Atazanavir Krka

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Atazanavir Krka 150 mg hard capsules 
Atazanavir Krka 200 mg hard capsules 
Atazanavir Krka 300 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Atazanavir Krka 150 mg hard capsules 
Each hard capsule contains 150 mg atazanavir (as sulphate). 
 
Excipient with known effect 
Each hard capsule contains 79.43 mg lactose monohydrate. 
 
Atazanavir Krka 200 mg hard capsules 
Each hard capsule contains 200 mg atazanavir (as sulphate). 
 
Excipient with known effect 
Each hard capsule contains 105.91 mg lactose monohydrate. 
 
Atazanavir Krka 300 mg hard capsules 
Each hard capsule contains 300 mg atazanavir (as sulphate). 
 
Excipient with known effect 
Each hard capsule contains 158.86 mg lactose monohydrate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule) 
 
Atazanavir Krka 150 mg hard capsules 
Hard gelatine capsule, size no. 1. The body of the capsule is white or almost white colour, the cap of 
the capsule is brownish-orange colour. The capsule cap is imprinted with black mark A150. The 
content of the capsule is yellowish-white to yellow-white powder. 
 
Atazanavir Krka 200 mg hard capsules 
Hard gelatine capsule, size no. 0. The body and the cap of the capsule are brownish-orange colour. 
The capsule cap is imprinted with black mark A200. The content of the capsule is yellowish-white to 
yellow-white powder. 
 
Atazanavir Krka 300 mg hard capsules 
Hard gelatine capsule, size no. 00. The body of the capsule is white or almost white colour, the cap of 
the capsule is dark brown colour. The capsule cap is imprinted with white mark A300. The content of 
the capsule is yellowish-white to yellow-white powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Atazanavir Krka capsules, co-administered with low dose ritonavir, are indicated for the treatment of 
HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other 
antiretroviral medicinal products (see section 4.2). 



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Based on available virological and clinical data from adult patients, no benefit is expected in patients 
with strains resistant to multiple protease inhibitors (≥ 4 PI mutations). 
 
The choice of Atazanavir Krka in treatment experienced adult and paediatric patients should be based 
on individual viral resistance testing and the patient’s treatment history (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 
Adults 
The recommended dose of Atazanavir Krka capsules is 300 mg once daily taken with ritonavir 100 
mg once daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics (see 
sections 4.5 and 5.1). (See also section 4.4 Withdrawal of ritonavir only under restrictive conditions). 
 
Paediatric patients (6 years to less than 18 years of age and weighing at least 15 kg) 
The dose of atazanavir capsules for paediatric patients is based on body weight as shown in Table 1 
and should not exceed the recommended adult dose. Atazanavir Krka capsules must be taken with 
ritonavir and have to be taken with food. 
 
Table 1: Dose for paediatric patients (6 years to less than 18 years of age and weighing 

at least 15 kg) for Atazanavir Krka capsules with ritonavir 
Body Weight (kg) Atazanavir Krka once daily dose ritonavir once daily dosea 
15 to less than 35 200 mg 100 mg 
at least 35 300 mg 100 mg 
a 
Ritonavir capsules, tablets or oral solution. 

 
Paediatric patients (at least 3 months of age and weighing at least 5 kg):  
Other formulations of this medicine may be available for paediatric patients at least 3 months of age 
and weighing at least 5 kg (see relevant Summary of Product Characteristics for alternative forms).  
Switching to capsules from other formulations is encouraged as soon as patients are able to 
consistently swallow capsules. 
 
When transitioning between formulations, a change in dose may be needed. Consult the dosing table 
for the specific formulation (see Summary of Product Characteristics for other formulations). 
 
Special populations 
Renal impairment 
No dosage adjustment is needed. Atazanavir Krka with ritonavir is not recommended in 
patients undergoing haemodialysis (see sections 4.4 and 5.2). 
 
Hepatic impairment 
Atazanavir with ritonavir has not been studied in patients with hepatic impairment. Atazanavir Krka 
with ritonavir should be used with caution in patients with mild hepatic impairment. Atazanavir Krka 
with ritonavir must not be used in patients with moderate to severe hepatic impairment (see sections 
4.3, 4.4 and 5.2). 
 
In case of withdrawal of ritonavir from the initial recommended ritonavir boosted regimen (see section 
4.4), unboosted Atazanavir Krka could be maintained in patients with mild hepatic impairment at a 
dose of 400 mg, and in patients with moderate hepatic impairment with a reduced dose of 300 mg once 
daily with food (see section 5.2). Unboosted Atazanavir Krka must not be used in patients with severe 
hepatic impairment. 
 
Pregnancy and Postpartum 
During the second and third trimesters of pregnancy: 



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Atazanavir Krka 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, 
especially when the activity of atazanavir or the whole regimen may be compromised due to drug 
resistance. Since there are limited data available and due to inter-patient variability during pregnancy, 
Therapeutic Drug Monitoring (TDM) may be considered to ensure adequate exposure. 
 
The risk of a further decrease in atazanavir exposure is expected when atazanavir is given with 
medicinal products known to reduce its exposure (e.g., tenofovir disoproxil or H2-receptor 
antagonists). 
- If tenofovir disoproxil or an H2-receptor antagonist is needed, a dose increase to Atazanavir Krka 

400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2). 
- It is not recommended to use Atazanavir Krka with ritonavir for pregnant patients who are 

receiving both tenofovir disoproxil and an H2-receptor antagonist. 
 
(See section 4.4 Withdrawal of ritonavir only under restrictive conditions). 
 
During postpartum: 
Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavir 
exposures might increase during the first two months after delivery (see section 5.2). Therefore, 
postpartum patients should be closely monitored for adverse reactions. 
- During this time, postpartum patients should follow the same dose recommendation as for 

non- pregnant patients, including those for co-administration of medicinal products known to 
affect atazanavir exposure (see section 4.5). 

 
Paediatric patients (less than 3 months of age) 
Atazanavir Krka should not be used in children less than 3 months because of safety concerns 
especially taking into account the potential risk of kernicterus. 
 
Method of administration 
For oral use. The capsules should be swallowed whole. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Atazanavir Krka is contraindicated in patients with severe hepatic insufficiency (see 
sections 4.2, 4.4 and 5.2). Atazanavir Krka with ritonavir is contraindicated in patients 
with moderate hepatic insufficiency (see sections 4.2, 4.4 and 5.2). 
 
Co-administration with simvastatin or lovastatin (see section 4.5).  
 
Combination of rifampicin (see section 4.5). 
 
Combination of the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial 
hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment of 
erectile dysfunction see sections 4.4 and 4.5. 
 
Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome 
P450 and have narrow therapeutic windows (e.g., quetiapine, lurasidone, alfuzosin, astemizole, 
terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for 
caution on parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, 
ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5). 
 
Co-administration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose 
combination (see section 4.5). 
 
Co-administration with glecaprevir/pibrentasvir fixed dose combination (see section 4.5) 
 



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Co-administration with products containing St. John’s wort (Hypericum perforatum) (see section 4.5). 
 
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. 
 
Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has not been 
clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir 
(cardiac effects, hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir with 
ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be 
considered. In this instance, close clinical monitoring is warranted (see Interaction with other 
Medicinal Products below). 
 
Patients with coexisting conditions 
 
Hepatic impairment: Atazanavir is primarily hepatically metabolised and increased plasma 
concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). The 
safety and efficacy of atazanavir has 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. 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 (see section 4.8). 
 
Patients with pre-existing liver dysfunction, including 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. 
 
Renal impairment: No dosage adjustment is needed in patients with renal impairment. However, 
Atazanavir Krka is not recommended in patients undergoing haemodialysis (see sections 4.2 and 
5.2). 
 
QT prolongation: Dose related asymptomatic prolongations in PR interval with atazanavir 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), Atazanavir Krka should be used with caution and 
only if the benefits exceed the risk (see section 5.1). Particular caution should be used when 
prescribing Atazanavir Krka 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. 
 



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In clinical studies, atazanavir (with or without ritonavir) has been shown to induce dyslipidaemia to a 
lesser extent than comparators. 
 
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 atazanavir should be 
evaluated for alternative aetiologies. Alternative antiretroviral therapy to Atazanavir Krka may be 
considered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not 
recommended because it may result in a loss of therapeutic effect and development of resistance. 
 
Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. 
Combinations of atazanavir and indinavir have not been studied and co-administration of these 
medicinal products is not recommended (see section 4.5). 
 
Withdrawal of ritonavir only under restrictive conditions 
The recommended standard treatment is Atazanavir Krka boosted with ritonavir, ensuring 
optimal pharmacokinetic parameters and level of virologic suppression. 
The withdrawal of ritonavir from the boosted regimen of Atazanavir Krka is not recommended, but 
may be considered in adults patients at the dose of 400 mg once daily with food only under the 
following combined restrictive conditions: 
- absence of prior virologic failure 
- undetectable viral load during the last 6 months under current regimen 
- viral strains not harbouring HIV resistance associated mutations (RAMs) to current regimen. 
 
Atazanavir Krka given without ritonavir should not be considered in patients treated with a backbone 
regimen containing tenofovir disoproxil and with other concomitant medications that reduce 
atazanavir bioavailability (see section 4.5 In case of withdrawal of ritonavir from the recommended 
atazanavir boosted regimen) or in case of perceived challenging compliance. 
 
Atazanavir Krka given without ritonavir should not be used in pregnant patients given that it could 
result of suboptimal exposure of particular concern for the mother infection and vertical transmission. 
 
Cholelithiasis 
Cholelithiasis has been reported in patients receiving atazanavir (see section 4.8). Some patients 
required hospitalization for additional management and some had complications. If signs or symptoms 
of cholelithiasis occur, 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 postmarketing 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 hospitalization 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 occur, 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. 



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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 occurs 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 
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 in patients receiving 
atazanavir. Patients should be advised of the signs and symptoms and monitored closely for skin 
reactions. Atazanavir Krka 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 
Atazanavir Krka, Atazanavir Krka may not be restarted. 
 
Interactions with other medicinal products 
The combination of Atazanavir Krka with atorvastatin is not recommended (see section 4.5). 
 
Co-administration of Atazanavir Krka with nevirapine or efavirenz is not recommended (see section 
4.5). If the co-administration of Atazanavir Krka with an NNRTI is required, an increase in the dose 
of both Atazanavir Krka and ritonavir to 400 mg and 200 mg, respectively, in combination with 
efavirenz could be considered with close clinical monitoring. 
 
Atazanavir is metabolised principally by CYP3A4. Co-administration of Atazanavir Krka and 
medicinal products that induce CYP3A4 is not recommended (see sections 4.3 and 4.5). 
 
PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be used when 
prescribing PDE5-inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment of erectile 
dysfunction in patients receiving Atazanavir Krka. Co-administration of Atazanavir Krka 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 Atazanavir Krka with ritonavir is not recommended, 
unless an assessment of the benefit/risk justifies the use of voriconazole. 
 
In the majority of patients, a reduction in both voriconazole and atazanavir exposures are expected. In 
a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole 
exposures are expected (see section 4.5). 
 
Concomitant use of Atazanavir Krka /ritonavir and fluticasone or other glucocorticoids that are 
metabolised 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). 
 
Concomitant use of salmeterol and Atazanavir Krka may result in increased cardiovascular adverse 



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events associated with salmeterol. Co-administration of salmeterol and Atazanavir Krka is not 
recommended (see section 4.5). 
 
The absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective of 
cause. 
 
Co-administration of Atazanavir Krka with proton pump inhibitors is not recommended (see 
section 4.5). If the combination of Atazanavir Krka with a proton pump inhibitor is judged 
unavoidable, close clinical monitoring is recommended in combination with an increase in the 
dose of Atazanavir Krka to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors 
comparable to omeprazole 20 mg should not be exceeded. 
 
Co-administration of Atazanavir Krka with other hormonal contraceptives or oral 
contraceptives containing progestogens other than norgestimate or norethindrone has not been 
studied, and therefore should be avoided (see section 4.5). 
 
Paediatric population 
Safety 
Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults. 
Asymptomatic first- and second-degree AV block was reported in paediatric patients (see 
section 4.8). 
Caution should be used with medicinal products known to induce PR prolongations. In paediatric 
patients with pre-existing conduction problems (second degree or higher atrioventricular or complex 
bundle-branch block), Atazanavir Krka should be used with caution and only if the benefits exceed the 
risk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia). 
 
Efficacy 
Atazanavir/ritonavir is not effective in viral strains harbouring multiple mutations of resistance. 
 
Excipients 
Lactose 
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-
galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
When Atazanavir Krka and ritonavir are co-administered, the metabolic drug interaction profile for 
ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The 
Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with 
Atazanavir Krka and ritonavir. 
 
Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, Atazanavir 
Krka is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow 
therapeutic index: quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, 
quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly 
ergotamine and dihydroergotamine (see section 4.3). 
 
Co-administration of atazanavir with grazoprevir-containing products, including elbasvir/grazoprevir 
fixed dose combination is contraindicated because of the increase in grazoprevir and elbasvir plasma 
concentrations and potential for the increase in risk of ALT elevations associated with increased 
grazoprevir concentrations (see section 4.3). Co-administration of atazanavir 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). 
 
Other interactions 
Interactions between atazanavir and other medicinal products are listed in the table below (increase is 



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indicated as “↑”, decrease as “↓”, no change as “↔”). If available, 90% confidence intervals (CI) are 
shown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unless 
otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not 
the recommended regimen of atazanavir (see section 4.4). 
 
If withdrawal of ritonavir is medically warranted under restrictive conditions (see section 4.4), special 
attention should be given to atazanavir interactions that may differ in the absence of ritonavir (see 
information below Table 2). 
 
Table 2: Interactions between atazanavir 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 atazanavir 
and elbasvir/grazoprevir is 
contraindicated because of a 
significant increase in 
grazoprevir plasma 
concentrations and an 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. 

Sofosbuvir 400 mg / 
velpatasvir 100 mg 
/voxilaprevir 100 mg 
single dose* 
 
(atazanavir 300 mg / 
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. 

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



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Expected: 
↔ Atazanavir 
↔ Ritonavir 
The mechanism of interaction 
between atazanavir/ritonavir and 
sofosbuvir/velpatasvir/voxilaprevir 
is inhibition of OATP1B, Pgp, and 
CYP3A. 
 

Glecaprevir 300 mg / 
pibrentasvir 120 mg 
once daily 
 
(atazanavir 300 mg / 
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%) 
* Effect of atazanavir and ritonavir 
on the first dose of glecaprevir and 
pibrentasvir is reported. 
 

Co-administration of atazanvir 
with glecaprevir/pibrentasvir 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) 

ANTI-RETROVIRALS 
Protease inhibitors: The co-administration of atazanavir /ritonavir and other protease inhibitors has not been 
studied but would be expected to increase exposure to other protease inhibitors. Therefore, such co- 
administration is not recommended. 
Ritonavir 100 mg once daily 
(atazanavir 300 mg once daily) 
 
Studies conducted in 
HIV- infected patients. 

Atazanavir AUC: ↑250% (↑144% 
↑403%)* 
Atazanavir cmax: ↑120% (↑56% 
↑211%)* 
Atazanavir cmin: ↑713% (↑359% 
↑1339%)* 
 
* In a combined analysis, 
atazanavir 300 mg and ritonavir 
100 mg (n=33) was compared to 
atazanavir 400 mg without 
ritonavir (n=28). 
The mechanism of interaction 
between atazanavir and ritonavir is 
CYP3A4 inhibition. 

Ritonavir 100 mg once daily is 
used as a booster of atazanavir 
pharmacokinetics. 

Indinavir Indinavir is associated with 
indirect unconjugated 
hyperbilirubinaemia due to 
inhibition of UGT. 

Co-administration of atazanavir 
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. 

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

Abacavir The co-administration of abacavir 
and atazanavir is not expected to 
significantly alter the exposure of 

 



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abacavir. 
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 at 
the fasted state 2 hours after 
atazanavir taken with food. The 
co-administration of stavudine 
with atazanavir is not expected 
to significantly alter the 
exposure of stavudine. 

Didanosine (enteric coated 
capsules) 400 mg single dose 
(atazanavir 300 mg once daily 
with ritonavir 100 mg once daily) 

Didanosine (with food) 
Didanosine AUC ↓34% (↓41% 
↓27%) Didanosine cmax ↓38% 
(↓48% ↓26%) Didanosine cmin 
↑25% (↓8% ↑69%) 
 
No significant effect on atazanavir 
concentrations was observed when 
administered with enteric-coated 
didanosine, but administration with 
food decreased didanosine 
concentrations. 

 

Tenofovir disoproxil fumarate 
300 mg once daily 
(atazanavir 300 mg once daily 
with ritonavir 100 mg once 
daily) 
 
300 mg tenofovir disoproxil 
fumarate is equivalent to 
245 mg tenofovir disoproxil 
 
Studies conducted in 
HIV- infected patients 

Atazanavir AUC ↓22% (↓35% 
↓6%) * 
Atazanavir cmax ↓16% (↓30% 
↔0%) * 
Atazanavir cmin ↓23% (↓43% ↑2%) 
* 
 
* In a combined analysis from 
several clinical studies, 
atazanavir/ritonavir 300/100 mg 
co-administered with tenofovir 
disoproxil fumarate 300 mg (n=39) 
was compared to 
atazanavir/ritonavir 300/100 mg 
(n=33). 
 
The efficacy of atazanavir 
/ritonavir in combination with 

When co-administered with 
tenofovir disoproxil fumarate, it 
is recommended that atazanavir 
300 mg be given with ritonavir 
100 mg and tenofovir disoproxil 
fumarate 300 mg (all as a single 
dose with food). 



12 

tenofovir disoproxil fumarate in 
treatment- experienced patients has 
been demonstrated in clinical study 
045 and in treatment naive patients 
in clinical study 138 (see sections 
4.8 and 5.1). The mechanism of 
interaction between atazanavir and 
tenofovir disoproxil fumarate is 
unknown. 

Tenofovir disoproxil fumarate 
300 mg once daily 
(atazanavir 300 mg once 
daily with ritonavir 100 
mg once daily) 
 
300 mg tenofovir 
disoproxil fumarate is 
equivalent to 245 mg 
tenofovir disoproxil. 

Tenofovir disoproxilfumarate 
AUC ↑37% (↑30% ↑45%) 
Tenofovir disoproxil fumarate Cmax 
↑34% (↑20% ↑51%) 
Tenofovir disoproxil fumarate Cmin 
↑29% (↑21% ↑36%) 

Patients should be closely 
monitored for tenofovir 
disoproxil fumarate-associated 
adverse reactions, including 
renal disorders. 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 
Efavirenz 600 mg once daily 
(atazanavir 400 mg once daily 
with ritonavir 100 mg once 
daily) 

Atazanavir (pm): all administered 
with food 
Atazanavir AUC ↔0% (↓9% 
↑10%)* 
Atazanavir cmax ↑17% (↑8% 
↑27%)* 
Atazanavir cmin ↓42% (↓51% 
↓31%)* 

Co-administration of efavirenz 
and atazanavir is not 
recommended (see section 4.4) 

Efavirenz 600 mg once daily 
(atazanavir 400 mg once daily 
with ritonavir 200 mg once daily) 

Atazanavir (pm): all administered 
with 
food 
Atazanavir AUC ↔6% (↓10% 
↑26%) 
*/** 
Atazanavir cmax ↔9% (↓5% 
↑26%) 
*/** 
Atazanavir cmin ↔12% (↓16% 
↑49%) 
*/** 
* When compared to atazanavir 
300 mg/ritonavir 100 mg once 
daily in the evening without 
efavirenz. This decrease in 
atazanavir cmin, might negatively 
impact the efficacy of atazanavir. 
The mechanism of 
efavirenz/atazanavir interaction is 
CYP3A4 induction. 
** Based on historical comparison. 

Nevirapine 200 mg twice daily 
(atazanavir 400 mg once daily 
with ritonavir 100 mg once daily) 
 
Study conducted in HIV 
infected patients 

Nevirapine AUC ↑26% (↑17% 
↑36%) 
Nevirapine cmax ↑21% (↑11% 
↑32%) 
Nevirapine cmin ↑35% (↑25% 
↑47%) 
 
Atazanavir AUC ↓19% (↓35% 
↑2%) * 
Atazanavir cmax ↔2% (↓15% 
↑24%) * 
Atazanavir cmin ↓59% (↓73% 

Co-administration of nevirapine 
and atazanavir is not 
recommended (see section 4.4) 



13 

↓40%) * 
 
* When compared to atazanavir 
300 mg and ritonavir 100 mg 
without nevirapine. This decrease 
in atazanavir Cmin, might 
negatively impact the efficacy of 
atazanavir. The mechanism of 
nevirapine/atazanavir interaction is 
CYP3A4 induction. 

Integrase Inhibitors 
Raltegravir 400 mg twice 
daily 
(atazanavir/ritonavir) 

Raltegravir AUC ↑41% 
Raltegravir cmax ↑24% 
Raltegravir c12hr ↑77% 
 
The mechanism is UGT1A1 
inhibition. 

No dose adjustment required for 
raltegravir. 

HCV Protease Inhibitors 
Boceprevir 800 mg three times 
daily 
(atazanavir 300 mg/ritonavir 
100 mg once daily) 

boceprevir AUC ↔5% 
boceprevir cmax ↔7% 
boceprevir cmin ↔18% 
 
atazanavir AUC ↓ 35% 
atazanavir cmax ↓ 25% 
atazanavir cmin ↓ 49% 
 
ritonavir AUC ↓ 36% 
ritonavir cmax ↓ 27% 
ritonavir cmin ↓ 45% 

Co-administration of 
atazanavir/ritonavir with 
boceprevir resulted in lower 
exposure of atazanavir which 
may be associated with lower 
efficacy and loss of HIV control. 
This co-administration might be 
considered on a case by case 
basis if deemed necessary, in 
patients with suppressed HIV 
viral loads and with HIV viral 
strain without any suspected 
resistance to the HIV regimen. 
Increased clinical and laboratory 
monitoring for HIV suppression 
is warranted. 

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%) 
 
A dose reduction of clarithromycin 
may result in subtherapeutic 
concentrations of 14-OH 
clarithromycin. The mechanism of 

No recommendation regarding 
dose reduction can be made; 
therefore, caution should be 
exercised if atazanavir is co- 
administered with 
clarithromycin. 



14 

the clarithromycin/atazanavir 
interaction is CYP3A4 inhibition. 

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

No significant effect on atazanavir 
concentrations was observed. 

Ketoconazole and itraconazole 
should be used cautiously with 
atazanavir /ritonavir, high doses 
of ketoconazole and itraconazole 
(>200 mg/day) are not 
recommended. Itraconazole Itraconazole, like ketoconazole, is 

a potent inhibitor as well as a 
substrate of CYP3A4. 

 Based on data obtained with other 
boosted PIs and ketoconazole, 
where ketoconazole AUC showed 
a 3-fold increase, atazanavir 
/ritonavir is expected to increase 
ketoconazole or itraconazole 
concentrations. 

Voriconazole 200 mg twice 
daily (atazanavir 300 
mg/ritonavir 100 mg once 
daily) 
 
Subjects with at least one 
functional CYP2C19 allele. 

Voriconazole AUC ↓33% (↓42% 
↓22%) 
Voriconazole cmax ↓10% (↓22% 
↓4%) 
Voriconazole cmin ↓39% (↓49% 
↓28%) 
 
Atazanavir AUC ↓12% (↓18% 
↓5% 
Atazanavir cmax ↓13% (↓20% 
↓4%) 
Atazanavir cmin ↓ 20 % (↓28% 
↓10%) 
 
 
Ritonavir AUC ↓12% (↓17% ↓7%) 
Ritonavir cmax ↓9% (↓17% ↔0%) 
Ritonavir cmin ↓25% (↓35% ↓14%) 
 
In the majority of patients with at 
least one functional CYP2C19 
allele, a reduction in both 
voriconazole and atazanavir 
exposures are expected. 

Co-administration of 
voriconazole and atazanavir with 
ritonavir is not recommended 
unless an assessment of the 
benefit/risk to the patient 
justifies the use of voriconazole 
(see section 4.4). 
 
At the time voriconazole 
treatment is required, a patient's 
CYP2C19 genotype should be 
performed if feasible. 
 
Therefore if the combination is 
unavoidable, the following 
recomendations are made 
according to the CYP2C19 
status: 
 
- in patients with at least one 
functional CYP2C19 allele, 
close clinical monitoring for a 
loss of both voriconazole 
(clinical signs) and atazanavir 
(virologic response) efficacy is 
recommended. 
 
- in patients without a functional 
CYP2C19 allele, close clinical 
and laboratory monitoring of 
voriconazole-associated adverse 
events is recommended. 
 
If genotyping is not feasible, full 
monitoring of safety and 
efficacy should be performed. 

Voriconazole 50 mg twice 
daily (atazanavir 
300 mg/ritonavir 100 mg once 
daily) 
 
Subjects without a functional 
CYP2C19 allele. 

Voriconazole AUC ↑561% 
(↑451% ↑699%) 
Voriconazole cmax ↑438% (↑355% 
↑539%) 
Voriconazole cmin ↑765% (↑571% 
↑1,020%) 
 
 
Atazanavir AUC ↓20% (↓35% 
↓3%) 
Atazanavir cmax ↓19% (↓34% 
↔0.2%) 
Atazanavir cmin ↓ 31 % (↓46 % 
↓13%) 
 
 
Ritonavir AUC ↓11% (↓20% ↓1%) 
Ritonavir cmax ↓11% (↓24% ↑4%) 
Ritonavir cmin ↓19% (↓35% ↑1%) 



15 

 
In a small number of patients 
without a functional CYP2C19 
allele, significantly increased 
voriconazole exposures are 
expected. 

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. 

No dosage adjustments are 
needed for fluconazole and 
atazanavir. 

ANTIMYCOBACTERIAL 
Rifabutin 150 mg twice 
weekly 
(atazanavir 300 mg and 
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%). 
 
In previous studies, the 
pharmacokinetics of atazanavir 
was not altered by rifabutin. 

When given with atazanavir, 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. No dose adjustment is 
needed for atazanavir. 

Rifampicin 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. During attempts to 
overcome the decreased exposure 
by increasing the dose of 
atazanavir or other protease 
inhibitors with ritonavir, a high 
frequency of liver reactions was 
seen. 

The combination of rifampicin 
and atazanavir is contraindicated 
(see section 4.3). 

ANTIPSYCHOTICS 
Quetiapine Due to CYP3A4 inhibition by 

atazanavir, concentrations of 
quetiapine are expected to 
increase. 

Co-administration of quetiapine 
with atazanavir is 
contraindicated as atazanavir 
may increase quetiapine-related 
toxicity. Increased plasma 
concentrations of quetiapine may 
lead to coma (see section 4.3). 

Lurasidone Atazanavir is expected to increase 
plasma levels of lurasidone due to 
CYP3A4 inhibition. 

Co-administration of lurasidone 
with atazanavir is 
contraindicated as this may 
increase lurasidone-related 
toxicity (see section 4.3). 

ACID REDUCING AGENTS 



16 

H2-Receptor antagonists 
Without Tenofovir disoproxil  
In HIV-infected patients with atazanavir/ritonavir at the recommended 
dose 300/100 mg once daily 

For patients not taking 
tenofovir disoproxil, if 
atazanavir 300 mg/ritonavir 100 
mg and H2-receptor antagonists 
are co-administered, a dose 
equivalent to famotidine 20 mg 
twice daily should not be 
exceeded. If a higher dose of an 
H2-receptor antagonist is 
required (e.g., famotidine 40 mg 
twice daily or equivalent) an 
increase of the atazanavir 
/ritonavir dose from 300/100 mg 
to 400/100 mg can be 
considered. 

Famotidine 20 mg twice daily Atazanavir AUC ↓18% (↓25% 
↑1%) 
Atazanavir cmax ↓20% (↓32% 
↓7%) 
Atazanavir cmin ↔1% (↓16% 
↑18%) 

Famotidine 40 mg twice daily Atazanavir AUC ↓23% (↓32% 
↓14%) 
Atazanavir cmax ↓23% (↓33% 
↓12%) 
Atazanavir cmin ↓20% (↓31% ↓8%) 

In Healthy volunteers with atazanavir/ritonavir at an increased dose 
of 400/100 mg once daily 
Famotidine 40 mg twice daily Atazanavir AUC ↔3% (↓14% 

↑22%) 
Atazanavir cmax ↔2% (↓13% 
↑8%) 
Atazanavir cmin ↓14% (↓32% ↑8%) 

With Tenofovir disoproxil fumarate 300 mg once daily (equivalent to 245 mg tenofovir disoproxil) 
In HIV-infected patients with atazanavir/ritonavir at the recommended 
dose of 300/100 mg once daily 

For patients who are taking 
tenofovir disoproxil, if 
atazanavir/ritonavir with both 
tenofovir disoproxil and an H2-
receptor antagonist are co-
administered, a dose increase of 
atazanavir to 400 mg with 100 
mg of ritonavir is recommended. 
A dose equivalent to famotidine 
40 mg twice daily should not be 
exceeded. 

Famotidine 20 mg twice daily Atazanavir AUC ↓21% (↓34% 
↓4%)* 
Atazanavir cmax ↓21% (↓36% 
↓4%)* 
Atazanavir cmin ↓19% (↓37% 
↑5%)* 

Famotidine 40 mg twice daily Atazanavir AUC ↓24% (↓36% 
↓11%)* 
Atazanavir cmax ↓23% (↓36% 
↓8%)* 
Atazanavir cmin ↓25% (↓47% 
↑7%)* 

In HIV-infected patients with atazanavir/ritonavir at an increased dose 
of 400/100 mg once daily 
Famotidine 20 mg twice daily Atazanavir AUC ↑18% (↑6.5% 

↑30%)* 
Atazanavir cmax ↑18% (↑6.7% 
↑31%)* 
Atazanavir cmin ↑24 % (↑10% 
↑39%)* 

Famotidine 40 mg twice daily Atazanavir AUC ↔2.3% (↓13% 
↑10%)* 
Atazanavir cmax ↔5% (↓17% 
↑8.4%)* 
Atazanavir cmin↔1.3% (↓10% 
↑15)* 



17 

 * When compared to atazanavir 
300 mg once daily with ritonavir 
100 mg once daily and tenofovir 
disoproxil fumarate 300 mg all as 
a single dose with food. When 
compared to atazanavir 300 mg 
with ritonavir 100 mg without 
tenofovir disoproxil, atazanavir 
concentrations are expected to be 
additionally decreased by about 
20%. 
 
The mechanism of interaction is 
decreased solubility of atazanavir 
as intra-gastric pH increases with 
H2- blockers. 

 

Proton pump inhibitors 
Omeprazole 40 mg once daily 
(atazanavir 400 mg once daily 
with ritonavir 100 mg once 
daily) 

Atazanavir (am): 2 hr after 
omeprazole 
Atazanavir AUC ↓61% (↓65% 
↓55%) 
Atazanavir cmax ↓66% (↓62% 
↓49%) 
Atazanavir cmin ↓65% (↓71% 
↓59%) 

Co-administration of atazanavir 
with ritonavir and proton pump 
inhibitors is not recommended. 
If the combination is judged 
unavoidable, close clinical 
monitoring is recommended in 
combination with an increase in 
the dose of atazanavir to 400 mg 
with 100 mg of ritonavir; doses 
of proton pump inhibitors 
comparable to omeprazole 20 
mg should not be exceeded (see 
section 4.4). 

Omeprazole 20 mg once daily 
(atazanavir 400 mg once daily with 
ritonavir 100 mg once daily) 

Atazanavir (am): 1 hr after 
omeprazole 
Atazanavir AUC ↓30% (↓43% 
↓14%)* 
Atazanavir cmax ↓31% (↓42% 
↓17%)* 
Atazanavir cmin ↓31% (↓46% 
↓12%)* 
 
* When compared to atazanavir 
300 mg once daily with ritonavir 
100 mg once daily. 
The decrease in AUC, cmax, and 
cmin was not mitigated when an 
increased dose of atazanavir 
/ritonavir (400/100 mg once daily) 
was temporally separated from 
omeprazole by 12 hours. Although 
not studied, similar results are 
expected with other proton pump 
inhibitors. This decrease in 
atazanavir exposure might 
negatively impact the efficacy of 
atazanavir. The mechanism of 
interaction is decreased solubility 
of atazanavir as intra-gastric pH 
increases with proton pump 
inhibitors. 

Antacids 
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 
atazanavir. 

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

ALPHA 1-ADRENORECEPTOR ANTAGONIST 
Alfuzosin Potential for increased alfuzosin Co-administration of alfuzosin 



18 

concentrations which can result in 
hypotension. The mechanism of 
interaction is CYP3A4 inhibition 
by atazanavir and/or ritonavir. 

with atazanavir is 
contraindicated (see section 4.3) 

ANTICOAGULANTS 
Warfarin Co-administration with atazanavir 

has the potential to increase or 
decrease warfarin concentrations. 

It is recommended that the 
International Normalised Ratio 
(INR) be monitored carefully 
during treatment with atazanavir, 
especially when commencing 
therapy. 

ANTIEPILEPTICS 
Carbamazepine Atazanavir may increase plasma 

levels of carbamazepine due to 
CYP3A4 inhibition. 
Due to carbamazepine inducing 
effect, a reduction in atazanavir 
exposure cannot be ruled out. 

Carbamazepine should be used 
with caution in combination with 
atazanavir. If necessary, monitor 
carbamazepine serum 
concentrations and adjust the 
dose accordingly. Close 
monitoring of the patient's 
virologic response should be 
excercised. 

Phenytoin, phenobarbital Ritonavir may decrease plasma 
levels of phenytoin and/or 
phenobarbital due to CYP2C9 and 
CYP2C19 induction. Due to 
phenytoin/phenobarbital inducing 
effect, a reduction in atazanavir 
exposure cannot be ruled out. 

Phenobarbital and phenytoin 
should be used with caution in 
combination with atazanavir 
/ritonavir. 
 
When atazanavir/ritonavir is co-
administered with either 
phenytoin or phenobarbital, a 
dose adjustment of phenytoin or 
phenobarbital may be required. 
 
Close monitoring of patient's 
virologic response should be 
exercised. 

Lamotrigine Co-administration of lamotrigine 
and atazanavir /ritonavir may 
decrease lamotrigine plasma 
concentrations due to UGT1A4 
induction. 

Lamotrigine should be used with 
caution in combination with 
atazanavir /ritonavir. 
 
If necessary, monitor 
lamotrigine concentrations and 
adjust the dose accordingly. 

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS 
Antineoplastics 
Irinotecan Atazanavir inhibits UGT and may 

interfere with the metabolism of 
irinotecan, resulting in increased 
irinotecan toxicities. 

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

Immunosuppressants 
Cyclosporin 
Tacrolimus 
Sirolimus 

Concentrations of these 
immunosuppressants may be 
increased when co-administered 
with atazanavir due to CYP3A4 
inhibition. 

More frequent therapeutic 
concentration monitoring of 
these medicinal products is 
recommended until plasma 
levels have been stabilised. 

CARDIOVASCULAR AGENTS 
Antiarrhythmics 
Amiodarone, 
Systemic lidocaine, 
Quinidine 

Concentrations of these 
antiarrhythmics may be increased 
when co-administered with 
atazanavir. The mechanism of 
amiodarone or systemic 
lidocaine/atazanavir interaction is 

Caution is warranted and 
therapeutic concentration 
monitoring is recommended 
when available. The concomitant 
use of quinidine is 
contraindicated (see section 4.3). 



19 

CYP3A inhibition. Quinidine has a 
narrow therapeutic window and is 
contraindicated due to potential 
inhibition of CYP3A by 
atazanavir. 

Calcium channel blockers 
Bepridil Atazanavir should 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. Co-
administration of diltiazem and 
atazanavir /ritonavir has not been 
studied. The mechanism of 
diltiazem/atazanavir interaction is 
CYP3A4 inhibition. 

An initial dose reduction of 
diltiazem by 50% is 
recommended, with subsequent 
titration as needed and ECG 
monitoring. 

Verapamil Serum concentrations of verapamil 
may be increased by atazanavir 
due to CYP3A4 inhibition. 

Caution should be exercised 
when verapamil is co- 
administered with atazanavir. 

CORTICOSTEROIDS 
Fluticasone propionate 
intranasal 50 µg 4 times daily 
for 7 days 
(ritonavir 100 mg capsules 
twice daily) 

The fluticasone propionate plasma 
levels increased significantly, 
whereas the intrinsic cortisol levels 
decreased by approximately 86% 
(90% confidence interval 82%-
89%). Greater effects may be 
expected when fluticasone 
propionate is inhaled. 
Systemic corticosteroid effects 
including Cushing’s syndrome and 
adrenal suppression have been 
reported in patients receiving 
ritonavir and inhaled or 
intranasally administered 
fluticasone propionate; this could 
also occur with other 
corticosteroids metabolised via the 
P450 3A pathway, e.g., 
budesonide. The effects of high 
fluticasone systemic exposure on 
ritonavir plasma levels are yet 
unknown. The mechanism of 
interaction is CYP3A4 inhibition. 

Co-administration of 
atazanavir/ritonavir and these 
glucocorticoids is not 
recommended unless the 
potential benefit of treatment 
outweighs the risk of systemic 
corticosteroid effects (see 
section 4.4). A dose reduction of 
the glucocorticoid should be 
considered with close 
monitoring of local and systemic 
effects or a switch to a 
glucocorticoid, which is not a 
substrate for CYP3A4 (e.g., 
beclomethasone). Moreover, in 
case of withdrawal of 
glucocorticoids, progressive 
dose reduction may have to be 
performed over a longer period. 



20 

ERECTILE DYSFUNCTION 
PDE5 Inhibitors 
Sildenafil, tadalafil, vardenafil Sildenafil, tadalafil and vardenafil 

are metabolised by CYP3A4. Co- 
administration with atazanavir 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. 

Patients should be warned about 
these possible side effects when 
using PDE5 inhibitors for 
erectile dysfunction with 
atazanavir (see section 4.4). Also 
see PULMONARY ARTERIAL 
HYPERTENSION in this table 
for futher information regarding 
co- administration of atazanavir 
with sildenafil. 

HERBAL PRODUCTS 
St. John’s wort (Hypericum 
perforatum) 

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

Co-administration of atazanavir 
with products containing St. 
John's wort is contraindicated. 

HORMONAL CONTRACEPTIVES 
Ethinyloestradiol 25 μg + 
norgestimate 
(atazanavir 300 mg once daily 
with ritonavir 100 mg once 
daily) 

Ethinyloestradiol AUC ↓19% 
(↓25% ↓13%) 
Ethinyloestradiol cmax ↓16% 
(↓26% ↓5%) 
Ethinyloestradiol cmin ↓37% 
(↓45% ↓29%) 
 
Norgestimate AUC ↑85% (↑67% 
↑105%) 
Norgestimate cmax ↑68% (↑51% 
↑88%) 
Norgestimate cmin ↑102% (↑77% 
↑131%) 
 
While the concentration of 
ethinyloestradiol was increased 
with atazanavir given alone, due to 
both UGT and CYP3A4 inhibition 
by atazanavir, the net effect of 
atazanavir/ritonavir is a decrease in 
ethinyloestradiol levels because of 
the inducing effect of ritonavir. 
 
The increase in progestin exposure 
may lead to related side-effects 
(e.g. insulin resistance, 
dyslipidemia, acne and spotting), 
thus possibly affecting the 
compliance. 

If an oral contraceptive is 
administered with 
atazanavir/ritonavir, it is 
recommended that the oral 
contraceptive contain at least 30 
μg of ethinyloestradiol and that 
the patient be reminded of strict 
compliance with this 
contraceptive dosing regimen. 
Co-administration of atazanavir 
/ritonavir with other hormonal 
contraceptives or oral 
contraceptives containing 
progestogens other than 
norgestimate has not been 
studied, and therefore should be 
avoided. An alternate reliable 
method of contraception is 
recommended. 

Ethinyloestradiol 35 µg + 
norethindrone 
(atazanavir 400 mg once daily) 

Ethinyloestradiol AUC ↑48% 
(↑31% ↑68%) 
Ethinyloestradiol cmax ↑15% (↓1% 
↑32%) 
Ethinyloestradiol cmin ↑91% 
(↑57% ↑133%) 
 
Norethindrone AUC ↑110% 
(↑68% 
↑162%) 

 



21 

Norethindrone cmax ↑67% (↑42% 
↑196%) 
Norethindrone cmin ↑262% 
(↑157% 
↑409%) 
 
The increase in progestin exposure 
may lead to related side-effects 
(e.g. insulin resistance, 
dyslipidemia, acne and spotting), 
thus possibly affecting the 
compliance. 

LIPID LOWERING AGENTS 
HMG-CoA reductase inhibitors 
Simvastatin 
Lovastatin 

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

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

Atorvastatin The risk of myopathy including 
rhabdomyolysis may also be 
increased with atorvastatin, which 
is also metabolised by CYP3A4. 

Co-administration of atorvastatin 
with atazanavir is not 
recommended. If the use of 
atorvastatin is considered strictly 
necessary, the lowest possible 
dose of atorvastatin should be 
administered with careful safety 
monitoring (see section 4.4). 

Pravastatin 
Fluvastatin 

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. 

Caution should be exercised. 

INHALED BETA AGONISTS 
Salmeterol Co-administration with atazanavir 

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/or ritonavir. 

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

OPIOIDS 
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. 
Concentrations of atazanavir 
(when given with ritonavir) were 
not significantly affected. 

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

Methadone, stable 
maintenance dose 

No significant effect on methadone 
concentrations was observed. 

No dosage adjustment is 
necessary if methadone is co- 



22 

(atazanavir 400 mg once daily) Given that low dose ritonavir (100 
mg twice daily) has been shown to 
have no significant effect on 
methadone concentrations, no 
interaction is expected if 
methadone is co- administered 
with atazanavir, based on these 
data. 

administered with atazanavir. 

PULMONARY ARTERIAL HYPERTENSION 
PDE5 Inhibitors 
Sildenafil Co-administration with atazanavir 

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/or ritonavir. 

A safe and effective dose in 
combination with atazanavir 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). 

SEDATIVES 
Benzodiazepines 
Midazolam 
Triazolam 

Midazolam and triazolam are 
extensively metabolised by 
CYP3A4. Co-administration with 
atazanavir may cause a large 
increase in the concentration of 
these benzodiazepines. No drug 
interaction study has been 
performed for the co- 
administration of atazanavir with 
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. 

Co-administration of atazanavir 
with triazolam or orally 
administered midazolam is 
contraindicated (see section 4.3), 
whereas caution should be used 
with co- administration of 
atazanavir and parenteral 
midazolam. If atazanavir 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. 

 
In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen (see section 4.4) 
The same recommendations for drug drug interactions would apply except: 
- that co-administration is not recommended with tenofovir, boceprevir, carbamazepine, 

phenytoin, phenobarbital, proton pump inhibitors, and buprenorphine. 
- that co-administration with famotidine is not recommended but if required, atazanavir without 

ritonavir should be administered either 2 hours after famotidine or 12 hours before. No single 
dose of famotidine should exceed 20 mg, and the total daily dose of famotidine should not 
exceed 40 mg. 

- the need to consider that 
-   co-administration of voriconazole and atazanavir without ritonavir may affect atazanavir 

concentrations 
-   co-administration of fluticasone and atazanavir without ritonavir may increase fluticasone 

concentrations relative to fluticasone given alone 
-   if an oral contraceptive is administered with atazanavir without ritonavir, it is 

recommended that the oral contraceptive contain no more than 30 µg of ethinyloestradiol 
-   no dose adjustment of lamotrigine is required 

 



23 

Paediatric population 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
A moderate amount of data in pregnant women (between 300-1000 pregnancy outcomes) 
indicate no malformative toxicity of atazanavir. Animal studies do not indicate reproductive 
toxicity (see section 5.3). The use of Atazanavir Krka with ritonavir may be considered 
during pregnancy only if the potential benefit justifies the potential risk. 
 
In clinical trial AI424-182 atazanavir /ritonavir (300/100 mg or 400/100 mg) in combination 
with zidovudine/lamivudine was administered to 41 pregnant women during the second or third 
trimester. Six of 20 (30%) women on atazanavir /ritonavir 300/100 mg and 13 of 21 (62%) 
women on atazanavir /ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. 
There were no cases of lactic acidosis observed in the clinical trial AI424-182. 
 
The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not 
include atazanavir) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 
months postpartum. Three of 20 infants (15%) born to women treated with atazanavir /ritonavir 
300/100 mg and four of 20 infants (20%) born to women treated with atazanavir /ritonavir 400/100 
mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 
infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of 
kernicterus in neonates. 
 
For dosing recommendations see section 4.2 and for pharmacokinetic data see section 5.2. 
 
It is not known whether atazanavir with ritonavir administered to the mother during pregnancy will 
exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In the 
prepartum period, additional monitoring should be considered. 
 
Breast-feeding 
Atazanavir has been detected in human milk. As a general rule, it is recommended that HIV infected 
women not breast-feed their infants in order to avoid transmission of HIV. 
 
Fertility 
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). 
 
4.7 Effects on ability to drive and use machines 
 
Patients should be informed that dizziness has been reported during treatment with regimens 
containing atazanavir (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Atazanavir has been evaluated for safety in combination therapy with other antiretroviral medicinal 
products in controlled clinical trials in 1,806 adult patients receiving atazanavir 400 mg once daily 
(1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or atazanavir 300 mg 
with ritonavir 100 mg once daily (655 patients, 96 weeks median duration and 108 weeks maximum 
duration). 
 
Adverse reactions were consistent between patients who received atazanavir 400 mg once daily and 
patients who received atazanavir 300 mg with ritonavir 100 mg once daily, except that jaundice and 
elevated total bilirubin levels were reported more frequently with atazanavir plus ritonavir. 
 



24 

Among patients who received atazanavir 400 mg once daily or atazanavir 300 mg with ritonavir 100 
mg once daily, the only adverse reactions of any severity reported very commonly with at least a 
possible relationship to regimens containing atazanavir and one or more NRTIs were nausea (20%), 
diarrhoea (10%), and jaundice (13%). Among patients receiving atazanavir 300 mg with ritonavir 100 
mg, the frequency of jaundice was 19%. 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. 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 4.4). 
 
Tabulated list of adverse reactions 
Assessment of adverse reactions for atazanavir is based on safety data from clinical studies and post- 
marketing experience. Frequency is defined using the following convention: very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very 
rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
Immune system disorders: uncommon: hypersensitivity 
Metabolism and nutrition 
disorders 

uncommon: weight decreased, weight gain, anorexia, appetite increased 

Psychiatric disorders: uncommon: depression, disorientation, anxiety, insomnia, sleep disorder, 
abnormal dream 

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

Eye disorders: common: ocular icterus 
Cardiac disorders: uncommon: torsades de pointesa 

rare: QTc prolongationa, oedema, palpitation 
Vascular disorders: uncommon: hypertension 
Respiratory, thoracic and 
meadiastinal disorders 

uncommon: dyspnoea 

Gastrointestinal disorders: common: vomiting, diarrhoea, abdominal pain, nausea, dyspepsia; 
uncommon: pancreatitis, gastritis, abdominal distension, stomatitis 
aphthous, flatulence, dry mouth 

Hepatobiliary disorders: common: jaundice; 
uncommon: hepatitis, cholelithiasisa, cholestasisa; 
rare: hepatosplenomegaly, cholecystitisa 

Skin and subcutaneous tissue 
disorders: 

common: rash; 
uncommon: erythemia multiformea,b, toxic skin eruptionsa,b, drug rash 
with eosinophilia and systemic symptoms (DRESS) syndromea,b, 
angioedemaa, urticaria, alopecia, pruritus; 
rare: Stevens-Johnson syndromea,b, vesiculobullous rash, eczema, 
vasodilatation 

Musculoskeletal and connective 
tissue disorders 

uncommon: muscle atrophy, arthralgia, myalgia; 
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 

General disorders and 
administration site conditions: 

common: fatigue; 
uncommon: chest pain, malaise, pyrexia, asthenia; 
rare: gait disturbance 

aThese 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 in randomised controlled and other 
available clinical trials (n = 2321). 



25 

bSee description of selected adverse reactions for more details. 
 
Description of selected adverse reactions 
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). 
 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (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). 
 
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 naive 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 a clinical study AI424-020, paediatric patients 3 months to less than 18 years of age who received 
either the oral powder or capsule formulation had a mean duration of treatment with atazanavir of 
115 weeks. The safety profile in this study 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. 
 
In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of age 
had a mean duration of treatment with atazanavir oral powder of 80 weeks. No deaths were reported. 
The safety profile in these studies was overall comparable to that seen in previous paediatric and adult 
studies. The most frequently reported laboratory abnormalities in paediatric patients receiving 



26 

atazanavir oral powder was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) and 
increased amylase (Grade 3-4; 33%), generally of non-pancreatic origin. Elevation in ALT levels were 
more frequently reported in paediatric patients in these studies than in adults. 
 
Other special populations 
Patients co-infected with hepatitis B and/or hepatitis C virus 
Among 1,151 patients receiving atazanavir 400 mg once daily, 177 patients were co-infected with 
chronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily with 
ritonavir 100 mg once daily, 97 patients were co-infected with chronic hepatitis B or C. Co-
infected patients 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). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Human experience of acute overdose with atazanavir is limited. Single doses up to 1,200 mg have 
been taken by healthy volunteers without symptomatic untoward effects. At high doses that lead to 
high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associated 
liver function test changes) or PR interval prolongations may be observed (see sections 4.4 and 4.8). 
 
Treatment of overdose with Atazanavir Krka should consist of general supportive measures, including 
monitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinical 
status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric 
lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. 
There is no specific antidote for overdose with Atazanavir Krka. Since atazanavir is extensively 
metabolised by the liver and is 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, protease inhibitors, ATC code: J05AE08. 
 
Mechanism of action 
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. 
 
Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 
activity in cell culture. 
 
Resistance 
Antiretroviral treatment naive adult patients 
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. In clinical trials of antiretroviral treatment naive patients 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
https://en.wikipedia.org/wiki/ATC_code_J05


27 

treated with boosted atazanavir, the I50L substitution did not emerge in any patient without baseline 
PI substitutions. The N88S substitution has been rarely observed in patients with virologic failure on 
atazanavir (with or without ritonavir). While it may contribute to decreased susceptibility to 
atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does 
not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical 
efficacy. 
 
Table 3. De novo substitutions in treatment naive patients failing therapy with atazanavir + 
ritonavir (Study 138, 96 weeks) 
Frequency de novo PI substitution (n=26)a 
>20% none 
10-20% none 
a 
Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). 

 
The M184I/V substitution emerged in 5/26 atazanavir /ritonavir and 7/26 lopinavir/ritonavir virologic 
failure patients, respectively. 
 
Antiretroviral treatment experienced adult patients 
In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from 
patients designated as virological failures on therapy that included either atazanavir, atazanavir + 
ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of 
the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) 
displayed the I50L phenotype previously described in naive patients. 
 
Table 4. De novo substitutions in treatment experienced patients failing therapy with atazanavir 
+ ritonavir (Study 045, 48 weeks) 
Frequency de novo PI substitution (n=35)a,b 
>20% M36, M46, I54, A71, V82 
10-20% L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90 
a 
Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). 

b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell 
culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, 
California, USA) 
 
None of the de novo substitutions (see Table 4) are specific to atazanavir and may reflect re- 
emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced 
population. 
 
The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the 
major and minor resistance substitutions described previously to be involved in protease inhibitor 
resistance. 
 
Clinical results 
In antiretroviral naive adult patients 
Study 138 is an international randomised, open-label, multicenter, prospective trial of treatment naïve 
patients comparing atazanavir /ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 
mg/100 mg twice daily), each in combination with fixed dose tenofovir disoproxil 
fumarate/emtricitabine (300 mg/200 mg tablets once daily). The atazanavir /ritonavir arm showed 
similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the 
proportion of patients with HIV RNA < 50 copies/ml at week 48 (Table 5). 
Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 5). 
 
Table 5: Efficacy Outcomes in Study 138a

 

 atazanavir /ritonavirb (300 mg/100 mg 
once daily) n=440 

Lopinavir/ritonavirc (400 mg/100 mg 
twice daily) n=443 

 Week 48 Week 96 Week 48 Week 96 
HIV RNA <50 copies/ml, % 
All patientsd 78 74 76 68 



28 

Difference estimate 
[95% CI]d 

Week 48: 1.7% [-3.8%, 7.1%] 
Week 96: 6.1% [0.3%, 12.0%] 

Per protocol 
analysise 86 (n=392

f) 91 (n=352) 
89 

(n=372) 
89 

(n=331) 
Difference estimatee 
[95% CI] 

Week 48: -3% [-7.6%, 1.5%] 
Week 96: 2.2% [-2.3%, 6.7%] 

HIV RNA <50 copies/ml, % by Baseline Characteristicd 

HIV RNA 
<100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) 

≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) 
CD4 count 
<50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 

50 to <100 
cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 

100 to <200 
cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) 

≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) 
HIV RNA Mean Change from Baseline, log10 copies/ml 
All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) 
CD4 Mean Change from Baseline, cells/mm3

 

All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) 
CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic 
HIV RNA 
<100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) 

≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) 
a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 
4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) 
b atazanavir /RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). 
c Lopinavir/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). 
d Intent-to-treat analysis, with missing values considered as failures. 
e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. 
f Number of patients evaluable. 
 
Data on withdrawal of ritonavir from atazanavir boosted regimen (see also section 4.4) 
Study 136 (INDUMA) 
In an open-label, randomised, comparative study following a 26- to 30-week induction phase with 
atazanavir 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted atazanavir 400 mg once 
daily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral 
efficacy compared with atazanavir + ritonavir and two NRTIs (n=85) in HIV infected subjects with 
fully suppressed HIV replication, as assessed by the proportion of subjects with HIV RNA < 50 
copies/ml: 78% of subjects on unboosted atazanavir and two NRTIs compared with 75% on atazanavir 
+ ritonavir and two NRTIs. 
 
Eleven subjects (13%) in the unboosted atazanavir group and 6 (7%) in the atazanavir + ritonavir 
group, had virologic rebound. Four subjects in the unboosted atazanavir group and 2 in the 
atazanavir + ritonavir group had HIV RNA > 500 copies/ml during the maintenance phase. No 
subject in either group showed emergence of protease inhibitor resistance. The M184V substitution 
in reverse transcriptase, which confers resistance to lamivudine and emtricitabine, was detected in 2 
subjects in the unboosted atazanavir and 1 subject in the atazanavir + ritonavir group. 
 
There were fewer treatment discontinuations in the unboosted atazanavir group (1 vs. 4 subjects in 
the atazanavir + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboosted 
atazanavir group compared with the atazanavir + ritonavir group (18 and 28 subjects, respectively). 
 
In antiretroviral experienced adult patients 
Study 045 is a randomised, multicenter trial comparing atazanavir /ritonavir (300/100 mg once daily) 
and atazanavir /saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose 
combination twice daily), each in combination with tenofovir disoproxil (see sections 4.5 and 4.8) and 
one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, 
NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 



29 

weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were 
receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the atazanavir + 
ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more 
of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty-two percent of patients in the study 
had a viral strain with fewer than two NRTI substitutions. 
 
The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through 
48 weeks (Table 6). 
 
Table 6: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) 
Parameter ATV/RTVb (300 mg/ 

100 mg once daily 
(n=120) 

LPV/RTVc (400 mg/ 
100 mg twice daily 

(n=123) 
 

Time-averaged difference 
ATV/RTV-LPV/RTV 

[97.5% CId] 

 Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 

HIV RNA Mean Change from Baseline, log10 copies/ml 
All patients -1.93 

(n=90e) 
-2.29 

(n=64) 
-1.87 

(n=99) 
-2.08 

(n=65) 
0.13 

[-0.12, 0.39] 
0.14 

[-0.13, 0.41] 

HIV RNA <50 copies/ml, %f (responder/evaluable) 

All patients 36 (43/120) 32 (38/120) 42 (52/123) 35 (41/118) NA NA 
HIV RNA <50 copies/ml by select baseline PI substitutions,f,g % (responder/evaluable) 

0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 
3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA 
≥ 4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA 
CD4 Mean Change from Baseline, cells/mm3 

All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA 
a The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV-1 
RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). 
b ATV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). 
c LPV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). 
d Confidence interval. 
e Number of patients evaluable. 
f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment 
before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 
53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. 
g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, 
G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. 
NA = not applicable. 
 
Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for atazanavir 
+ ritonavir and lopinavir + ritonavir were similar (non-inferior). Consistent results were obtained 
with the last observation carried forward method of analysis (time-averaged difference of 0.11, 
97.5% confidence interval [-0.15, 0.36]). By as-treated analysis, excluding missing values, the 
proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the atazanavir + 
ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. 
 
Through 96 weeks of treatment, mean HIV RNA changes from baseline for atazanavir + ritonavir 
and lopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistent 
results were obtained with the last observation carried forward method of analysis. By as-treated 
analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml 
(<50 copies/ml) for atazanavir + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% 
(72%). It is important to note that at time of the 96-week analysis, 48 % of patients overall 
remained on study. 
 
Atazanavir + saquinavir was shown to be inferior to lopinavir + ritonavir. 



30 

 
Paediatric population 
Assessment of the pharmacokinetics, safety, tolerability, and efficacy of atazanavir is based on 
data from the open-label, multicenter clinical trial AI424-020 conducted in patients from 3 
months to 21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naive 
and 101 antiretroviral-experienced) received once daily atazanavir (capsule or powder 
formulation), with or without ritonavir, in combination with two NRTIs. 
 
The clinical data derived from this study are inadequate to support the use of atazanavir capsules 
(with or without ritonavir) in children below 6 years of age. 
 
Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received 
atazanavir capsules with ritonavir are presented in Table 7. For treatment-naive paediatric patients, the 
mean baseline CD4 cell count was 344 cells/mm3 (range: 2 to 800 cells/ mm3) and mean baseline 
plasma HIV-1 RNA was 4.67 log10 copies/ml (range: 3.70 to 5.00 log10 copies/ml). For treatment- 
experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm3 (range: 100 to 
1157 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.09 log10 copies/ml (range: 3.28 to 5.00 
log10 copies/ml). 
 
Table 7: Efficacy Outcomes (paediatric patients 6 years to less than 18 years of age) at 

Week 48 (Study AI424-020) 
Parameter Treatment-Naive atazanavir 

Capsules/ritonavir (300 mg/100 
mg once daily) 

n=16 

Treatment- Experienced 
atazanavir 

Capsules/ritonavir (300 mg/100 
mg once daily) 

n=25 
HIV RNA <50 copies/ml, % a 
All patients 81 (13/16) 24 (6/25) 
HIV RNA <400 copies/ml, % a 
All patients 88 (14/16) 32 (8/25) 
CD4 Mean Change from Baseline, cells/mm3 
All patients 293 (n=14b) 229 (n=14b) 
HIV RNA <50 copies/ml by select baseline PI substitutions,c % (responder/evaluabled) 
0-2 NA 27 (4/15) 
3 NA - 
≥4 NA 0 (0/3) 
a Intent-to-treat analysis, with missing values considered as failures. 
b Number of patients evaluable. 
c PI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY, I54ALMSTV, L76V, V82AFLST, I84V, 
N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V. 
d Includes patients with baseline resistance data.  
NA = not applicable. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected 
patients; significant differences were observed between the two groups. The pharmacokinetics of 
atazanavir exhibit a non-linear disposition. 
 
Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of atazanavir 300 mg 
once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for 
atazanavir, cmax of 4466 (42%) ng/ml, with time to cmax of approximately 2.5 hours. The geometric 
mean (CV%) for atazanavir cmin and AUC was 654 (76%) ng/ml and 44185 (51%) ng•h/ml, 
respectively. 
 
In HIV-infected patients (n=13), multiple dosing of atazanavir 400 mg (without ritonavir) once daily 
with food produced a geometric mean (CV%) for atazanavir cmax of 2298 (71) ng/ml, with time to cmax 
of approximately 2.0 hours. The geometric mean (CV%) for atazanavir cmin and AUC were 120 (109) 
ng/ml and 14874 (91) ng•h/ml, respectively. 



31 

 
Food effect: co-administration of atazanavir and ritonavir with food optimises the bioavailability of 
atazanavir. Co-administration of a single 300 mg dose of atazanavir and 100 mg dose of ritonavir with 
a light meal resulted in a 33% increase in the AUC and a 40% increase in both the cmax and the 24 hour 
concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal did not 
affect the AUC of atazanavir relative to fasting conditions and the cmax was within 11% of fasting 
values. The 24 hour concentration following a high fat meal was increased by approximately 33% due 
to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Administration of atazanavir 
with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and 
cmax by approximately 25% compared to the fasting state. To enhance bioavailability and minimise 
variability, atazanavir is to be taken with food. 
 
Distribution: 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. 
 
Metabolism: 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. 
 
Elimination: 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. 
 
Special populations 
 
Renal impairment: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 
7% of the administered dose. There are no pharmacokinetic data available for atazanavir with ritonavir 
in patients with renal insufficiency. atazanavir (without ritonavir) 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.). 
 
Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. Atazanavir 
(without ritonavir) has been studied in adult subjects with moderate-to-severe hepatic impairment (14 
Child-Pugh Class B and 2 Child-Pugh Class C subjects) after a single 400 mg dose. The mean 
AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. The 
mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in 
healthy subjects. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 
mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavir 
are expected to be increased in patients with moderately or severely impaired hepatic function (see 
sections 4.2, 4.3, and 4.4). 
 
Age/Gender: a study of the pharmacokinetics of atazanavir was performed in 59 healthy male and 
female subjects (29 young, 30 elderly). There were no clinically important pharmacokinetic 
differences based on age or gender. 
 



32 

Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated no 
effect of race on the pharmacokinetics of atazanavir. 
 
Pregnancy: 
The pharmacokinetic data from HIV-infected pregnant women receiving atazanavir capsules with 
ritonavir are presented in Table 8. 
 
Table 8: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected 
Pregnant Women in the Fed State 
 atazanavir 300 mg with ritonavir 100 mg 
Pharmacokinetic Parameter 2nd Trimester 

(n=9) 
3rd Trimester 

(n=20) 
postpartuma 

(n=36) 
Cmax ng/mL 

Geometric mean (CV%) 
3729.09 

(39) 
3291.46 

(48) 
5649.10 

(31) 
AUC ng•h/mL 

Geometric mean (CV%) 
34399.1 

(37) 
34251.5 

(43) 
60532.7 

(33) 
Cmin ng/mLb 

Geometric mean (CV%) 
663.78 

(36) 
668.48 

(50) 
1420.64 

(47) 
a Atazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during the postpartum period (4-
12 weeks) than those observed historically in HIV infected, non-pregnant patients. Atazanavir plasma trough concentrations 
were approximately 2-fold higher during the postpartum period when compared to those observed historically in HIV infected 
non-pregnant patients. 
b Cmin is concentration 24 hours post-dose 
 
Paediatric population 
There is a trend toward a higher clearance in younger children when normalised for body weight. As a 
result, greater peak to trough ratios are observed; however at recommended doses, geometric mean 
atazanavir exposures (cmin, cmax and AUC) in paediatric patients are expected to be similar to those 
observed in adults. 
 
5.3 Preclinical safety data 
 
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 exposure to 



33 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule contents 
lactose monohydrate 
crospovidone (type A) 
magnesium stearate 
 
Capsule shell of Atazanavir Krka 150 mg hard capsules 
Body: 
titanium dioxide (E171) 
gelatine 
 
Cap: 
titanium dioxide (E171) 
yellow ferric oxide (E172) 
red ferric oxide (E172) 
gelatine 
ink: 

shellac  
black ferric oxide (E172) 
potassium hydroxide 

 
Capsule shell of Atazanavir Krka 200 mg hard capsules 
Body: 
titanium dioxide (E171) 
yellow ferric oxide (E172) 
red ferric oxide (E172) 
gelatine 
 
Cap: 
titanium dioxide (E171) 
yellow ferric oxide (E172) 
red ferric oxide (E172) 
gelatine 
ink: 

shellac 
black ferric oxide (E172) 



34 

potassium hydroxide 
 
Capsule shell of Atazanavir Krka 300 mg hard capsules 
Body: 
titanium dioxide (E171) 
gelatine 
 
Cap: 
titanium dioxide (E171) 
yellow ferric oxide (E172) 
red ferric oxide (E172) 
black ferric oxide (E172) 
gelatine 
ink: 

shellac 
titanium dioxide (E171) 
potassium hydroxide 

 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
Shelf life after first opening is 2 months, stored below 25°C. 
 
6.4 Special precautions for storage 
 
Store below 30°C. 
Keep the container tightly closed in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Atazanavir Krka 150 mg and 200 mg hard capsules 
HDPE tablet container with child-resistant tamper evident PP with desiccant closure: 60 hard capsules, 
in a box. 
 
Atazanavir Krka 300 mg hard capsules 
HDPE tablet container with child-resistant tamper evident PP with desiccant closure: 30 hard capsules 
and 90 (3 x 30) hard capsules, in a box. 
 
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 
 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 



35 

 
150 mg hard capsules: 
60 hard capsules: EU/1/19/1353/001 
 
200 mg hard capsules: 
60 hard capsules: EU/1/19/1353/002 
 
300 mg hard capsules: 
30 hard capsules: EU/1/19/1353/003 
90 (3 x 30) hard capsules: EU/1/19/1353/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 
 
 
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. 

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


36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



37 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
KRKA, d.d., Novo mesto 
Šmarješka cesta 6 
8501 Novo mesto 
Slovenia 
 
TAD Pharma GmbH 
Heinz-Lohmann-Straße 5 
27472 Cuxhaven 
Germany 
 
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 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

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

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

 



38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



39 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



40 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Atazanavir Krka 150 mg hard capsules 
 
atazanavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 150 mg atazanavir (as sulphate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains also lactose monohydrate. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
60 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Capsules should be swallowed whole. 
 
 
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: 
 
Shelf life after first opening is 2 months, stored below 25°C. 
Date of opening:____________ 
 
 



41 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
Keep the container tightly closed in order to protect from moisture. 
 
 
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 
 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1353/001 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Atazanavir Krka 150 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



42 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
CONTAINER LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Atazanavir Krka 150 mg hard capsules 
 
atazanavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 150 mg atazanavir (as sulphate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains also lactose monohydrate. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
60 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Capsules should be swallowed whole. 
 
 
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: 
 
Shelf life after first opening is 2 months, stored below 25°C. 
Date of opening:____________ 
 
 
9. SPECIAL STORAGE CONDITIONS 



43 

 
Store below 30°C. 
Keep the container tightly closed in order to protect from moisture. 
 
 
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 
 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1353/001 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



44 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Atazanavir Krka 200 mg hard capsules 
 
atazanavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 200 mg atazanavir (as sulphate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains also lactose monohydrate. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
60 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Capsules should be swallowed whole. 
 
 
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: 
 
Shelf life after first opening is 2 months, stored below 25°C. 
Date of opening:____________ 
 
 



45 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
Keep the container tightly closed in order to protect from moisture. 
 
 
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 
 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1353/002 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Atazanavir Krka 200 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



46 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
CONTAINER LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Atazanavir Krka 200 mg hard capsules 
 
atazanavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 200 mg atazanavir (as sulphate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains also lactose monohydrate. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
60 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Capsules should be swallowed whole. 
 
 
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: 
 
Shelf life after first opening is 2 months, stored below 25°C. 
Date of opening:____________ 
 
 



47 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
Keep the container tightly closed in order to protect from moisture. 
 
 
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 
 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1353/002 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



48 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Atazanavir Krka 300 mg hard capsules 
 
atazanavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 300 mg atazanavir (as sulphate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains also lactose monohydrate. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
30 hard capsules 
90 (3 x 30) hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Capsules should be swallowed whole. 
 
 
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: 
 
Shelf life after first opening is 2 months, stored below 25°C. 
Date of opening:____________ 
 
 



49 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
Keep the container tightly closed in order to protect from moisture. 
 
 
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 
 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1353/003 30 hard capsules 
EU/1/19/1353/004 90 (3 x 30) hard capsules 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Atazanavir Krka 300 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



50 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
CONTAINER LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Atazanavir Krka 300 mg hard capsules 
 
atazanavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 300 mg atazanavir (as sulphate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains also lactose monohydrate. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
30 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Capsules should be swallowed whole. 
 
 
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: 
 
Shelf life after first opening is 2 months, stored below 25°C. 
Date of opening:____________ 
 
 



51 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
Keep the container tightly closed in order to protect from moisture. 
 
 
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 
 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1353/003 30 hard capsules 
EU/1/19/1353/004 90 (3 x 30) hard capsules 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



52 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



53 

Package leaflet: Information for the patient 
 

Atazanavir Krka 150 mg hard capsules 
Atazanavir Krka 200 mg hard capsules 
Atazanavir Krka 300 mg hard capsules 

atazanavir 
 

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 Atazanavir Krka is and what it is used for 
2. What you need to know before you take Atazanavir Krka 
3. How to take Atazanavir Krka 
4. Possible side effects 
5. How to store Atazanavir Krka 
6. Contents of the pack and other information 
 
 
1. What Atazanavir Krka is and what it is used for 
 
Atazanavir Krka is an antiviral (or antiretroviral) medicine. It is one of a group called protease 
inhibitors. These medicines control Human Immunodeficiency Virus (HIV) infection by stopping a 
protein that the 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 Krka reduces the risk 
of developing illnesses linked to HIV infection. 
 
Atazanavir Krka capsules may be used by adults and children 6 years of age and older. Your doctor 
has prescribed Atazanavir Krka for you because you are infected by the HIV that causes Acquired 
Immunodeficiency Syndrome (AIDS). It is normally used in combination with other anti-HIV 
medicines. Your doctor will discuss with you which combination of these medicines with Atazanavir 
Krka is best for you. 
 
 
2. What you need to know before you take Atazanavir Krka 
 
Do not take Atazanavir Krka: 
- if you are allergic to atazanavir or any of the other ingredients of this medicine (listed in 

section 6). 
- if you have moderate to severe liver problems. Your doctor will evaluate how severe 

yourliver disease is before deciding whether you can take Atazanavir Krka 
- if you are taking any of these medicines: see also Other medicines and Atazanavir Krka 

- rifampicin (an antibiotic used to treat tuberculosis) 
- 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); quinidine or bepridil (used to 
correct heart rhythm); ergotamine, dihydroergotamine, ergonovine, 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) 



54 

- 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 and lovastatin (used to lower blood cholesterol). 
- 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 Atazanavir Krka 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 
 
Atazanavir Krka 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 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. 
 
Some people will need special care before or while taking Atazanavir Krka. Talk to your doctor or 
pharmacist before taking Atazanavir Krka and make sure your doctor knows: 

- if you have hepatitis B or C 
- if you develop signs or symptoms of gall stones (pain at the right side of your stomach) 
- if you have type A or B haemophilia 
- if you require haemodialysis 

 
Atazanavir Krka may affect how well your kidneys work. 
 
Kidney stones have been reported in patients taking atazanavir. 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. 
 
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. 
 
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 atazanavir. The signs may be a mild yellowing of the skin or eyes. If you notice any of these 
symptoms please inform your doctor. 



55 

 
Serious skin rash, including Stevens-Johnson syndrome, has been reported in patients taking 
atazanavir. If you develop a rash inform your doctor immediately. 
 
If you notice a change in the way your heart beats (heart rhythm changes), please inform your doctor. 
Children receiving Atazanavir Krka may require their heart to be monitored. Your child's doctor will 
decide this. 
 
Children 
Do not give this medicine to children younger than 3 months of age and weighing less than 5 kg. The 
use of Atazanavir Krka in children less than 3 months of age and weighing less than 5 kg has not been 
studied due to the risk of serious complications. 
 
Other medicines and Atazanavir Krka 
You must not take Atazanavir Krka with certain medicines. These are listed under Do not take 
Atazanavir Krka, at the start of Section 2. 
 
There are other medicines that may not mix with Atazanavir Krka. Tell your doctor if you are taking, 
have recently taken, or might take any other medicines. It is especially important to mention these: 

- other medicines to treat HIV infection (e.g. indinavir, nevirapine and efavirenz) 
- boceprevir and sofosbuvir/velpatasvir/voxilaprevir (used to treat hepatitis C) 
- sildenafil, vardenafil, or tadalafil (used by men to treat impotence (erectile dysfunction)) 
- if you are taking an oral contraceptive ("the Pill") with Atazanavir Krka to prevent pregnancy, 

be sure to take it exactly as instructed by your doctor and not miss any doses 
- any medicines used to treat diseases related to the acid in the stomach (e.g. antacids to be 

taken 1 hour before taking Atazanavir Krka or 2 hours after taking Atazanavir Krka, H2-
blockers like famotidine and proton pump inhibitors like omeprazole) 

- medicines to lower blood pressure, to slow heart rate, or to correct heart rhythm (amiodarone, 
diltiazem, systemic lidocaine, verapamil) 

- atorvastatin, pravastatin, and fluvastatin (used to lower blood cholesterol) 
- salmeterol (used to treat asthma) 
- cyclosporin, tacrolimus, and sirolimus (medicines to decrease the effects of body's immune 

system) 
- certain antibiotics (rifabutin, clarithromycin) 
- ketoconazole, itraconazole, and voriconazole (antifungals) 
- warfarin (anticoagulant, used to reduce the blood clots) 
- carbamazepine, phenytoin, phenobarbital, lamotrigine (antiepileptics) 
- irinotecan (used to treat cancer) 
- sedative agents (e.g. midazolam administered by injection) 
- buprenorphine (used to treat opioid addiction and pain). 

 
Some medicines may interact with ritonavir, a medicine that is taken with Atazanavir Krka. It is 
important to tell your doctor if you are taking fluticasone or budesonide (given by nose or inhaled to 
treat allergic symptoms or asthma). 
 
Atazanavir Krka with food and drink 
It is important that you take Atazanavir Krka with food (a meal or a substantial snack) as this helps the 
body absorb the medicine. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. Atazanavir, the active substance of 
Atazanavir Krka, is excreted in human milk. Patients should not breast-feed while taking Atazanavir 
Krka. 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 



56 

If you feel dizzy or lightheaded, do not drive or use machines and contact your doctor immediately. 
 
Atazanavir Krka contains lactose monohydrate 
If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact 
your doctor before taking this medicinal product. 
 
 
3. How to take Atazanavir Krka 
 
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 virus 
developing resistance to the treatment. 
 
The recommended adult dose of Atazanavir Krka capsules is 300 mg once daily with 100 mg 
ritonavir once daily and with food, in combination with other anti-HIV medicines. Your doctor may 
adjust the dose of Atazanavir Krka according to your anti-HIV therapy. 
 
For children (6 to less than 18 years of age), your child's doctor will decide the right dose based 
on your child's weight. The dose of Atazanavir Krka capsules for children is calculated by body 
weight and is taken once daily with food and 100 mg ritonavir as shown below: 

Body weight (kg) Atazanavir Krka Dose once daily 
(mg) 

Ritonavir Dose* once daily (mg) 

15 to less than 35 200 100 
At least 35 300 100 

*Ritonavir capsules, tablets or oral solution may be used. 
 
Other formulations of this medicine may be available for paediatric patients at least 3 months of age 
and weighing at least 5 kg (see relevant Summary of Product Characteristics for alternative forms).  
Switching to capsules from other formulations is encouraged as soon as patients are able to 
consistently swallow capsules. 
 
Take Atazanavir Krka capsules with food (a meal or a substantial snack). Swallow the capsules 
whole. 
Do not open the capsules. 
 
If you take more Atazanavir Krka than you should 
Yellowing of the skin and/or eyes (jaundice) and irregular heart beat (QTc prolongation) may occur if 
you or your child take too much Atazanavir Krka. 
If you accidentally take more Atazanavir Krka capsules than your doctor recommended, contact your 
HIV doctor at once or contact the nearest hospital for advice. 
 
If you forget to take Atazanavir Krka 
If you miss a dose, take the missed dose as soon as possible with food and then take your next 
scheduled dose at its regular time. If it is almost time for your next dose, do not take the missed dose. 
Wait and take the next dose at its regular time. Do not take a double dose to make up for a forgotten 
dose. 
 
If you stop taking Atazanavir Krka 
Do not stop taking Atazanavir Krka before talking to your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. When 
treating HIV infection, it is not always easy to identify what side effects are caused by Atazanavir 



57 

Krka, by the other medicines you are taking, or by the HIV infection itself. Tell your doctor if you 
notice anything unusual about your health. 
 
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. 
 
Tell your doctor immediately if you develop any of the following serious side effects: 
 

- Skin rash, itching that may occasionally be severe has been reported. The rash usually 
disappears within 2 weeks without any change to your atazanavir treatment. Severe rash may 
be developed in association with other symptoms which could be serious. Stop taking 
Atazanavir Krka and talk to your doctor immediately if you develop a severe rash or a rash 
with flu-like illness symptoms, blisters, fever, mouth sores, muscle or joint pain, swelling in 
the face, inflammation of the eye which causes redness (conjunctivitis), painful, warm, or red 
lumps (nodules). 

- Yellowing of your skin or the white part of your eyes caused by high levels of bilirrubin in 
your blood has been commonly reported. This side effect is usually not dangerous in adults 
and infants older than 3 months of age; but it might be a symptom of a serious problem. If 
your skin or the white part of your eyes turns yellow, talk to your doctor immediately. 

- Changes in the way your heart beats (heart rhythm change) may occasionally happen. Talk to 
your doctor immediately if you get dizzy, lightheaded or if you suddenly faint. These could be 
symptoms of a serious heart problem. 

- Liver problems may uncommonly happen. Your doctor should do blood tests prior you start 
Atazanavir Krka and during treatment. If you have liver problems, including hepatitis B or C 
infection, you may experience a worsening of your liver problems. Talk to your doctor 
immediately if you get dark (tea-colored) urine, itching, yellowing of your skin or the white 
part of your eyes, pain around the stomach, pale colored stools or nausea. 

- Gallbladder problems uncommonly happen in people taking atazanavir. Symptoms of 
gallbladder problems may include pain in the right or middle upper stomach area, nausea, 
vomiting, fever or yellowing your skin or the white part of your eyes. 

- Atazanavir Krka may affect how well your kidneys work. 
- Kidney stones uncommonly happen in people taking atazanavir. Talk to your doctor 

immediately if you get symptoms of kidney stones which may include, pain in your low back 
or low stomach-area, blood in your urine or pain when you urinate. 

 
Other side effects reported for patients treated with atazanavir are the following: 
Common (may affect up to 1 in 10 people): 

- headache 
- vomiting, diarrhoea, abdominal pain (stomach pain of discomfort), nausea, dyspepsia 

(indigestion) 
- fatigue (extreme tiredness) 

Uncommon (may affect up to 1 in 100 people): 
- peripheral neuropathy (numbness, weakness, tingling or pain in the arms and legs) 
- hypersensitivity (allergic reaction) 
- asthenia (unusual tiredness or weakness) 
- weight decreased, weight gain, anorexia (loss of appetite), appetite increased 
- depression, anxiety, sleep disorder 
- disorientation, amnesia (loss of memory), dizziness, somnolence (sleepiness), abnormal dream 
- syncope (fainting), hypertension (high blood pressure) 
- dyspnoea (shortness of breath) 
- pancreatitis (inflammation of the pancreas), gastritis (inflammation of the stomach), stomatitis, 

aphthous (mouth ulcers and cold sores), dysgeusia (impairment of the sense of taste), 
flatulence (wind), dry mouth, abdominal distension 

- angioedema (severe swelling of the skin and other tissues most often the lips or the eyes) 
- alopecia (unusual hair loss or thinning), pruritus (itching) 
- muscle atrophy (muscle shrinkage), arthralgia (joint pain), myalgia (aching muscles) 



58 

- interstitial nephritis (kidney inflammation), haematuria (blood in the urine), proteinuria (excess 
protein in the urine), pollakiuria (increased frequency of urination) 

- gynaecomastia (breast enlargement in men) 
- chest pain, malaise (generally feeling unwell), fever 
- insomnia (difficulty sleeping) 

Rare (may affect up to 1 in 1,000 people): 
- gait disturbance (abnormal manner of walking) 
- oedema (swelling) 
- hepatosplenomegaly (enlargement of the liver and spleen) 
- myopathy (aching muscles, muscle tenderness of weakness, not caused by exercise) 
- kidney pain 

 
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 Atazanavir Krka 
 
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 packaging after EXP. The expiry 
date refers to the last day of that month. 
 
Store below 30°C. 
Keep the container tightly closed in order to protect from moisture. 
Shelf life after first opening is 2 months, stored below 25°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 Atazanavir Krka contains 
- The active substance is atazanavir. 

Atazanavir Krka 150 mg hard capsules 
Each hard capsule contains 150 mg atazanavir (as sulphate). 
Atazanavir Krka 200 mg hard capsules 
Each hard capsule contains 200 mg atazanavir (as sulphate). 
Atazanavir Krka 300 mg hard capsules 
Each hard capsule contains 300 mg atazanavir (as sulphate). 
 

- The other ingredients are: 
Capsule contents: lactose monohydrate, crospovidone (type A) and magnesium stearate. See 
section 2 "Atazanavir Krka contains lactose monohydrate". 
 
Capsule shell of Atazanavir Krka 150 mg hard capsules: 
Body: titanium dioxide (E171) and gelatine 
Cap: titanium dioxide (E171), yellow ferric oxide (E172), red ferric oxide (E172), gelatine and 
ink (shellac, black ferric oxide (E172), potassium hydroxide 
 
Capsule shell of Atazanavir Krka 200 mg hard capsules 
Body: titanium dioxide (E171), yellow ferric oxide (E172), red ferric oxide (E172) and gelatine 
Cap: titanium dioxide (E171), yellow ferric oxide (E172), red ferric oxide (E172), gelatine and 

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


59 

ink (shellac, black ferric oxide (E172), potassium hydroxide 
 
Capsule shell of Atazanavir Krka 300 mg hard capsules 
Body: titanium dioxide (E171) and gelatine 
Cap: titanium dioxide (E171), yellow ferric oxide (E172), red ferric oxide (E172), black ferric 
oxide (E172), gelatine and ink (shellac, titanium dioxide (E171), potassium hydroxide 

 
What Atazanavir Krka looks like and contents of the pack 
Atazanavir Krka 150 mg hard capsules 
Hard gelatine capsule (capsule), size no. 1. The body of the capsule is white or almost white colour, 
the cap of the capsule is brownish-orange colour. The capsule cap is imprinted with black mark A150. 
The content of the capsule is yellowish-white to yellow-white powder. 
 
Atazanavir Krka 200 mg hard capsules 
Hard gelatine capsule (capsule), size no. 0. The body and the cap of the capsule are brownish-orange 
colour. The capsule cap is imprinted with black mark A200. The content of the capsule is yellowish-
white to yellow-white powder. 
 
Atazanavir Krka 300 mg hard capsules 
Hard gelatine capsule (capsule), size no. 00. The body of the capsule is white or almost white colour, 
the cap of the capsule is dark brown colour. The capsule cap is imprinted with white mark A300. The 
content of the capsule is yellowish-white to yellow-white powder. 
 
Atazanavir Krka 150 mg and 200 mg hard capsules are available in containers containing 60 hard 
capsules; in a box. 
Atazanavir Krka 300 mg hard capsules are available in containers containing 30 hard capsules or 90 
(3 x 30) hard capsules; in a box. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
 
Manufacturers 
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia 
TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
KRKA Belgium, SA. 
Tél/Tel: + 32 (0) 487 50 73 62 
 

Lietuva 
UAB KRKA Lietuva 
Tel: + 370 5 236 27 40 

България 
КРКА България ЕООД 
Teл.: + 359 (02) 962 34 50 

Luxembourg/Luxemburg 
KRKA Belgium, SA. 
Tél/Tel: + 32 (0) 487 50 73 62 (BE) 
 

Česká republika 
KRKA ČR, s.r.o. 
Tel: + 420 (0) 221 115 150 
 

Magyarország 
KRKA Magyarország Kereskedelmi Kft. 
Tel.: + 36 (1) 355 8490 

Danmark 
KRKA Sverige AB 
Tlf: + 46 (0)8 643 67 66 (SE) 
 

Malta 
E. J. Busuttil Ltd. 
Tel: + 356 21 445 885 



60 

Deutschland 
TAD Pharma GmbH 
Tel: + 49 (0) 4721 606-0 
 

Nederland 
KRKA Belgium, SA. 
Tel: + 32 (0) 487 50 73 62 (BE) 
 

Eesti 
KRKA, d.d., Novo mesto Eesti filiaal 
Tel: + 372 (0) 6 671 658 
 

Norge 
KRKA Sverige AB 
Tlf: + 46 (0)8 643 67 66 (SE) 

Ελλάδα 
QUALIA PHARMA S.A. 
Τηλ: + 30 210 6256177 
 

Österreich 
KRKA Pharma GmbH, Wien 
Tel: + 43 (0)1 66 24 300  

España 
KRKA Farmacéutica, S.L. 
Tel: + 34 911 61 03 81 
 

Polska 
KRKA-POLSKA Sp. z o.o. 
Tel.: + 48 (0)22 573 7500 

France 
KRKA France Eurl 
Tél: + 33 (0)1 57 40 82 25 
 

Portugal 
KRKA Farmacêutica, Sociedade Unipessoal Lda. 
Tel: + 351 (0)21 46 43 650 

Hrvatska 
KRKA - FARMA d.o.o. 
Tel: + 385 1 6312 100 

România 
KRKA Romania S.R.L., Bucharest 
Tel: + 4 021 310 66 05 
 

Ireland 
KRKA Pharma Dublin, Ltd. 
Tel: + 353 1 293 91 80 
 

Slovenija 
KRKA, d.d., Novo mesto 
Tel: + 386 (0) 1 47 51 100 

Ísland 
LYFIS ehf. 
Sími: + 354 534 3500 
 

Slovenská republika 
KRKA Slovensko, s.r.o. 
Tel: + 421 (0) 2 571 04 501 

Italia 
KRKA Farmaceutici Milano S.r.l. 
Tel: + 39 02 3300 8841 

Suomi/Finland 
KRKA Finland Oy 
Puh/Tel: + 358 20 754 5330 
 

Κύπρος 
Kipa Pharmacal Ltd. 
Τηλ: + 357 24 651 882 
 

Sverige 
KRKA Sverige AB 
Tel: + 46 (0)8 643 67 66 (SE) 

Latvija 
KRKA Latvija SIA 
Tel: + 371 6 733 86 10 

United Kingdom 
Consilient Health (UK) Ltd. 
Tel: + 44 (0)203 751 1888 
 

 
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. 
 

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

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