmax ↑17% (↑9% 
↑25%) 
Nevirapine Cmin ↑32% (↑22% 
↑43%) 
 
Atazanavir AUC ↓42% (↓52% 
↓29%)  
Atazanavir Cmax ↓28% (↓40% 
↓14%)  
Atazanavir Cmin ↓72% (↓80% 
↓60%)  
 
Co-administration of nevirapine 
and cobicistat is expected to 
decrease cobicistat plasma 
concentrations while nevirapine 
plasma concentrations may be 
increased.  
 
The mechanism of interaction is 
CYP3A4 induction by nevirapine 
and CYP3A4 inhibition by 
atazanavir and cobicistat. 

Co-administration of EVOTAZ 
and nevirapine is not 
recommended and may result in a 
loss of therapeutic effect of 
EVOTAZ and development of 
resistance to atazanavir. 
Co-administration of nevirapine 
and EVOTAZ is expected to 
increase nevirapine plasma 
concentrations which may increase 
the risk of nevirapine-associated 
toxicity (see section 4.4). 



 

16 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Rilpivirine EVOTAZ is expected to increase 
rilpivirine plasma concentrations. 
 
The mechanism of interaction is 
CYP3A inhibition. 

Co-administration of EVOTAZ 
and rilpivirine can be used without 
dose adjustments, as the expected 
increase in rilpivirine 
concentrations is not considered 
clinically relevant. 

Integrase Inhibitors 

Dolutegravir Co-administration with EVOTAZ 
is expected to increase 
dolutegravir plasma 
concentrations. Dolutegravir is not 
expected to affect the 
pharmacokinetics of EVOTAZ. 
 
The mechanism of interaction is 
inhibition of UGT1A1 by 
atazanavir. 

EVOTAZ and dolutegravir can be 
used without dose adjustments. 

Raltegravir 400 mg twice daily 
(atazanavir 400 mg) 

Raltegravir AUC ↑72% 
Raltegravir Cmax ↑53% 
Raltegravir C12hr ↑95% 
 
The mechanism is UGT1A1 
inhibition by atazanavir. 

No dose adjustment is required for 
raltegravir if co-administered with 
EVOTAZ. 



 

17 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

CCR5 Antagonists 

Maraviroc 
 

Maraviroc is a substrate of 
CYP3A and its plasma 
concentration increases when 
co-administered with potent 
CYP3A inhibitors.  
 
Maraviroc is not expected to have 
an impact on concentrations of 
atazanavir and cobicistat. 
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 

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

ANTIBIOTICS  

Clarithromycin 500 mg 
twice daily 
(atazanavir 400 mg once daily) 

Clarithromycin AUC ↑94% (↑75% 
↑116%) 
Clarithromycin Cmax ↑50% (↑32% 
↑71%) 
Clarithromycin Cmin ↑160% 
(↑135% ↑188%) 
 
14-OH clarithromycin 
14-OH clarithromycin AUC ↓70% 
(↓74% ↓66%) 
14-OH clarithromycin Cmax ↓72% 
(↓76% ↓67%) 
14-OH clarithromycin Cmin ↓62% 
(↓66% ↓58%) 
 
Atazanavir AUC ↑28% (↑16% 
↑43%) 
Atazanavir Cmax ↔6% (↓7% 
↑20%) 
Atazanavir Cmin ↑91% (↑66% 
↑121%) 
 
Clarithromycin may increase 
concentrations of atazanavir and 
cobicistat. Exposure to 
clarithromycin is expected to 
increase if co-administered with 
EVOTAZ. 
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and/or cobicistat and 
clarithromycin. 

Alternative antibiotics should be 
considered. 

ANTIDIABETICS 



 

18 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

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

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

 

ANTIFUNGALS 

Ketoconazole 200 mg once daily 
(atazanavir 400 mg once daily) 

No significant effect on atazanavir 
concentrations was observed. 

Caution is warranted. Specific 
dosing recommendations are not 
available for co-administration of 
EVOTAZ with either ketoconazole 
or itraconazole. 
If co-administration is required, 
the daily dose of ketoconazole or 
itraconazole should not exceed 
200 mg. 

Itraconazole Itraconazole, like ketoconazole, is 
a potent inhibitor as well as a 
substrate of CYP3A4. 
 
Concentrations of ketoconazole, 
itraconazole, and/or cobicistat may 
be increased with 
co-administration of ketoconazole 
or itraconazole with EVOTAZ. 
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir, 
cobicistat and ketoconazole or 
itraconazole. 

Voriconazole Effects unknown Voriconazole should not be 
co-administered with EVOTAZ 
unless the benefit/risk assessment 
justifies the use of voriconazole 
(see section 4.4). Clinical 
monitoring may be needed upon 
co-administration with EVOTAZ. 

Fluconazole 200 mg once daily 
(atazanavir 300 mg and ritonavir 
100 mg once daily) 

Atazanavir and fluconazole 
concentrations were not 
significantly modified when 
atazanavir/ritonavir was 
co-administered with fluconazole. 
 
Concentration of fluconazole may 
be increased if co-administered 
with cobicistat. 

Clinical monitoring is 
recommended upon 
co-administration with EVOTAZ. 

ANTIGOUT 



 

19 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Colchicine Colchicine plasma concentrations 
may be increased when 
co-administered with EVOTAZ. 
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 

EVOTAZ must not be 
co-administered with colchicine to 
patients with renal or hepatic 
impairment. 

Recommended dosage of 
colchicine when administered 
with EVOTAZ in patients 
without renal or hepatic 
impairment: a dose reduction in 
colchicine dosage or an 
interruption of colchicine 
treatment is recommended in 
patients with normal renal or 
hepatic function if treatment with 
EVOTAZ is required. 
 

ANTIMYCOBACTERIALS 



 

20 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Rifabutin 150 mg twice weekly 
(atazanavir 300 mg once daily 
with ritonavir 100 mg once daily) 

Rifabutin AUC ↑48% (↑19% 
↑84%)* 
Rifabutin Cmax ↑149% (↑103% 
↑206%)* 
Rifabutin Cmin ↑40% (↑5% 
↑87%)* 
 
25-O-desacetyl-rifabutin AUC 
↑990% (↑714% ↑1361%)* 
25-O-desacetyl-rifabutin Cmax 
↑677% (↑513% ↑883%)* 
25-O-desacetyl-rifabutin Cmin 
↑1045% (↑715% ↑1510%)* 
 
*When compared to rifabutin 
150 mg once daily alone. Total 
rifabutin and 
25-O-desacetyl-rifabutin AUC 
↑119% (↑78% ↑169%). 

Co-administration of EVOTAZ 
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 
rifabutin. Further dosage reduction 
of rifabutin to 150 mg twice 
weekly on set days is 
recommended for patients in 
whom the 150 mg dose 3 times per 
week is not tolerated. It should be 
kept in mind that the twice weekly 
dosage of 150 mg may not provide 
an optimal exposure to rifabutin 
thus leading to a risk of rifamycin 
resistance and a treatment failure. 
Consideration should be given to 
official guidance on the 
appropriate treatment of 
tuberculosis in HIV infected 
patients.  

Rifabutin 150 mg every other 
day/elvitegravir 150 mg 
once daily/cobicistat 150 mg 
once daily 

Cobicistat:  
AUC: ↔  
Cmax: ↔  
Cmin: ↓66%  
 
Rifabutin:  
AUC: ↔8%  
Cmax: ↔9% 
Cmin: ↔6%  
 
25-O-desacetyl-rifabutin:  
AUC: ↑525%  
Cmax: ↑384%  
Cmin: ↑394%  
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 

Rifampicin 600 mg once daily 
(atazanavir 300 mg once daily 
with ritonavir 100 mg once daily) 

Rifampicin is a strong CYP3A4 
inducer and has been shown to 
cause a 72% decrease in 
atazanavir AUC which can result 
in virological failure and 
resistance development.  
 
The mechanism of interaction is 
CYP3A4 induction by rifampicin. 

Rifampicin substantially decreases 
plasma concentrations of 
atazanavir, which may result in 
loss of therapeutic effect of 
EVOTAZ and development of 
resistance to atazanavir. The 
combination of rifampicin and 
EVOTAZ is contraindicated (see 
section 4.3). 

ACID REDUCING AGENTS 

H2-Receptor antagonists 

Without Tenofovir 



 

21 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Famotidine 20 mg twice daily 
(atazanavir 300 mg/ritonavir 
100 mg once daily) in 
HIV-infected patients 
 
 
 

Atazanavir AUC ↓18% (↓25% 
↑1%) 
Atazanavir Cmax ↓20% (↓32% 
↓7%) 
Atazanavir Cmin ↔1% (↓16% 
↑18%) 
 
 
 

For patients not taking 
tenofovir, EVOTAZ once daily 
with food should be administered 
simultaneously with, and/or at 
least 10 hours after, a dose of the 
H2-receptor antagonist. The dose 
of the H2-receptor antagonist 
should not exceed a dose 
comparable to famotidine 20 mg 
twice daily. 

With Tenofovir DF 300 mg once daily 
Famotidine 20 mg twice daily 
(atazanavir 300 mg/ritonavir 
100 mg/tenofovir DF 300 mg once 
daily, simultaneous 
administration) 
 
 

Atazanavir AUC ↓10% (↓18% 
↓2%)  
Atazanavir Cmax ↓9% (↓16% ↓1%)  
Atazanavir Cmin ↓19% (↓31% 
↓6%)  
 
The mechanism of interaction is 
decreased solubility of atazanavir 
as intra-gastric pH increases with 
H2 blockers. 

For patients who are taking 
tenofovir DF, it is not 
recommended to co-administer 
EVOTAZ with an H2-receptor 
antagonist. 

Proton pump inhibitors 

Omeprazole 40 mg once daily 
(atazanavir 400 mg once daily, 
2 hours after omeprazole) 
 

Atazanavir AUC ↓94% (↓95% 
↓93%) 
Atazanavir Cmax ↓96% (↓96% 
↓95%) 
Atazanavir Cmin ↓95% (↓97% 
↓93%) 

Co-administration of EVOTAZ 
with proton pump inhibitors is not 
recommended. 

Omeprazole 40 mg once daily 
(atazanavir 300 mg once daily 
with ritonavir 100 mg once daily, 
2 hours after omeprazole) 
 

Atazanavir AUC ↓76% (↓78% 
↓73%) 
Atazanavir Cmax ↓72% (↓76% 
↓68%) 
Atazanavir Cmin ↓78% (↓81% 
↓74%) 

Omeprazole 20 mg once daily 
am (atazanavir 300 mg once daily 
with ritonavir 100 mg once daily 
pm, 12 hours after omeprazole) 

Atazanavir AUC ↓42% (↓66% 
↓25%) 
Atazanavir Cmax ↓39% (↓64% 
↓19%) 
Atazanavir Cmin ↓46% (↓59% 
↓29%) 
 
The mechanism of interaction is 
decreased solubility of atazanavir 
as intra-gastric pH increases with 
proton pump inhibitors. 

Antacids 



 

22 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Antacids and medicinal 
products containing buffers 

Reduced plasma concentrations of 
atazanavir may be the 
consequence of increased gastric 
pH if antacids, including buffered 
medicinal products, are 
administered with EVOTAZ.  

EVOTAZ should be administered 
2 hours before or 1 hour after 
antacids or buffered medicinal 
products. 

ALPHA 1-ADRENORECEPTOR ANTAGONIST 

Alfuzosin Potential for increased alfuzosin 
concentrations which can result in 
hypotension.  
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 

Co-administration of EVOTAZ 
with alfuzosin is contraindicated 
(see section 4.3) 

ANTICOAGULANTS 

Dabigatran Co-administration with EVOTAZ 
may increase dabigatran plasma 
levels with similar effects as seen 
with other strong P-gp inhibitors. 
 
The mechanism of interaction is 
P-gp inhibition by cobicistat. 

Co-administration of EVOTAZ 
with dabigatran is contraindicated 
(see section 4.3). 

Ticagrelor Co-administration of EVOTAZ 
and ticagrelor may increase 
concentrations of the 
anticoagulant. 
 
The mechanism of interaction is 
CYP3A and/or P-glycoprotein 
inhibition by atazanavir and 
cobicistat. 

Concomitant administration of 
EVOTAZ with ticagrelor is 
contraindicated.  
 
Use of other antiplatelets not 
affected by CYP inhibition or 
induction (e.g. prasugrel) is 
recommended (see section 4.3). 

Warfarin Co-administration with EVOTAZ 
has the potential to increase 
warfarin plasma concentrations.  
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 

Co-administration with EVOTAZ 
has the potential to produce 
serious and/or life-threatening 
bleeding due to increased exposure 
to warfarin and has not been 
studied. It is recommended that the 
INR (International Normalized 
Ratio) be monitored. 

Apixaban 
Edoxaban 
Rivaroxaban  
 

Co administration with EVOTAZ 
may result in increased plasma 
concentrations of the DOACs, 
which may lead to an increased 
risk of bleeding. 
 
The mechanism of interaction is 
CYP3A4 and/or P-gp inhibition 
by cobicistat. 

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

ANTIEPILEPTICS 



 

23 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Carbamazepine 
Phenobarbital 
Phenytoin 

These antiepileptics are expected 
to decrease atazanavir and/or 
cobicistat plasma concentrations. 
 
The mechanism of interaction is 
CYP3A induction by the 
antiepileptic. 

Co-administration of EVOTAZ 
and these antiepileptics is 
contraindicated (see section 4.3). 

ANTIHISTAMINE AGENTS 

Astemizole 
Terfenadine 

EVOTAZ must not be used in 
combination with medicinal 
products that are substrates of 
CYP3A4 and have a narrow 
therapeutic index. 

Co-administration of EVOTAZ 
with astemizole and terfenadine is 
contraindicated (see section 4.3). 

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS 

Antineoplastics 

Irinotecan Atazanavir inhibits UGT and may 
interfere with the metabolism of 
irinotecan, resulting in increased 
irinotecan toxicities.  

If EVOTAZ is co-administered with 
irinotecan, patients should be closely 
monitored for adverse reactions 
related to irinotecan. 

Dasatinib 
Nilotinib 
Vinblastine 
Vincristine 
 

Concentrations of these medicinal 
products may be increased when 
co-administered with EVOTAZ. 
 
The mechanism of interaction is 
CYP3A4 inhibition by cobicistat. 

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

Immunosuppressants 

Ciclosporin 
Tacrolimus 
Sirolimus 
 

Concentrations of these 
immunosuppressants may be 
increased when co-administered 
with EVOTAZ. 
 
The mechanism of interaction is 
inhibition of CYP3A4 by 
atazanavir and cobicistat. 

More frequent therapeutic 
concentration monitoring is 
recommended for 
immunosuppressant agents when 
co-administered with EVOTAZ. 



 

24 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

ANTIPSYCHOTICS 

Pimozide 
Quetiapine 
Lurasidone 

Concentrations of these medicinal 
products may be increased when 
co-administered with EVOTAZ. 
 
The mechanism of interaction is 
CYP3A inhibition by atazanavir 
and cobicistat. 

The combination of pimozide, 
quetiapine or lurasidone and 
EVOTAZ is contraindicated (see 
section 4.3). 

CARDIOVASCULAR AGENTS 

Antiarrhythmics 

Disopyramide  
Flecainide  
Mexiletine  
Propafenone  

Concentrations of these 
antiarrhythmics may be increased 
when co-administered with 
EVOTAZ. 
 
The mechanism of interaction is 
CYP3A inhibition by atazanavir 
and cobicistat. 

Co-administration with EVOTAZ 
has the potential to produce 
serious and/or life-threatening 
adverse reactions. Caution is 
warranted and therapeutic 
concentration monitoring of these 
medicinal products is 
recommended if they are used 
concomitantly with EVOTAZ. 

Amiodarone 
Dronedarone 
Quinidine 
Systemic lidocaine 
 

Concentrations of these 
antiarrhythmics may be increased 
when co-administered with 
EVOTAZ. 
 
The mechanism of interaction is 
CYP3A inhibition by atazanavir 
and cobicistat. 

Amiodarone, dronedarone, 
quinidine and systemic lidocaine 
have a narrow therapeutic window 
and are contraindicated due to 
potential inhibition of CYP3A by 
EVOTAZ (see section 4.3). 

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

Plasma concentrations of digoxin 
may be increased when 
co-administered with EVOTAZ. 
 
Digoxin:  
AUC: ↔  
Cmax: ↑41%  
Cmin: not determined  
 
The mechanism of interaction is 
inhibition of P-gp by cobicistat. 

The peak concentration of digoxin 
is increased when co-administered 
with cobicistat. When 
co-administering with EVOTAZ, 
titrate the digoxin dose and 
monitor digoxin concentrations. 
The lowest dose of digoxin should 
initially be prescribed. 
 



 

25 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Antihypertensives 

Metoprolol  
Timolol  
 

Concentrations of beta-blockers 
may be increased when 
co-administered with EVOTAZ. 
 
The mechanism of interaction is 
inhibition of CYP2D6 by 
cobicistat. 

Clinical monitoring is 
recommended when 
co-administered with EVOTAZ 
and a dose reduction of the 
beta-blocker may be necessary.  
 
 

Calcium channel blockers 

Bepridil EVOTAZ must not be used in 
combination with medicinal 
products that are substrates of 
CYP3A4 and have a narrow 
therapeutic index. 

Co-administration with bepridil is 
contraindicated (see section 4.3). 

Diltiazem 180 mg once daily 
(atazanavir 400 mg once daily) 

Diltiazem AUC ↑125% (↑109% 
↑141%) 
Diltiazem Cmax ↑98% (↑78% 
↑119%) 
Diltiazem Cmin ↑142% (↑114% 
↑173%) 
 
Desacetyl-diltiazem AUC ↑165% 
(↑145% ↑187%) 
Desacetyl-diltiazem Cmax ↑172% 
(↑144% ↑203%) 
Desacetyl-diltiazem Cmin ↑121% 
(↑102% ↑142%) 
 
No significant effect on atazanavir 
concentrations was observed. 
There was an increase in the 
maximum PR interval compared to 
atazanavir alone. 
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 

Exposure to diltiazem and a 
metabolite, desacetyl-diltiazem, is 
increased when diltiazem is 
co-administered with atazanavir, a 
component of EVOTAZ. An initial 
dose reduction of diltiazem by 
50% should be considered, and 
electrocardiogram monitoring is 
recommended. 

Amlodipine 
Felodipine 
Nicardipine 
Nifedipine 
Verapamil 

Concentrations of these calcium 
channel blockers may be increased 
when co-administered with 
EVOTAZ. 
 
The mechanism of interaction is 
inhibition of CYP3A4 by 
atazanavir and cobicistat. 

Caution is warranted. Dose 
titration of the calcium channel 
blockers should be considered. 
Electrocardiogram monitoring is 
recommended. 
 

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



 

26 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Endothelin Receptor Antagonists 

Bosentan Co-administration of bosentan 
with cobicistat may lead to 
decreased cobicistat plasma 
concentrations. 
 
The mechanism of interaction is 
induction of CYP3A4 by 
bosentan. 

Atazanavir 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). 

CORTICOSTEROIDS 

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

Interaction not studied with any of 
the components of EVOTAZ. 
 
Plasma concentrations of these 
medicinal products may be 
increased when co–administered 
with EVOTAZ, resulting in 
reduced serum cortisol 
concentrations. 

Concomitant use of EVOTAZ 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. 

ANTIDEPRESSANTS 

Other antidepressants: 

Trazodone Plasma concentrations of 
trazodone may be increased when 
co-administered with EVOTAZ. 
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 
 

If trazodone is co-administered 
with EVOTAZ, the combination 
should be used with caution and a 
lower dose of trazodone should be 
considered. 



 

27 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

ERECTILE DYSFUNCTION 

PDE5 Inhibitors 

Sildenafil 
Tadalafil 
Vardenafil 
Avanafil 

Sildenafil, tadalafil, and vardenafil 
are metabolised by CYP3A4. 
Co-administration with EVOTAZ 
may result in increased 
concentrations of the PDE5 
inhibitor and an increase in 
PDE5-associated adverse events, 
including hypotension, visual 
changes, and priapism.  
 
The mechanism of this interaction 
is CYP3A4 inhibition by 
atazanavir and cobicistat. 

Patients should be warned about 
these possible side effects when 
using PDE5 inhibitors for erectile 
dysfunction with EVOTAZ (see 
section 4.4). 
 
For the treatment of erectile 
dysfunction, it is recommended 
that when co-administered with 
EVOTAZ, sildenafil should be 
used with caution at reduced doses 
of 25 mg every 48 hours; tadalafil 
should be used with caution at 
reduced doses of 10 mg every 
72 hours; vardenafil should be 
used with caution at reduced doses 
of no more than 2.5 mg every 
72 hours.  
 
Increase monitoring for adverse 
reactions. 
 
The combination of avanafil and 
EVOTAZ is contraindicated (see 
section 4.3). 
 
Also see PULMONARY 
ATERIAL HYPERTENSION in 
this table for further information 
regarding co-administration of 
EVOTAZ with sildenafil. 

HERBAL PRODUCTS 

St. John’s wort (Hypericum 
perforatum) 

Concomitant use of St. John's wort 
with EVOTAZ may be expected to 
result in significant reduction in 
plasma levels of cobicistat and 
atazanavir. This effect may be due 
to an induction of CYP3A4. There 
is a risk of loss of therapeutic 
effect and development of 
resistance to atazanavir (see 
section 4.3). 

Co-administration of EVOTAZ 
with products containing St. John's 
wort is contraindicated (see 
section 4.3). 



 

28 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

HORMONAL CONTRACEPTIVES 

Progestin/estrogen Concentrations of ethinyl estradiol 
and norethindrone are increased 
when a combined oral 
contraceptive containing those 
agents is co-administered with 
atazanavir. The mechanism of 
interaction is inhibition of 
metabolism by atazanavir. 
 
Effects of co-administration of 
EVOTAZ on progestin and 
estrogen are unknown. 

Co-administration of EVOTAZ 
and hormonal contraceptives 
should be avoided. An alternate 
(non-hormonal) reliable method of 
contraception is recommended. 

Drospirenone/ethinyloestradiol 
3 mg/0.02 mg single dose 
(atazanavir 300 mg once daily 
with cobicistat 150 mg once daily) 
 

Drospirenone AUC: ↑ 130% 
Drospirenone Cmax: ↔  
Drospirenone Cmin: Not calculated 
 
Ethinyloestradiol AUC: ↔ 
Ethinyloestradiol Cmax: ↔ 
Ethinyloestradiol Cmin: Not 
calculated  

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. 

LIPID-MODIFYING AGENTS 

Lomitapide The co-administration of 
lomitapide with any of the 
components of EVOTAZ has not 
been studied.  
 
Lomitapide is highly dependent on 
CYP3A4 for its metabolism and 
co-administration with EVOTAZ 
may result in increased 
concentrations of lomitapide. 

There is a potential for risk of 
markedly increased transaminase 
levels and hepatotoxicity 
associated with increased plasma 
concentrations of lomitapide. 
 
Co-administration of lomitapide 
with EVOTAZ is contraindicated 
(see section 4.3). 

HMG-CoA reductase inhibitors 

Simvastatin 
Lovastatin 

Simvastatin and lovastatin are 
highly dependent on CYP3A4 for 
their metabolism and 
co-administration with EVOTAZ 
may result in increased 
concentrations.  

Co-administration of simvastatin 
or lovastatin with EVOTAZ is 
contraindicated due to an 
increased risk of myopathy 
including rhabdomyolysis (see 
section 4.3). 

Atorvastatin 10 mg single dose 
(atazanavir 300 mg once daily 
with cobicistat 150 mg once 
daily) 

Atorvastatin AUC: ↑ 822% 
Atorvastatin Cmax: ↑ 1785%  
Atorvastatin Cmin: Not calculated 
 
Atazanavir AUC ↓5% 
Atazanavir Cmax ↓7% 
Atazanavir Cmin ↓10% 

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



 

29 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Pravastatin 
Fluvastatin 
Pitavastatin  
 

Although not studied, there is a 
potential for an increase in 
pravastatin or fluvastatin exposure 
when co-administered with 
protease inhibitors. Pravastatin is 
not metabolised by CYP3A4. 
Fluvastatin is partially metabolised 
by CYP2C9. 
 
Plasma concentrations of 
pitavastatin may be increased if 
co-administered with EVOTAZ. 

Caution should be exercised. 

Rosuvastatin (10 mg single dose) 
(atazanavir 300 mg once daily 
with cobicistat 150 mg once daily) 

Rosuvastatin AUC: ↑ 242% 
Rosuvastatin Cmax: ↑ 958%  
Rosuvastatin Cmin: Not calculated 
 
Atazanavir AUC: ↔ 
Atazanavir Cmax:↔ 
Atazanavir Cmin: ↑ 6% 

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. 

INHALED BETA AGONISTS 

Salmeterol Co-administration with EVOTAZ 
may result in increased 
concentrations of salmeterol and 
an increase in 
salmeterol-associated adverse 
events. 
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 

Co-administration of salmeterol 
with EVOTAZ is not 
recommended (see section 4.4). 

ERGOT DERIVATES 

Dihydroergotamine 
Ergometrine  
Ergotamine 
Methylergonovine 

EVOTAZ must not be used in 
combination with medicinal 
products that are substrates of 
CYP3A4 and have a narrow 
therapeutic index. 

Co-administration of EVOTAZ 
and these ergot derivates is 
contraindicated (see section 4.3). 

NEUROLEPTICS 

Perphenazine 
Risperidone 
Thioridazine 

Co-administration of neuroleptics 
with EVOTAZ may result in 
increased plasma concentrations of 
neuroleptics. 
 
The mechanism of interaction is 
inhibition of CYP3A4 and/or 
CYP2D6 by atazanavir and/or 
cobicistat. 

A decrease in the dose of 
neuroleptics metabolized by 
CYP3A or CYP2D6 may be 
required when co-administered 
with EVOTAZ. 

OPIOIDS 



 

30 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

Buprenorphine, once daily, 
stable maintenance dose 
(atazanavir 300 mg once daily 
with ritonavir 100 mg once daily) 
 
 
 
 
 
 

Buprenorphine AUC ↑67% 
Buprenorphine Cmax ↑37%  
Buprenorphine Cmin ↑69% 
 
Norbuprenorphine AUC ↑105% 
Norbuprenorphine Cmax ↑61% 
Norbuprenorphine Cmin ↑101% 
 
The mechanism of interaction is 
CYP3A4 and UGT1A1 inhibition 
by atazanavir. 
 
Concentrations of atazanavir were 
not significantly affected. 

Co-administration warrants 
clinical monitoring for sedation 
and cognitive effects. A dose 
reduction of buprenorphine may 
be considered. 
 
 
 
 
 
 

Buprenorphine/naloxone in 
combination with cobicistat 

Buprenorphine AUC: ↑35% 
Buprenorphine Cmax: ↑66% 
Buprenorphine Cmin: ↑12% 
 
Naloxone AUC: ↓28% 
Naloxone Cmax: ↓28% 
 
The mechanism of interaction is 
CYP3A4 inhibition by cobicistat. 

Methadone, stable maintenance 
dose 
(atazanavir 400 mg once daily) 

No significant effect on 
methadone concentrations was 
observed when co-administered 
with atazanavir. Given that 
cobicistat has been shown to have 
no significant effect on methadone 
concentrations, no interaction is 
expected if methadone is 
co-administered with EVOTAZ. 

No dosage adjustment is necessary 
if methadone is co-administered 
with EVOTAZ. 
 

PULMONARY ARTERIAL HYPERTENSION 

PDE5 Inhibitors 

Sildenafil Co-administration with EVOTAZ 
may result in increased 
concentrations of the PDE5 
inhibitor and an increase in 
PDE5 inhibitor-associated adverse 
events. 
 
The mechanism of interaction is 
CYP3A4 inhibition by atazanavir 
and cobicistat. 

A safe and effective dose in 
combination with EVOTAZ has 
not been established for sildenafil 
when used to treat pulmonary 
arterial hypertension. Sildenafil, 
when used for the treatment of 
pulmonary arterial hypertension, is 
contraindicated (see section 4.3). 



 

31 
 

Medicinal products by 
therapeutic area 

Interaction Recommendations concerning 
co-administration 

SEDATIVES/HYPNOTICS 

Midazolam 
Triazolam 

Midazolam and triazolam are 
extensively metabolized by 
CYP3A4. Co-administration with 
EVOTAZ may cause a large 
increase in the concentration of 
these benzodiazepines. Based on 
data for other CYP3A4 inhibitors, 
plasma concentrations of 
midazolam are expected to be 
significantly higher when 
midazolam is given orally. Data 
from concomitant use of parenteral 
midazolam with other protease 
inhibitors suggest a possible 3-4 
fold increase in midazolam plasma 
levels. 

EVOTAZ should not be 
co-administered with triazolam or 
orally administered midazolam 
(see section 4.3), whereas caution 
should be used with 
co-administration of EVOTAZ and 
parenteral midazolam. If 
EVOTAZ is co-administered with 
parenteral midazolam, it should be 
done in an intensive care unit 
(ICU) or similar setting which 
ensures close clinical monitoring 
and appropriate medical 
management in case of respiratory 
depression and/or prolonged 
sedation. Dosage adjustment for 
midazolam should be considered, 
especially if more than a single 
dose of midazolam is 
administered. 

Buspirone 
Clorazepate 
Diazepam  
Estazolam  
Flurazepam  
Zolpidem  

Concentrations of these 
sedatives/hypnotics may be 
increased when co-administered 
with EVOTAZ. 
 
The mechanism of interaction is 
inhibition of CYP3A4 by 
cobicistat. 

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

GASTROINTESTINAL MOTILITY AGENTS 

Cisapride  EVOTAZ must not be used in 
combination with medicinal 
products that are substrates of 
CYP3A4 and have a narrow 
therapeutic index. 

Co-administration of EVOTAZ 
and cisapride is contraindicated 
(see section 4.3). 

 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
EVOTAZ is not recommended during pregnancy nor should it be initiated in pregnant patients; an 
alternative regimen is recommended (see sections 4.2 and 4.4). This is due to substantially lower 
exposures of cobicistat and consequently, lower exposures of co-administered antiretroviral agents, 
including atazanavir, during the second and third trimesters, compared to postpartum. 
 
Animal studies with EVOTAZ are insufficient with respect to reproductive toxicity (see section 5.3). 
 



 

32 
 

Breast-feeding 
 
Atazanavir, an active component of EVOTAZ, has been detected in human milk. It is unknown if 
cobicistat/metabolites are excreted in human milk. Studies in animals have been shown excretion of 
cobicistat/metabolites in milk. Because of both the potential for HIV transmission and the potential for 
serious adverse reactions in breast-feeding infants, women should be instructed not to breast-feed if 
they are receiving EVOTAZ.  
 
Fertility 
 
The effect of EVOTAZ on fertility in humans has not been studied. In a nonclinical fertility and early 
embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or 
fertility (see section 5.3). 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 
 
EVOTAZ has a minor influence on the ability to drive or use machines.  Dizziness may occur 
following administration of regimens containing atazanavir and cobicistat (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The overall safety profile of EVOTAZ is based on available data from clinical trials conducted with 
atazanavir, atazanavir boosted with either cobicistat or ritonavir, and post-marketing data. 
 
As EVOTAZ contains atazanavir and cobicistat, the adverse reactions associated with each of the 
individual components may be expected. 
 
In a Phase III study (GS-US-216-0114), the most frequently reported adverse reactions in the 
atazanavir boosted with cobicistat group were associated with elevated bilirubin levels (see Table 2).  
 
In two controlled clinical trials, where subjects received atazanavir alone (400 mg once daily) or 
atazanavir (300mg daily) boosted with ritonavir (100mg daily), the most frequently reported adverse 
reactions were nausea, diarrhoea and jaundice. In the majority of cases, jaundice was reported within a 
few days to a few months after the initiation of treatment (see section 4.4). 
 
 
Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has 
been reported during postmarketing surveillance (see section 4.4). 
 
Tabulated list of adverse reactions 
 
Adverse reactions are listed by system organ class and frequency: very common (≥1/10), common 
(≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to 1/1,000). Within each 
frequency grouping, undesirable effects are presented in order of decreasing seriousness.  
 
Table 2: Tabulated summary of adverse reactions 
 



 

33 
 

System Organ Class 
Frequency 

Adverse Reactions 

Immune system disorders 
uncommon hypersensitivity 

Metabolism and nutrition disorders 
common increased appetite 
uncommon weight decreased, weight gain, anorexia  

Psychiatric disorders 
common insomnia, abnormal dreams 
uncommon depression, sleep disorder, disorientation, anxiety  

Nervous system disorders 
common headache, dizziness, somnolence, dysgeusia 
uncommon peripheral neuropathy, syncope, amnesia 

Eye disorders 
very common ocular icterus 

Cardiac disorders 
uncommon torsades de pointesa 
rare QTc prolongationa, oedema, palpitation 

Vascular disorders 
uncommon hypertension 

Respiratory, thoracic and mediastinal disorders 
uncommon dyspnoea 

Gastrointestinal disorders 
very common nausea 
common vomiting, diarrhoea, dyspepsia, abdominal pain, abdominal distension, 

flatulence, dry mouth 
uncommon pancreatitis, gastritis, stomatitis aphthous 

Hepatobiliary disorders 
very common jaundice 
common hyperbilirubinaemia 
uncommon hepatitis, cholelithiasisa, cholestasisa 
rare hepatosplenomegaly, cholecystitisa 

Skin and subcutaneous tissue disorders 
common rash 
uncommon pruritus, erythema multiformea,b, toxic skin eruptionsa,b, drug rash with 

eosinophilia and systemic symptoms (DRESS) syndromea,b, angioedemaa, 
urticaria, alopecia 

rare Stevens-Johnson syndromea,b, vesiculobullous rash, eczema, vasodilatation 
Musculoskeletal and connective tissue disorders 

uncommon myalgia, muscle atrophy, arthralgia 
rare myopathy 

Renal and urinary disorders 
uncommon nephrolithiasisa, haematuria, proteinuria, pollakiuria, interstitial nephritis, 

chronic kidney diseasea 
rare kidney pain 

Reproductive system and breast disorders 
uncommon gynaecomastia 



 

34 
 

System Organ Class 
Frequency 

Adverse Reactions 

General disorders and administration site conditions 
common fatigue 
uncommon pyrexia, asthenia, chest pain, malaise 
rare gait disturbance 

a These adverse reactions were identified through post-marketing surveillance; however, the frequencies 
were estimated from a statistical calculation based on the total number of patients exposed to atazanavir 
(with and without ritonavir) in randomised controlled and other available clinical trials (n = 2321). 
b See section Description of selected adverse reactions for more details. 

 
Description of selected adverse reactions 
 
Immune reactivation syndrome and autoimmune disorders 
In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4). 
 
Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown 
(see section 4.4). 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy 
(see section 4.4). 
 
Rash and associated syndromes 
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks 
of starting therapy with atazanavir. 
 
Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with 
eosinophilia and systemic symptoms (DRESS) syndrome have been reported with the use of 
atazanavir (see section 4.4). 
 
Renal impairment 
Cobicistat, a component of EVOTAZ, 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 
atazanavir boosted with cobicistat plus emtricitabine and tenofovir DF fixed-dose combination group 
and -8.0 ± 16.8 ml/min in the atazanavir boosted with ritonavir plus emtricitabine and tenofovir DF 
fixed-dose combination group. 
 
Effects on the liver  
In study GS-US-216-0114, through 144 weeks of treatment hyperbilirubinaemia (> 1 x ULN) was 
common: 97.7% in the atazanavir boosted with cobicistat plus emtricitabine and tenofovir DF 
fixed-dose combination group, and 97.4% in the atazanavir boosted with ritonavir plus emtricitabine 
and tenofovir DF fixed-dose combination group. However, a higher percentage of subjects in the 
atazanavir boosted with cobicistat group had increases in total bilirubin > 2 x ULN than those in the 



 

35 
 

atazanavir boosted with ritonavir 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. 
 
Laboratory abnormalities 
The most frequently reported laboratory abnormality in patients receiving regimens containing 
atazanavir and one or more NRTIs was elevated total bilirubin reported predominantly as elevated 
indirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin 
was noted in 37% (6% Grade 4). Among experienced patients treated with atazanavir 300 mg once 
daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3-4 total 
bilirubin elevations. Among naïve patients treated with atazanavir 300 mg once daily with 100 mg 
ritonavir once daily for a median duration of 96 weeks, 48% had Grade 3-4 total bilirubin elevations 
(see section 4.4). 
 
Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receiving 
regimens containing atazanavir and one or more NRTIs included: elevated creatine kinase (7%), 
elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), low 
neutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
(AST/SGOT) (3%), and elevated lipase (3%). 
 
Two percent of patients treated with atazanavir experienced concurrent Grade 3-4 ALT/AST and 
Grade 3-4 total bilirubin elevations. 
 
Paediatric population 
 
In clinical studies, paediatric patients 3 months to less than 18 years of age had a mean duration of 
treatment with atazanavir of 115 weeks. The safety profile in these studies was overall comparable to 
that seen in adults. Both asymptomatic first-degree (23%) and second-degree (1%) atrioventricular 
block were reported in paediatric patients. The most frequently reported laboratory abnormality in 
paediatric patients receiving atazanavir was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4) 
which occurred in 45% of patients. 
 
Other special populations 
 
Patients co-infected with hepatitis B and/or hepatitis C virus 
Co-infected patients with hepatitis B and/or C were more likely to have baseline hepatic transaminase 
elevations than those without chronic viral hepatitis. No differences in frequency of bilirubin 
elevations were observed between these patients and those without viral hepatitis. The frequency of 
treatment emergent hepatitis or transaminase elevations in co-infected patients was comparable 
between atazanavir and comparator regimens (see section 4.4). 
 
Patients with chronic hepatitis B or hepatitis C virus co-infection: 
In GS-US-216-0114, 3.6% of subjects were hepatitis B virus surface antigen positive and 5.3% were 
hepatitis C virus seropositive. Subjects with significant liver function test abnormalities generally had 
abnormal baseline transaminases (AST or ALT), underlying chronic or acute hepatitis B or C 
co-infection, concomitant hepatotoxic medicinal products (e.g., isoniazid), or a medical history of 
alcoholism or alcohol abuse. 
 
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 



 

36 
 

professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Human experience of acute overdose with EVOTAZ is limited. 
 
There is no specific antidote for overdose with EVOTAZ. If overdose occurs with EVOTAZ, the 
patient must be monitored for evidence of toxicity. Treatment should consist of general supportive 
measures including monitoring of vital signs and ECG as well as observation of the patient’s clinical 
status. Since atazanavir and cobicistat are extensively metabolised by the liver and highly protein 
bound, dialysis is unlikely to be beneficial in significant removal of this medicinal product. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antivirals for systemic use; antivirals for treatment of HIV infections, 
combinations. ATC code: J05AR15 
 
Mechanism of action 
 
EVOTAZ is a fixed-dose combination of the antiviral drug atazanavir boosted by the pharmacokinetic 
enhancer cobicistat. 
 
Atazanavir 
Atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the 
virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation 
of mature virions and infection of other cells. 
 
Cobicistat 
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, where bioavailability is limited and half-life is shortened by 
CYP3A-dependent metabolism. 
 
Antiviral activity in vitro 
 
Atazanavir 
Atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 activity in cell culture. 
 
Cobicistat 
Cobicistat has no antiviral activity. 
 
Pharmacodynamic effects 
 
Effect of cobicistat on atazanavir pharmacokinetics 
The antiretroviral effect of EVOTAZ is due to the atazanavir component. The activity of cobicistat as 
a pharmacokinetic enhancer to atazanavir has been demonstrated in pharmacokinetic trials. In these 
pharmacokinetic trials, the exposure of atazanavir 300 mg with cobicistat 150 mg was consistent with 
that observed when boosted with ritonavir 100 mg. EVOTAZ is bioequivalent to atazanavir 300 mg 
once daily in combination with cobicistat 150 mg once daily coadministered as single agents (see 
section 5.2).  
 



 

37 
 

Clinical efficacy and safety 
 
In treatment-naïve HIV-1 infected patients 
The safety and efficacy of atazanavir with cobicistat 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 with cobicistat 150 mg 
once daily or atazanavir 300 mg with ritonavir 100 mg once daily, each administered with a fixed 
background regimen containing tenofovir DF 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 DF 
at baseline. 
 
The demographic and baseline characteristics were similar between the atazanavir with cobicistat and 
atazanavir with ritonavir groups. The median age of subjects was 36 years (range: 19-70). The median 
baseline plasma HIV-1 RNA was 4.81 log10 copies/ml (range: 3.21-6.44). The median baseline CD4+ 
cell count was 352 cells/mm3 (range: 1-1455) and 16.9% had CD4+ cell counts ≤200 cells/mm3. The 
percentage of subjects with baseline viral loads >100,000 copies/ml was 39.7%. Treatment outcomes 
at weeks 48 and 144 for study GS-US-216-0114 are presented in Table 3. 
 
Table 3: Virologic outcome of randomised treatment of study GS-US-216-0114 at weeks 48a and 

144b 
 

 Week 48 Week 144 
Atazanavir 

with 
cobicistatf 
(n = 344) 

Atazanavir 
with 

ritonavirf 
(n = 348) 

Atazanavir 
with 

cobicistatf 
(n = 344) 

Atazanavir 
with 

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 week 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. 



 

38 
 

f Plus background regimen of emtricitabine 200 mg and tenofovir DF 300 mg fixed-dose combination. 

 
Atazanavir with cobicistat and emtricitabine and tenofovir DF fixed-dose combination was 
non-inferior in achieving HIV-1 RNA <50 copies/ml when compared to atazanavir with ritonavir and 
emtricitabine and tenofovir DF fixed-dose combination.  
 
In study GS-US-216-0114, the mean increase from baseline in CD4+ cell count at weeks 48 and 144 
were 213 and 310 cells/mm3 in patients receiving atazanavir boosted with cobicistat and 219 and 
332 cells/mm3 in patients receiving atazanavir boosted with ritonavir, respectively. 
 
Resistance 
 
The resistance profile of EVOTAZ is driven by atazanavir. Cobicistat does not select any HIV 
resistance mutations, due to its lack of antiviral activity. 
 
Atazanavir 
In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L 
substitution, sometimes in combination with an A71V change, is the signature resistance substitution 
for atazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence of 
phenotypic cross resistance to other PIs. For more information consult the REYATAZ Summary of 
Product Characteristics. 
 
Atazanavir with cobicistat 
Limited data are available on the development of resistance to atazanavir boosted with cobicistat. 
 
In an analysis of treatment-failure subjects who received atazanavir 300 mg co-administered with 
cobicistat 150 mg 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 this group (6%, 
21/344). Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution 
M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E or any 
primary resistance substitution associated with protease inhibitors. In the group receiving atazanavir 
300 mg co-administered with ritonavir 100 mg, evaluable genotypic data was available for all 
19 virologic failures (5%, 19/348). Among the 19 patients, 1 developed the emtricitabine-associated 
resistance substitution M184V with no tenofovir or protease inhibitor associated resistance 
substitutions. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
EVOTAZ in the treatment of HIV-1 infection (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
One EVOTAZ tablet is bioequivalent to one atazanavir capsule (300 mg) plus one cobicistat tablet 
(150 mg) following single oral dose administration with a light meal in healthy subjects (n=62). 
 
The following statements reflect the pharmacokinetic properties of atazanavir in combination with 
cobicistat or the individual components of EVOTAZ. 
 
Absorption 
In a trial where HIV-infected subjects (n=22) were instructed to take atazanavir 300 mg with cobicistat 
150 mg once daily with food, the steady-state atazanavir Cmax, AUCtau and Ctau (mean ± SD) values 
were 3.9 ± 1.9 μg/ml, 46.1 ± 26.2 μg•hr/ml and 0.80 ± 0.72 μg/ml, respectively. Steady-state cobicistat 
Cmax, AUCtau and Ctau (mean ± SD) values were 1.5 ± 0.5 μg/ml, 11.1 ± 4.5 μg•hr/ml and 
0.05 ± 0.07 μg/ml, respectively (n=22).  



 

39 
 

 
Food effect 
Administration of a single dose of EVOTAZ with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) 
resulted in a 42% increase in atazanavir Cmax, a 28% increase in atazanavir AUC, a 31% increase in 
cobicistat Cmax, and a 24% increase in cobicistat AUC relative to the fasting state. Administration of a 
single dose of EVOTAZ with a high fat meal (1,038 kcal, 59 g fat, 37 g protein) resulted in a 14% 
reduction in atazanavir Cmax with no change in atazanavir AUC or cobicistat exposures (Cmax, AUC) 
relative to the fasting state. The 24-hour atazanavir concentration following a high-fat meal was 
increased approximately 23% due to delayed absorption; the median Tmax increased from 2.0 to 
3.5 hours. Cmax and AUCs after a high fat meal decreased 36% and 25% in comparison to a light meal, 
respectively; however, the 24-hour atazanavir concentration was similar when EVOTAZ was given 
with a light meal and a high fat meal. To enhance bioavailability, EVOTAZ is to be taken with food. 
 
Distribution 
 
Atazanavir 
Atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 
to 10,000 ng/ml. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar 
extent (89% and 86%, respectively, at 1,000 ng/ml). In a multiple-dose study in HIV-infected patients 
dosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in 
the cerebrospinal fluid and semen. 
 
Cobicistat 
Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drug 
concentration ratio was 2. 
 
Biotransformation 
 
Atazanavir 
Studies in humans and in vitro studies using human liver microsomes have demonstrated that 
atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are 
then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic 
pathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma 
have been characterised. Neither metabolite demonstrated in vitro antiviral activity. 
 
Cobicistat 
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 
 
Atazanavir 
Following a single 400 mg dose of [14C]atazanavir, 79% and 13% of the total radioactivity was 
recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 
7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion of 
unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult 
patients (n=33, combined studies), the mean half-life within a dosing interval for atazanavir was 
12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light 
meal.  
 
Cobicistat 



 

40 
 

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 
cobicistat is approximately 3-4 hours. 
 
Linearity/non-linearity 
 
Atazanavir 
Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in 
AUC and Cmax values over the dose range of 200 mg to 800 mg once daily.  
 
Cobicistat 
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. 
 
Special populations 
 
Renal impairment 
Atazanavir 
In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the 
administered dose. There are no pharmacokinetic data available for atazanavir in combination with 
cobicistat in patients with renal insufficiency. Atazanavir has been studied in adult patients with severe 
renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. 
Although this study presented some limitations (i.e., unbound drug concentrations not studied), results 
suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients 
undergoing haemodialysis compared to patients with normal renal function. The mechanism of this 
decrease is unknown (see sections 4.2 and 4.4.) 
 
Cobicistat 
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 
Atazanavir 
Atazanavir is metabolised and eliminated primarily by the liver. The effects of hepatic impairment on 
the pharmacokinetics of atazanavir given with cobicistat have not been studied. Concentrations of 
atazanavir given with cobicistat are expected to be increased in patients with impaired hepatic function 
(see sections 4.2 and 4.4). 
 
Cobicistat 
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. The effect of severe hepatic 
impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied. 
 
Elderly 
The pharmacokinetics of atazanavir and cobicistat, alone or in combination, have not been evaluated 
in an elderly population (65 years of age and older). 
 
Paediatric population 
No data are available on the pharmacokinetics of atazanavir and cobicistat in combination in paediatric 
patients. 
 



 

41 
 

Gender 
No clinically relevant pharmacokinetic differences due to gender have been identified for atazanavir or 
cobicistat.  
 
Race 
No clinically relevant pharmacokinetic differences due to ethnicity have been identified for atazanavir 
or cobicistat. 
 
5.3 Preclinical safety data 
 
In a 3-month combination oral toxicity study of atazanavir and cobicistat in rats, there were no 
toxicologic interactions apparent as no additive or synergistic toxicities were observed. When 
compared to their single-agent profiles all findings could be attributed to either atazanavir or 
cobicistat.  
 
In an ex vivo rabbit pharmacology study, isolated hearts were exposed to atazanavir, cobicistat, or 
atazanavir and cobicistat in combination. Each single agent produced effects on left ventricular 
contractility and PR prolongation at concentrations at least 35-fold higher than the free atazanavir and 
cobicistat concentrations at the recommended human dose (RHD) Cmax. When administered in 
combination, no clear additive or synergistic cardiovascular effects were observed at atazanavir and 
cobicistat concentrations at least 2-fold higher than the free atazanavir and cobicistat concentrations at 
the RHD Cmax.  
 
The following statements reflect the preclinical safety results of the individual active substances of 
EVOTAZ. 
 
Atazanavir 
 
In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were 
generally confined to the liver and included generally minimal to mild increases in serum bilirubin and 
liver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic 
single-cell necrosis. Systemic exposures of atazanavir in mice (males), rats, and dogs at doses 
associated with hepatic changes were at least equal to that observed in humans given 400 mg 
once daily. In female mice, atazanavir exposure at a dose that produced single-cell necrosis was 
12 times the exposure in humans given 400 mg once daily. Serum cholesterol and glucose were 
minimally to mildly increased in rats but not in mice or dogs. 
 
During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a 
concentration (30 μM) of atazanavir corresponding to 30 fold the free drug concentration at Cmax in 
humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) 
in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR 
interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an 
initial 2 week oral toxicity study performed in dogs. Subsequent 9 month oral toxicity studies in dogs 
showed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical data 
is unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 
and 4.8). The potential for PR prolongation should be considered in cases of overdose 
(see section 4.9). 
 
In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no 
effects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxic 
doses. In pregnant rabbits, gross lesions of the stomach and intestines were observed in dead or 
moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive 
embryo-development study. In the pre- and postnatal development assessment in rats, atazanavir 
produced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemic 



 

42 
 

exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly 
greater than that observed in humans given 400 mg once daily. 
 
Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations 
in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir 
did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled 
DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro. 
 
In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign 
hepatic adenomas was seen in female mice only. The increased incidence of benign hepatic adenomas 
in female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and 
is considered to have no relevance for humans at intended therapeutic exposures. There were no 
tumorigenic findings in male mice or in rats. 
 
Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it may 
be an ocular irritant upon direct contact with the eye. 
 
Cobicistat 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
cellulose, microcrystalline (E460(i)) 
croscarmellose sodium (E468) 
sodium starch glycolate 
crospovidone (E1202) 
stearic acid (E570) 
magnesium stearate (E470b) 
hydroxypropylcellulose (E463) 
silica (E551) 
 
Film-coating  
 
hypromellose (hydroxypropyl methyl cellulose, E464) 
titanium dioxide (E171) 
talc (E553b) 
triacetin (E1518) 



 

43 
 

red iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable.  
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure. Each bottle 
contains 30 film-coated tablets and a silica gel dessicant. 
 
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 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1025/001-002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13 July 2015 
Date of latest renewal: 
 
 
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. 
 



 

44 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER 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 



 

45 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 - Anagni (FR) 
Italy 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
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 (PSURs) 
 
The requirements for submission of PSURs 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 marketing authorisation holder (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.  

 
 
 
  



 

46 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



 

47 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



 

48 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON TEXT AND BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
EVOTAZ 300 mg/150 mg film-coated tablets 
atazanavir/cobicistat  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 300 mg of atazanavir (as sulphate) and 150 mg of cobicistat. 
 
 
3. LIST OF EXCIPIENTS 
 
 
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 
 
Do not store above 30°C. 
 



 

49 
 

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 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1025/001 30 film-coated tablets 
EU/1/15/1025/002 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 
 
evotaz 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



 

50 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

51 
 

Package leaflet: Information for the user 
 

EVOTAZ 300 mg/150 mg film-coated tablets 
atazanavir/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 EVOTAZ is and what it is used for 
2. What you need to know before you take EVOTAZ 
3. How to take EVOTAZ 
4. Possible side effects 
5. How to store EVOTAZ 
6. Contents of the pack and other information 
 
 
1. What EVOTAZ is and what it is used for 
 
EVOTAZ contains two active substances: 
 atazanavir, an antiviral (or antiretroviral) medicine. It is one of a group called protease 

inhibitors. These medicines control human immunodeficiency virus (HIV) infection by stopping 
production of a protein that HIV needs for its multiplication. They work by reducing the amount 
of HIV in your body and this in turn, strengthens your immune system. In this way atazanavir 
reduces the risk of developing illnesses linked to HIV infection. 

 cobicistat, a booster (pharmacokinetic enhancer) to help improve the effects of atazanavir. 
Cobicistat, does not directly treat your HIV, but boosts the levels of atazanavir in the blood. It 
does this by slowing down the breakdown of atazanavir which will make it stay in the body for 
longer. 

 
EVOTAZ may be used by adults aged 18 years of age and older who are infected with HIV, the virus 
that causes acquired immunodeficiency syndrome (AIDS). It is used in combination with other 
anti-HIV medicines to help control your HIV infection. Your doctor will discuss with you which 
combination of these medicines with EVOTAZ is best for you. 
 
 
2. What you need to know before you take EVOTAZ 
 
Do not take EVOTAZ 
 if you are allergic to atazanavir, cobicistat or any of the other ingredients of this medicine (listed 

in section 6) 
 if you have moderate to severe liver problems 
 if you are taking any of these medicines: see also Other medicines and EVOTAZ  

 rifampicin (an antibiotic used to treat tuberculosis) 
 carbamazepine, phenobarbital and phenytoin (antiepileptics used to prevent seizures) 
 astemizole or terfenadine (commonly used to treat allergy symptoms, these medicines may 

be available without prescription); cisapride (used to treat gastric reflux, sometimes called 
heartburn); pimozide (used to treat schizophrenia); amiodarone, dronedarone, quinidine, 



 

52 
 

lidocaine (injectable) or bepridil (used to correct heart rhythm); ergotamine, 
dihydroergotamine, ergonovine, ergometrine and methylergonovine (used to treat 
headaches); and alfuzosin (used to treat enlarged prostatic gland) 

 quetiapine (used to treat schizophrenia, bipolar disorder and major depressive disorder); 
lurasidone (used to treat schizophrenia) 

 medicines containing St. John’s wort (Hypericum perforatum, a herbal preparation). 
 triazolam and oral (taken by mouth) midazolam (used to help you sleep and/or to relieve 

anxiety) 
 simvastatin, lovastatin, and lomitapide (used to lower blood cholesterol) 
 avanafil (used to treat erectile dysfunction) 
 colchicine (used to treat gout), if you have kidney and/or liver problems 
 dabigatran and ticagrelor (used to prevent and reduce the blood clots) 
 grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination, and 

glecaprevir/pibrentasvir fixed dose combination (used to treat chronic hepatitis C infection) 
 
Do not take sildenafil with EVOTAZ when sildenafil is used for the treatment of pulmonary arterial 
hypertension. Sildenafil is also used for the treatment of erectile dysfunction. Tell your doctor if you 
are using sildenafil for the treatment of erectile dysfunction. 
 
Tell your doctor at once if any of these apply to you. 
 
Warnings and precautions  
 
Some people will need special care before or while taking EVOTAZ. Talk to your doctor or 
pharmacist before taking EVOTAZ.  
 
EVOTAZ is not a cure for HIV infection. You may continue to develop infections or other illnesses 
linked to HIV infection. You can still pass on HIV to other people 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. 
 
Make sure your doctor knows: 
 if you have liver problems 
 if you develop signs or symptoms of gall stones (pain in your right side). Gall stones have been 

reported in patients taking atazanavir, a component of EVOTAZ.  
 if you have type A or B haemophilia. You may notice increased bleeding. 
 if you have problems with your kidneys or require haemodialysis. Kidney stones have been 

reported in patients taking atazanavir, a component of EVOTAZ. If you develop signs or 
symptoms of kidney stones (pain in your side, blood in your urine, pain when you urinate), 
please inform your doctor immediately 

 if you are taking oral contraceptives ("the Pill") to prevent pregnancy. If you are currently 
using an oral contraceptive or using a patch contraceptive to prevent pregnancy, you should use 
an additional or different type of contraception (e.g. condom) 

 
In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs 
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is 
started. It is believed that these symptoms are due to an improvement in the body’s immune response, 
enabling the body to fight infections that may have been present with no obvious symptoms. If you 
notice any symptoms of infection, please inform your doctor immediately. In addition to the 
opportunistic infections, autoimmune disorders (a condition that occurs when the immune system 
attacks healthy body tissue) may also occur after you start taking medicines for the treatment of your 
HIV infection. Autoimmune disorders may occur many months after the start of treatment. If you 
notice any symptoms of infection or other symptoms such as muscle weakness, weakness beginning in 
hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, 
please inform your doctor immediately to seek necessary treatment. 
 



 

53 
 

Some patients taking combination antiretroviral therapy may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe 
immunosuppression, higher body mass index, among others, may be some of the many risk factors for 
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the 
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor. 
 
Hyperbilirubinaemia (an increase in the level of bilirubin in the blood) has occurred in patients 
receiving EVOTAZ. The signs may be a mild yellowing of the skin or eyes. If you notice any of these 
symptoms please inform your doctor. 
 
Serious skin rash, including Stevens-Johnson syndrome, may develop in patients taking EVOTAZ. If 
you develop a rash inform your doctor immediately. 
 
EVOTAZ may affect how well your kidneys work. 
 
If you notice a change in the way your heart beats (heart rhythm changes), please inform your doctor. 
 
Children and adolescents 
Do not give this medicine to children and adolescents under 18 years of age. The use of EVOTAZ 
in children and adolescents has not yet been studied.  
 
Other medicines and EVOTAZ 
 
You must not take EVOTAZ with certain medicines. These are listed under Do not take EVOTAZ, 
at the start of section 2. 
 
There are other medicines that may not be taken together or may require a change in their mode of 
administration when taken with EVOTAZ. Tell your doctor or pharmacist if you are taking, have 
recently taken or might take any other medicines. It is especially important to mention these: 
 medicines containing ritonavir or cobicistat (booster agents) 
 other medicines to treat HIV infection (e.g. indinavir, didanosine, tenofovir disoproxil, tenofovir 

alafenamide, efavirenz, etravirine, nevirapine and maraviroc) 
 sofosbuvir/velpatasvir/voxilaprevir (used to treat hepatitis C) 
 sildenafil, vardenafil and tadalafil (used by men to treat impotence [erectile dysfunction])  
 if you are taking an oral contraceptive ("the Pill"). You should also use an additional or different 

type of contraception (eg. condom). 
 any medicines used to treat diseases related to the acid in the stomach (“heartburn”) (e.g. antacids, 

H2-blockers like famotidine and proton pump inhibitors like omeprazole) 
 disopyramide, flecainide, mexiletine, propafenone, digoxin, bosentan, amlodipine, felodipine, 

nicardipine, nifedipine, verapamil, diltiazem, metoprolol and timolol (medicines to lower blood 
pressure, to slow heart rate or to correct heart rhythm) 

 atorvastatin, pravastatin, fluvastatin, pitavastatin and rosuvastatin (used to lower blood 
cholesterol) 

 salmeterol (used to treat asthma) 
 ciclosporin, tacrolimus and sirolimus (medicines to decrease the effects of body's immune system)  
 certain antibiotics (rifabutin, clarithromycin) 
 ketoconazole, itraconazole, voriconazole and fluconazole (antifungals) 
 metformin (used to treat type 2 diabetes) 
 warfarin, apixaban, edoxaban and rivaroxaban (used to reduce blood clots) 
 irinotecan, dasatinib, nilotinib, vinblastine and vincristine (used to treat cancer) 
 trazodone (used to treat depression) 
 perphenazine, risperidone, thioridazine, midazolam (given by injection), buspirone, clorazepate, 

diazepam, estazolam, flurazepam and zolpidem (used to treat nevous system disorders) 
 buprenorphine (used to treat opioid addiction and pain) 



 

54 
 

 
It is important to tell your doctor if you are taking: 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. 
 
Pregnancy and breast-feeding 
 
EVOTAZ should not be used during pregancy, because the drug levels in your blood may be lower 
during pregancy and may no longer be high enough to control HIV. Your doctor may prescribe 
different medicines if you become pregnant while taking EVOTAZ. 
 
Atazanavir, a component of EVOTAZ is excreted in human milk. It is unknown if cobicistat, the other 
component of EVOTAZ, is excreted in human milk but it has been shown in animals that it is excreted 
in milk. Talk to your doctor about breast-feeding if you are taking EVOTAZ. Patients should not 
breast-feed while taking EVOTAZ. It is recommended that women infected with HIV do not 
breast-feed because the virus might be transmitted through the breast milk.  
 
Driving and using machines 
Some patients have reported dizziness when taking atazanavir or cobicistat, active substances of 
EVOTAZ. If you feel dizzy or lightheaded, do not drive, use any tools or use machines and contact 
your doctor immediately. 
 
 
3. How to take EVOTAZ 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. This way, you can be sure your medicine is fully effective and you reduce the risk of the 
HIV-virus developing resistance to the treatment. 
 
The recommended adult dose of EVOTAZ is one tablet daily by mouth and with food, in combination 
with other anti-HIV medicines. The tablets have a poor taste, therefore swallow the tablet whole; do 
not crush or chew the tablets. This will help ensure you get the full dose. 
 
If you take more EVOTAZ than you should 
If you accidentally take more EVOTAZ than your doctor recommended, contact your doctor at once or 
contact the nearest hospital for advice. 
 
If you forget to take EVOTAZ 
If you miss a dose of EVOTAZ by 12 hours or less, take it right away with food and then take your 
next scheduled dose at the usual time. If you miss a dose and it is more than 12 hours from the time 
you should have taken EVOTAZ, do not take the missed dose. Wait and take the next dose at the usual 
time. Do not double the next dose. It is important that you do not miss any doses of EVOTAZ or your 
other anti-HIV medicines. 
 
If you stop taking EVOTAZ 
Do not stop taking EVOTAZ before talking to your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 



 

55 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your 
doctor if you notice anything unusual about your health. 
 
 
The following side effects may occur when taking EVOTAZ 
 
Very common (may affect more than 1 in 10 people) 
 yellowing of the skin or the white part of your eyes  
 nausea 
 
Common (may affect up to 1 in 10 people) 
 increased levels of bilirubin in the blood 
 vomiting, diarrhoea, stomach pain or discomfort, indigestion, bloated or distended tummy 

(abdomen), wind (flatulence) 
 headache, dizziness 
 extreme tiredness 
 increased appetite, impairment of the sense of taste, dry mouth 
 difficulty sleeping, abnormal dreams, sleepiness 
 rash 
 
Uncommon (may affect up to 1 in 100 people) 
 life threatening irregular heart beat (torsade de pointes) 
 allergic reaction (hypersensitivity) 
 inflammation of the liver 
 inflammation of the pancreas, inflammation of the stomach 
 allergic reactions including rash, a high temperature, increased levels of liver enzymes seen in 

blood tests, an increase in a type of white blood cell [esosinophilia] and/or enlarged lymph nodes 
(see section 2) 

 severe swelling of the skin and other tissues most often the lips or the eyes 
 fainting, high blood pressure 
 chest pain, generally feeling unwell, fever 
 shortness of breath 
 formation of kidney stones, kidney inflammation, blood in the urine, excess protein in the urine, 

increased frequency of urination, chronic kidney disease (how well your kidneys work)   
 gallstones 
 muscle shrinkage, joint pain, aching muscles 
 breast enlargement in men 
 depression, anxiety, sleep disorder 
 unusual tiredness or weakness 
 loss of appetite, weight loss, weight gain 
 disorientation, loss of memory 
 numbness, weakness, tingling or pain in the arms and legs 
 mouth ulcers and cold sores 
 itchy rash, unusual hair loss or thinning, itching 
 
 
Rare (may affect up to 1 in 1,000 people) 
 allergic reactions including serious skin rash, a high temperature and enlarged lymph nodes 

(Stevens-Johnson syndrome, see section 2). 
 fast or irregular heartbeat (QTc prolongation) 
 enlargement of the liver and spleen 
 gallbladder inflammation 
 kidney pain 
 swelling 
 visible accumulation of fluid under the skin, skin rash, widening of blood vessels 
 abnormal manner of walking 



 

56 
 

 aching muscles, muscle tenderness or weakness not caused by exercise 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes. 
 
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. 
 
 
5. How to store EVOTAZ 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The 
expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
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 EVOTAZ contains 
 The active substances are atazanavir and cobicistat. Each film-coated tablet contains 300 mg of 

atazanavir (as sulphate), and 150 mg cobicistat. 
 The other ingredients are: 

Tablet core - cellulose, microcrystalline (E460(i)), croscarmellose sodium (E468), sodium 
starch glycolate, crospovidone (E1202), stearic acid (E570), magnesium stearate (E470b), 
hydroxypropyl cellulose (E463), silica (E551) 
Film-coating - hypromellose (hydroxypropyl methyl cellulose, E464), titanium dioxide (E171), 
talc (E553b), triacetin (E1518), red iron oxide (E172) 

 
What EVOTAZ looks like and contents of the pack 
EVOTAZ film-coated tablets are pink, oval, biconvex, of approximate dimensions of 
19 mm x 10.4 mm, debossed on one side with "3641" and plain-faced on the other side of the tablet. 
 
EVOTAZ film-coated tablets are supplied in bottles of 30 tablets. 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 packages may be marketed in your country. 
 
Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 

Manufacturer 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 Anagni (FR) 
Italy 
 



 

57 
 

Swords Laboratories T/A Bristol-Myers Squibb 
Pharmaceutical Operations, External 
Manufacturing 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 

 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: + 370 5 236 9140 
 

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480 
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel: + 36 1 9206 550 
 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 356 23976333 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: 0800 0752002 (+49 (0)89 121 42 350) 
 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 
 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: + 372 6401030 
 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 2606400 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)810 410 500 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 
 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
TEL: +385 1 2078-508 
 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 



 

58 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: +386 1 2355 100 
 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 
 

Κύπρος 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: + 371 66164750 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET