ATAZANAVIR KRKA 300mg capsules medication leaflet

Atazanavir Krka 150 mg hard capsules

Atazanavir Krka 200 mg hard capsules

Atazanavir Krka 300 mg hard capsules

Atazanavir Krka 150 mg hard capsules

Each hard capsule contains 150 mg atazanavir (as sulphate).

Each hard capsule contains 79.43 mg lactose monohydrate.

Atazanavir Krka 200 mg hard capsules

Each hard capsule contains 200 mg atazanavir (as sulphate).

Each hard capsule contains 105.91 mg lactose monohydrate.

Atazanavir Krka 300 mg hard capsules

Each hard capsule contains 300 mg atazanavir (as sulphate).

Each hard capsule contains 158.86 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

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 ofthe capsule is brownish-orange colour. The capsule cap is imprinted with black mark A150. Thecontent 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 toyellow-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 ofthe capsule is dark brown colour. The capsule cap is imprinted with white mark A300. The content ofthe capsule is yellowish-white to yellow-white powder.

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 otherantiretroviral medicinal products (see section 4.2).

Based on available virological and clinical data from adult patients, no benefit is expected in patientswith strains resistant to multiple protease inhibitors (≥ 4 PI mutations).

The choice of Atazanavir Krka in treatment-experienced adult and paediatric patients should be basedon individual viral resistance testing and the patient’s treatment history (see sections 4.4 and 5.1).

Therapy should be initiated by a physician experienced in the management of HIV infection.

The recommended dose of Atazanavir Krka capsules is 300 mg once daily taken with ritonavir 100mg once daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics (seesections 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 1and should not exceed the recommended adult dose. Atazanavir Krka capsules must be taken withritonavir and have to be taken with food.

Table 1: Dose for paediatric patients (6 years to less than 18 years of age and weighingat least 15 kg) for Atazanavir Krka capsules with ritonavir

Body Weight (kg) Atazanavir Krka once daily dose ritonavir once daily dosea15 to less than 35 200 mg 100 mgat least 35 300 mg 100 mga

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 ageand 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 toconsistently swallow capsules.

When transitioning between formulations, a change in dose may be needed. Consult the dosing tablefor the specific formulation (see Summary of Product Characteristics for other formulations).

No dosage adjustment is needed. Atazanavir Krka with ritonavir is not recommended inpatients undergoing haemodialysis (see sections 4.4 and 5.2).

Atazanavir with ritonavir has not been studied in patients with hepatic impairment. Atazanavir Krkawith ritonavir should be used with caution in patients with mild hepatic impairment. Atazanavir Krkawith ritonavir must not be used in patients with moderate to severe hepatic impairment (see sections4.3, pct. 4.4 and 5.2).

In case of withdrawal of ritonavir from the initial recommended ritonavir-boosted regimen (see section4.4), unboosted Atazanavir Krka could be maintained in patients with mild hepatic impairment at adose of 400 mg, and in patients with moderate hepatic impairment with a reduced dose of 300 mg oncedaily with food (see section 5.2). Unboosted Atazanavir Krka must not be used in patients with severehepatic impairment.

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

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 drugresistance. 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 withmedicinal products known to reduce its exposure (e.g., tenofovir disoproxil or H2-receptorantagonists).

- If tenofovir disoproxil or an H2-receptor antagonist is needed, a dose increase to Atazanavir Krka400 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 arereceiving 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, atazanavirexposures 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 fornon- pregnant patients, including those for co-administration of medicinal products known toaffect 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 concernsespecially taking into account the potential risk of kernicterus.

For oral use. The capsules should be swallowed whole.

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 (seesections 4.2, pct. 4.4 and 5.2). Atazanavir Krka with ritonavir is contraindicated in patientswith moderate hepatic insufficiency (see sections 4.2, pct. 4.4 and 5.2).

Co-administration with simvastatin or lovastatin (see section 4.5).

Combination of the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterialhypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment oferectile 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 (forcaution on parenterally administered midazolam, see section 4.5), lomitapide, and ergot alkaloids,particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5).

Co-administration with medicinal products that are strong inducers of CYP3A4 due to the potentialfor loss of therapeutic effect and development of possible resistance (e.g., rifampicin, St. John'swort, apalutamide, encorafenib, ivosidenib, carbamazepine, phenobarbital and phenytoin) (seesection 4.5).

Co-administration with grazoprevir-containing products, including elbasvir/grazoprevir fixed-dosecombination (see section 4.5).

Co-administration with glecaprevir/pibrentasvir fixed-dose combination (see section 4.5).

Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has not beenclinically 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 withritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could beconsidered. 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 plasmaconcentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). Thesafety and efficacy of atazanavir has not been established in patients with significant underlyingliver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviraltherapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In caseof concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summaryof Product Characteristics for these medicinal products (see section 4.8).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, 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 and5.2).

QT prolongation: Dose-related asymptomatic prolongations in PR interval with atazanavir have beenobserved in clinical studies. Caution should be used with medicinal products known to induce PRprolongations. In patients with pre-existing conduction problems (second degree or higheratrioventricular or complex bundle-branch block), Atazanavir Krka should be used with caution andonly if the benefits exceed the risk (see section 5.1). Particular caution should be used whenprescribing Atazanavir Krka in association with medicinal products which have the potential toincrease 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 skinhaematomas and haemarthroses, in type A and B haemophiliac patients treated with proteaseinhibitors. 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.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to the disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

In clinical studies, atazanavir (with or without ritonavir) has been shown to induce dyslipidaemia to alesser extent than comparators.

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT) have occurred in patients receiving atazanavir (see section 4.8). Hepatictransaminase elevations that occur with elevated bilirubin in patients receiving atazanavir should beevaluated for alternative aetiologies. Alternative antiretroviral therapy to Atazanavir Krka may beconsidered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is notrecommended 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 thesemedicinal 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, ensuringoptimal pharmacokinetic parameters and level of virologic suppression.

The withdrawal of ritonavir from the boosted regimen of Atazanavir Krka is not recommended, butmay be considered in adults patients at the dose of 400 mg once daily with food only under thefollowing 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 backboneregimen containing tenofovir disoproxil and with other concomitant medications that reduceatazanavir bioavailability (see section 4.5 In case of withdrawal of ritonavir from the recommendedatazanavir boosted regimen) or in case of perceived challenging compliance.

Atazanavir Krka given without ritonavir should not be used in pregnant patients given that it couldresult in suboptimal exposure of particular concern for the mother infection and vertical transmission.

Cholelithiasis has been reported in patients receiving atazanavir (see section 4.8). Some patientsrequired hospitalization for additional management and some had complications. If signs or symptomsof cholelithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, hasbeen reported during postmarketing surveillance. A large prospective observational study has shownan association between an increased incidence of chronic kidney disease and cumulative exposure toatazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. Thisassociation was observed independently of exposure to tenofovir disoproxil. Regular monitoring of therenal function of patients should be maintained throughout the treatment duration (see section 4.8).

Nephrolithiasis has been reported in patients receiving atazanavir (see section 4.8). Some patientsrequired 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 symptomsof nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.

In HIV-infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,such reactions have been observed within the first few weeks or months of initiation of CART.

Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections,and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated andtreatment instituted when necessary. Autoimmune disorders (such as Graves' disease and autoimmunehepatitis) have also been reported to occur in the setting of immune reactivation; however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV disease and/or long-term exposure to combinationantiretroviral therapy (CART). Patients should be advised to seek medical advice if they experiencejoint aches and pain, joint stiffness or difficulty in movement.

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeksof starting therapy with atazanavir.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash witheosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receivingatazanavir. Patients should be advised of the signs and symptoms and monitored closely for skinreactions. Atazanavir Krka should be discontinued if severe rash develops.

The best results in managing these events come from early diagnosis and immediate interruption ofany suspect medicines. If the patient has developed SJS or DRESS associated with the use of

Atazanavir Krka, Atazanavir Krka may not be restarted.

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 section4.5). If the co-administration of Atazanavir Krka with an NNRTI is required, an increase in the doseof both Atazanavir Krka and ritonavir to 400 mg and 200 mg, respectively, in combination withefavirenz could be considered with close clinical monitoring.

Atazanavir is metabolised principally by CYP3A4. Co-administration of Atazanavir Krka andmedicinal products that induce CYP3A4 is not recommended (see section 4.5).

PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be used whenprescribing PDE5 inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment of erectiledysfunction in patients receiving Atazanavir Krka. Co-administration of Atazanavir Krka with thesemedicinal 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. Ina small number of patients without a functional CYP2C19 allele, significantly increased voriconazoleexposures are expected (see section 4.5).

Concomitant use of Atazanavir Krka /ritonavir and fluticasone or other glucocorticoids that aremetabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs therisk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (seesection 4.5).

Concomitant use of salmeterol and Atazanavir Krka may result in increased cardiovascular adverseevents associated with salmeterol. Co-administration of salmeterol and Atazanavir Krka is notrecommended (see section 4.5).

The absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective ofcause.

Co-administration of Atazanavir Krka with proton pump inhibitors is not recommended (seesection 4.5). If the combination of Atazanavir Krka with a proton pump inhibitor is judgedunavoidable, close clinical monitoring is recommended in combination with an increase in thedose of Atazanavir Krka to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitorscomparable to omeprazole 20 mg should not be exceeded.

Co-administration of Atazanavir Krka with other hormonal contraceptives or oralcontraceptives containing progestogens other than norgestimate or norethindrone has not beenstudied, and therefore should be avoided (see section 4.5).

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 (seesection 4.8).

Caution should be used with medicinal products known to induce PR prolongations. In paediatricpatients with pre-existing conduction problems (second degree or higher atrioventricular or complexbundle-branch block), Atazanavir Krka should be used with caution and only if the benefits exceed therisk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).

Atazanavir/ritonavir is not effective in viral strains harbouring multiple mutations of resistance.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

When Atazanavir Krka and ritonavir are co-administered, the metabolic drug interaction profile forritonavir 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 Krkais contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeuticindex: quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil,triazolam, orally administered midazolam, lomitapide, and ergot alkaloids, particularly ergotamine anddihydroergotamine (see section 4.3).

Co-administration of atazanavir with grazoprevir-containing products, including elbasvir/grazoprevirfixed-dose combination is contraindicated because of the increase in grazoprevir and elbasvir plasmaconcentrations and potential for the increase in risk of ALT elevations associated with increasedgrazoprevir concentrations (see section 4.3). Co-administration of atazanavir withglecaprevir/pibrentasvir fixed-dose combination is contraindicated because of the potential increase inthe risk of ALT elevations due to a significant increase in glecaprevir and pibrentasvir plasmaconcentrations (see section 4.3).

Interactions between atazanavir and other medicinal products are listed in the table below (increase isindicated as “↑”, decrease as “↓”, no change as “↔”). If available, 90% confidence intervals (CI) areshown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unlessotherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is notthe recommended regimen of atazanavir (see section 4.4).

If withdrawal of ritonavir is medically warranted under restrictive conditions (see section 4.4), specialattention should be given to atazanavir interactions that may differ in the absence of ritonavir (seeinformation below Table 2).

Interactions between atazanavir and other medicinal products, including those for which co-administration is contraindicated, are listed in the table below:

Table 2: Interactions between atazanavir and other medicinal products

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

ANTI-HCV AGENTS

Grazoprevir 200 mg Atazanavir AUC: ↑43% (↑30% Co-administration ofonce daily ↑57%) atazanavir and(atazanavir 300 mg/ Atazanavir cmax: ↑12% (↑1% elbasvir/grazoprevir isritonavir 100 mg once ↑24%) contraindicated because of adaily) Atazanavir cmin: ↑23% (↑13% significant increase in↑134%) grazoprevir plasmaconcentrations and an

Grazoprevir AUC: ↑958% (↑678% associated potential increase↑1339%) in the risk of ALT elevations

Grazoprevir cmax: ↑524% (↑342% (see section 4.3).↑781%)

Grazoprevir cmin: ↑1064% (↑696%↑1602%)

Grazoprevir concentrations weregreatly increased when co-administered withatazanavir/ritonavir.

Elbasvir 50 mg once Atazanavir AUC: ↑7% (↓2%daily ↑17%)(atazanavir 300 mg/ Atazanavir cmax: ↑2% (↓4% ↑8%)ritonavir 100 mg once Atazanavir cmin: ↑15% (↑2%daily) ↑29%)

Elbasvir AUC: ↑376% (↑307%↑456%)

Elbasvir cmax: ↑315% (↑246%↑397%)

Elbasvir cmin: ↑545% (↑451%↑654%)

Elbasvir concentrations wereincreased when co-administeredwith atazanavir/ritonavir.

Sofosbuvir 400 mg/Sofosbuvir AUC: ↑40% (↑25% Co-administration ofvelpatasvir 100 mg ↑57%) atazanavir with voxilaprevir-/voxilaprevir 100 mg Sofosbuvir cmax: ↑29% (↑9% containing products issingle dose* ↑52%) expected to increase the

Velpatasvir AUC: ↑93% (↑58% concentration of voxilaprevir.(atazanavir 300 mg/↑136%) Co-administration ofritonavir 100 mg once Velpatasvir cmax: ↑29% (↑7% atazanavir with voxilaprevir-daily) ↑56%) containing regimens is not

Voxilaprevir AUC: ↑331% recommended.(↑276% ↑393%)

Voxilaprevir cmax: ↑342% (↑265%↑435%)

*Lack of pharmacokineticsinteraction bounds 70-143%

Effect on atazanavir and ritonavirexposure has not been studied.

Expected:↔ Atazanavir↔ Ritonavir

The mechanism of interactionbetween atazanavir/ritonavir andsofosbuvir/velpatasvir/voxilapreviris inhibition of OATP1B, P-gp,and CYP3A.

Glecaprevir 300 mg/Glecaprevir AUC: ↑553% (↑424% Co-administration ofpibrentasvir 120 mg ↑714%) atazanavir withonce daily Glecaprevir cmax: ↑306% (↑215% glecaprevir/pibrentasvir is↑423%) contraindicated because of the(atazanavir 300 mg/Glecaprevir cmin: ↑1330% (↑885% potential increase in the riskritonavir 100 mg once ↑1970%) of ALT elevations due to adaily*) Pibrentasvir AUC: ↑64% (↑48% significant increase in↑82%) glecaprevir and pibrentasvir

Pibrentasvir cmax: ↑29% (↑15% plasma concentrations (see↑45%) section 4.3)

Pibrentasvir cmin: ↑129% (↑95%↑168%)

*Effect of atazanavir and ritonaviron the first dose of glecaprevir andpibrentasvir is reported.

ANTIPLATELETS

Ticagrelor The mechanism of the interaction Co-administration ofis CYP3A4 inhibition by atazanavir with ticagrelor isatazanavir and/or ritonavir. not recommended due topotential increase in theantiplatelet activity ofticagrelor.

Clopidogrel The mechanism of the interaction Co-administration withis CYP3A4 inhibition by clopidogrel is notatazanavir and or/ritonavir. recommended due to potentialreduction of the antiplateletactivity of clopidogrel.

Prasugrel The mechanism of the interaction No dose adjustment is neededis CYP3A4 inhibition by when prasugrel isatazanavir and or/ritonavir. co-administered withatazanavir (with or withoutritonavir).

ANTI-RETROVIRALS

Protease inhibitors: The co-administration of atazanavir /ritonavir and other protease inhibitors has not beenstudied but would be expected to increase exposure to other protease inhibitors. Therefore, such co-administration is not recommended.

Ritonavir 100 mg once daily Atazanavir AUC: ↑250% (↑144% Ritonavir 100 mg once daily is(atazanavir 300 mg once daily) ↑403%)* used as a booster of atazanavir

Atazanavir cmax: ↑120% (↑56% pharmacokinetics.

Studies conducted in ↑211%)*

HIV- infected patients. Atazanavir cmin: ↑713% (↑359%↑1339%)*

*In a combined analysis,atazanavir 300 mg and ritonavir100 mg (n=33) was compared toatazanavir 400 mg withoutritonavir (n=28).

The mechanism of interactionbetween atazanavir and ritonavir is

CYP3A4 inhibition.

Indinavir Indinavir is associated with Co-administration ofindirect unconjugated atazanavir and indinavir is nothyperbilirubinaemia due to recommended (see sectioninhibition of UGT. 4.4).

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

Lamivudine 150 mg twice No significant effect on Based on these data anddaily + zidovudine 300 mg lamivudine and zidovudine because ritonavir is nottwice daily concentrations was observed. expected to have a significant(atazanavir 400 mg once impact on thedaily) pharmacokinetics of NRTIs,the co-administration of thesemedicinal products andatazanavir is not expected tosignificantly alter the exposureof the co-administeredmedicinal products.

Abacavir The co-administration of abacavirand atazanavir is not expected tosignificantly alter the exposure ofabacavir.

Didanosine (buffered tablets) Atazanavir, simultaneous Didanosine should be taken at200 mg/stavudine 40 mg, both administration with ddI+d4T the fasted state 2 hours aftersingle dose (fasted) atazanavir taken with food.(atazanavir 400 mg single dose) Atazanavir AUC: ↓87% (↓92% The co-administration of↓79%) stavudine with atazanavir is

Atazanavir cmax: ↓89% (↓94% not expected to significantly↓82%) alter the exposure of

Atazanavir cmin: ↓84% (↓90% stavudine.

↓73%)

Atazanavir, dosed 1 hr afterddI+d4T (fasted)

Atazanavir AUC: ↔3% (↓36%↑67%)

Atazanavir cmax: ↑12% (↓33%↑18%)

Atazanavir cmin: ↔3% (↓39%↑73%)

Atazanavir concentrations weregreatly decreased when co-administered with didanosine(buffered tablets) and stavudine.

The mechanism of interaction is areduced solubility of atazanavirwith increasing pH related to thepresence of anti-acid agent indidanosine buffered tablets.

No significant effect on didanosineand stavudine concentrations wasobserved.

Didanosine (enteric coated Didanosine (with food)capsules) 400 mg single dose Didanosine AUC ↓34% (↓41%(atazanavir 300 mg once daily ↓27%) Didanosine cmax ↓38%with ritonavir 100 mg once daily) (↓48% ↓26%) Didanosine cmin↑25% (↓8% ↑69%)

No significant effect on atazanavirconcentrations was observed whenadministered with enteric-coateddidanosine, but administration withfood decreased didanosineconcentrations.

Tenofovir disoproxil fumarate Atazanavir AUC: ↓22% (↓35% When co-administered with300 mg once daily ↓6%) * tenofovir disoproxil fumarate,(atazanavir 300 mg once daily Atazanavir cmax: ↓16% (↓30% it is recommended thatwith ritonavir 100 mg once ↔0%) * atazanavir 300 mg be givendaily) Atazanavir cmin: ↓23% (↓43% with ritonavir 100 mg and↑2%) * tenofovir disoproxil fumarate300 mg tenofovir disoproxil 300 mg (all as a single dosefumarate is equivalent to *In a combined analysis from with food).245 mg tenofovir disoproxil several clinical studies,atazanavir/ritonavir 300/100 mg

Studies conducted in co-administered with tenofovir

HIV- infected patients disoproxil fumarate 300 mg (n=39)was compared toatazanavir/ritonavir 300/100 mg(n=33).

The efficacy of atazanavir/ritonavir in combination withtenofovir disoproxil fumarate intreatment- experienced patients hasbeen demonstrated in clinical study045 and in treatment naïve patientsin clinical study 138 (see sections4.8 and 5.1). The mechanism ofinteraction between atazanavir andtenofovir disoproxil fumarate isunknown.

Tenofovir disoproxil fumarate Tenofovir disoproxil fumarate Patients should be closely300 mg once daily AUC: ↑37% (↑30% ↑45%) monitored for tenofovir(atazanavir 300 mg once Tenofovir disoproxil fumarate disoproxil fumarate-associateddaily with ritonavir 100 Cmax: ↑34% (↑20% ↑51%) adverse reactions, includingmg once daily) Tenofovir disoproxil fumarate renal disorders.

Cmin: ↑29% (↑21% ↑36%)300 mg tenofovirdisoproxil fumarate isequivalent to 245 mgtenofovir disoproxil.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz 600 mg once daily Atazanavir (pm): all administered Co-administration of efavirenz(atazanavir 400 mg once daily with food and atazanavir is notwith ritonavir 100 mg once Atazanavir AUC: ↔0% (↓9% recommended (see sectiondaily) ↑10%)* 4.4)

Atazanavir cmax: ↑17% (↑8%↑27%)*

Atazanavir cmin: ↓42% (↓51%↓31%)*

Efavirenz 600 mg once daily Atazanavir (pm): all administered(atazanavir 400 mg once daily withwith ritonavir 200 mg once daily) food

Atazanavir AUC: ↔6% (↓10%↑26%)

*/**

Atazanavir cmax: ↔9% (↓5%↑26%)

*/**

Atazanavir cmin: ↔12% (↓16%↑49%)

*/**

*When compared to atazanavir300 mg/ritonavir 100 mg oncedaily in the evening withoutefavirenz. This decrease inatazanavir cmin, might negativelyimpact the efficacy of atazanavir.

The mechanism ofefavirenz/atazanavir interaction is

CYP3A4 induction.

** Based on historical comparison.

Nevirapine 200 mg twice daily Nevirapine AUC: ↑26% (↑17% Co-administration of(atazanavir 400 mg once daily ↑36%) nevirapine and atazanavir iswith ritonavir 100 mg once daily) Nevirapine cmax: ↑21% (↑11% not recommended (see section↑32%) 4.4)

Study conducted in HIV Nevirapine cmin: ↑35% (↑25%infected patients ↑47%)

Atazanavir AUC: ↓19% (↓35%↑2%) *

Atazanavir cmax: ↔2% (↓15%↑24%) *

Atazanavir cmin: ↓59% (↓73%↓40%) *

*When compared to atazanavir300 mg and ritonavir 100 mgwithout nevirapine. This decreasein atazanavir Cmin, mightnegatively impact the efficacy ofatazanavir. The mechanism ofnevirapine/atazanavir interaction is

CYP3A4 induction.

Integrase Inhibitors

Raltegravir 400 mg twice Raltegravir AUC: ↑41% No dose adjustment requireddaily Raltegravir cmax: ↑24% for raltegravir.(atazanavir/ritonavir) Raltegravir c12hr: ↑77%

The mechanism is UGT1A1inhibition.

ANTIBIOTICS

Clarithromycin 500 mg twice Clarithromycin AUC: ↑94% No recommendation regardingdaily (↑75% dose reduction can be made;(atazanavir 400 mg once ↑116%) therefore, caution should bedaily) Clarithromycin cmax: ↑50% (↑32% exercised if atazanavir is co-↑71%) administered with

Clarithromycin cmin: ↑160% clarithromycin.

(↑135%↑188%)14-OH clarithromycin14-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 clarithromycinmay result in subtherapeuticconcentrations of 14-OHclarithromycin. The mechanism ofthe clarithromycin/atazanavirinteraction is CYP3A4 inhibition.

ANTIFUNGALS

Ketoconazole 200 mg once No significant effect on atazanavir Ketoconazole and itraconazoledaily concentrations was observed. should be used cautiously with(atazanavir 400 mg once daily) atazanavir /ritonavir, highdoses of ketoconazole anditraconazole (>200 mg/day)are not recommended.

Itraconazole Itraconazole, like ketoconazole, isa strong inhibitor as well as asubstrate of CYP3A4.

Based on data obtained with otherboosted PIs and ketoconazole,where ketoconazole AUC showeda 3-fold increase, atazanavir/ritonavir is expected to increaseketoconazole or itraconazoleconcentrations.

Voriconazole 200 mg twice Voriconazole AUC: ↓33% (↓42% Co-administration ofdaily (atazanavir 300 ↓22%) voriconazole and atazanavirmg/ritonavir 100 mg once Voriconazole cmax: ↓10% (↓22% with ritonavir is notdaily) ↓4%) recommended unless an

Voriconazole cmin: ↓39% (↓49% assessment of the benefit/risk

Subjects with at least one ↓28%) to the patient justifies the usefunctional CYP2C19 allele. of voriconazole (see section

Atazanavir AUC: ↓12% (↓18% 4.4).

↓5%

Atazanavir c : ↓13% (↓20% At the time voriconazolemax↓4%) treatment is required, a

Atazanavir cmin: ↓ 20 % (↓28% patient's CYP2C19 genotype↓10%) should be performed iffeasible.

Ritonavir AUC: ↓12% (↓17% Therefore if the combination↓7%) is unavoidable, the following

Ritonavir cmax: ↓9% (↓17% ↔0%) recomendations are madeaccording to the CYP2C19

Ritonavir cmin: ↓25% (↓35%status:

↓14%)

- in patients with at least one

In the majority of patients with atfunctional CYP2C19 allele,least one functional CYP2C19close clinical monitoring for aallele, a reduction in bothloss of both voriconazolevoriconazole and atazanavir(clinical signs) and atazanavirexposures are expected.

(virologic response) efficacy

Voriconazole 50 mg twice Voriconazole AUC: ↑561% is recommended.daily (atazanavir (↑451% ↑699%)300 mg/ritonavir 100 mg once Voriconazole cmax : ↑438% (↑355%

- in patients without adaily) ↑539%) functional CYP2C19 allele,

Voriconazole cmin: ↑765% (↑571% close clinical and laboratory

Subjects without a functional ↑1,020%) monitoring of voriconazole-

CYP2C19 allele. associated adverse events isrecommended.

Atazanavir AUC: ↓20% (↓35%↓3%)

If genotyping is not feasible,

Atazanavir cmax: ↓19% (↓34% full monitoring of safety and↔0.2%)

Atazanavir cmin: ↓ 31 % (↓46 % efficacy should be performed.↓13%)

Ritonavir AUC: ↓11% (↓20%↓1%) Ritonavir cmax: ↓11% (↓24%↑4%) Ritonavir cmin:↓19% (↓35%↑1%)

In a small number of patientswithout a functional CYP2C19allele, significantly increasedvoriconazole exposures areexpected.

Fluconazole 200 mg once daily Atazanavir and fluconazole No dosage adjustments are(atazanavir 300 mg and concentrations were not needed for fluconazole andritonavir 100 mg once significantly modified when atazanavir.daily) atazanavir /ritonavir was co-administered with fluconazole.

ANTIMYCOBACTERIAL

Rifabutin 150 mg twice Rifabutin AUC: ↑48% (↑19% When given with atazanavir,weekly ↑84%) ** the recommended dose of(atazanavir 300 mg and Rifabutin cmax: ↑149% (↑103% rifabutin is 150 mg 3 times perritonavir 100 mg once ↑206%) ** week on set days (for exampledaily) Rifabutin cmin: ↑40% (↑5% ↑87%) Monday-Wednesday-Friday).

** Increased monitoring forrifabutin-associated adverse25-O-desacetyl-rifabutin AUC: reactions including↑990% (↑714% ↑1361%) ** neutropenia and uveitis is25-O-desacetyl-rifabutin c : warranted due to an expectedmax↑677% (↑513% ↑883%) ** increase in exposure to25-O-desacetyl-rifabutin c : rifabutin. Further dosagemin↑1045% (↑715% ↑1510%) ** reduction of rifabutin to 150mg twice weekly on set days

** When compared to rifabutin is recommended for patients150 mg once daily alone. Total in whom the 150 mg dose 3rifabutin and 25-O-desacetyl- times per week is notrifabutin AUC: ↑119% (↑78% tolerated. It should be kept in↑169%). mind that the twice weeklydosage of 150 mg may not

In previous studies, the provide an optimal exposurepharmacokinetics of atazanavir to rifabutin thus leading to awas not altered by rifabutin. risk of rifamycin resistanceand a treatment failure. Nodose adjustment is needed foratazanavir.

Rifampicin Rifampicin is a strong CYP3A4 The combination of rifampicininducer and has been shown to and atazanavir iscause a 72% decrease in atazanavir contraindicated (see section

AUC which can result in 4.3).virological failure and resistancedevelopment. During attempts toovercome the decreased exposureby increasing the dose ofatazanavir or other proteaseinhibitors with ritonavir, a highfrequency of liver reactions wasseen.

ANTIPSYCHOTICS

Quetiapine Due to CYP3A4 inhibition by Co-administration ofatazanavir, concentrations of quetiapine with atazanavir isquetiapine are expected to contraindicated as atazanavirincrease. may increase quetiapine-related toxicity. Increasedplasma concentrations ofquetiapine may lead to coma(see section 4.3).

Lurasidone Atazanavir is expected to increase Co-administration ofplasma levels of lurasidone due to lurasidone with atazanavir is

CYP3A4 inhibition. contraindicated as this mayincrease lurasidone-relatedtoxicity (see section 4.3).

ACID REDUCING AGENTS

H2-Receptor antagonists

Without Tenofovir disoproxil

In HIV-infected patients with atazanavir/ritonavir at the recommended For patients not takingdose 300/100 mg once daily tenofovir disoproxil, if

Famotidine 20 mg twice daily Atazanavir AUC: ↓18% (↓25% atazanavir 300 mg/ritonavir↑1%) 100 mg and H2-receptor

Atazanavir cmax: ↓20% (↓32% antagonists are co-↓7%) administered, a dose

Atazanavir cmin: ↔1% (↓16% equivalent to famotidine 20↑18%) mg twice daily should not be

Famotidine 40 mg twice daily Atazanavir AUC: ↓23% (↓32% exceeded. If a higher dose of↓14%) an H2-receptor antagonist is

Atazanavir c : ↓23% (↓33% required (e.g., famotidine 40max↓12%) mg twice daily or equivalent)

Atazanavir c : ↓20% (↓31% an increase of the atazanavirmin↓8%) /ritonavir dose from 300/100

In healthy volunteers with atazanavir/ritonavir at an increased dose mg to 400/100 mg can beof 400/100 mg once daily considered.

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 For patients who are takingdose of 300/100 mg once daily tenofovir disoproxil, if

Famotidine 20 mg twice daily Atazanavir AUC: ↓21% (↓34% atazanavir/ritonavir with both↓4%)* tenofovir disoproxil and an

Atazanavir cmax: ↓21% (↓36% H2-receptor antagonist are co-↓4%)* administered, a dose increase

Atazanavir cmin: ↓19% (↓37% of atazanavir to 400 mg with↑5%)* 100 mg of ritonavir is

Famotidine 40 mg twice daily Atazanavir AUC: ↓24% (↓36% recommended. A dose↓11%)* equivalent to famotidine 40

Atazanavir c : ↓23% (↓36% mg twice daily should not bemax↓8%)* exceeded.

Atazanavir cmin: ↓25% (↓47%↑7%)*

In HIV-infected patients with atazanavir/ritonavir at an increased doseof 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)*

*When compared to atazanavir300 mg once daily with ritonavir100 mg once daily and tenofovirdisoproxil fumarate 300 mg all asa single dose with food. Whencompared to atazanavir 300 mgwith ritonavir 100 mg withouttenofovir disoproxil, atazanavirconcentrations are expected to beadditionally decreased by about20%.

The mechanism of interaction isdecreased solubility of atazanaviras intra-gastric pH increases with

H2- blockers.

Omeprazole 40 mg once daily Atazanavir (am): 2 hr after Co-administration of(atazanavir 400 mg once daily omeprazole atazanavir with ritonavir andwith ritonavir 100 mg once Atazanavir AUC: ↓61% (↓65% proton pump inhibitors is notdaily) ↓55%) recommended. If the

Atazanavir cmax: ↓66% (↓62% combination is judged↓49%) unavoidable, close clinical

Atazanavir cmin: ↓65% (↓71% monitoring is recommended in↓59%) combination with an increase

Omeprazole 20 mg once daily Atazanavir (am): 1 hr after in the dose of atazanavir to(atazanavir 400 mg once daily with omeprazole 400 mg with 100 mg ofritonavir 100 mg once daily) Atazanavir AUC: ↓30% (↓43% ritonavir; doses of proton↓14%)* pump inhibitors comparable to

Atazanavir c : ↓31% (↓42% omeprazole 20 mg should notmax↓17%)* be exceeded (see section 4.4).

Atazanavir cmin: ↓31% (↓46%↓12%)*

*When compared to atazanavir300 mg once daily with ritonavir100 mg once daily.

The decrease in AUC, cmax, andcmin was not mitigated when anincreased dose of atazanavir/ritonavir (400/100 mg once daily)was temporally separated fromomeprazole by 12 hours. Althoughnot studied, similar results areexpected with other proton pumpinhibitors. This decrease inatazanavir exposure mightnegatively impact the efficacy ofatazanavir. The mechanism ofinteraction is decreased solubilityof atazanavir as intra-gastric pHincreases with proton pumpinhibitors.

Antacids

Antacids and medicinal I Reduced plasma concentrations of I Atazanavir should beproducts containing atazanavir may be the consequence administered 2 hours before orbuffers of increased gastric pH if antacids, 1 hour after antacids orincluding buffered medicinal buffered medicinal products.products, are administered withatazanavir.

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Potential for increased alfuzosin Co-administration of alfuzosinconcentrations which can result in with atazanavir ishypotension. The mechanism of contraindicated (see sectioninteraction is CYP3A4 inhibition 4.3)by atazanavir and/or ritonavir.

ANTICOAGULANTS

Direct-acting oral anticoagulants (DOACs)

Potential for increased apixaban and Co-administration of apixaban

Apixaban rivaroxaban concentrations which or rivaroxaban and atazanavir

Rivaroxabancan result in a higher risk of with ritonavir is notbleeding. recommended

The mechanism of interaction isinhibition of CYP3A4/and P-gp byatazanavir/ritonavir.

Ritonavir is a strong inhibitor ofboth CYP3A4 and P-gp.

Atazanavir is an inhibitor of

CYP3A4. The potential inhibitionof P-gp by atazanavir is unknownand cannot be excluded.

Potential for increased dabigatran Co-administration of dabigatran

Dabigatranconcentrations which can result in a and atazanavir with ritonavir ishigher risk of bleeding. The not recommended.mechanism of interaction is P-gpinhibition.

Ritonavir is a strong P-gp inhibitor.

Potential P-gp inhibition byatazanavir is unknown and cannotbe excluded.

Potential for increased edoxaban Exercise caution when edoxaban

Edoxabanconcentrations which can result in a is used with atazanavir.higher risk of bleeding. Themechanism of interaction is P-gp Please refer to the edoxabaninhibition by atazanavir /ritonavir. SmPC sections 4.2 and 4.5 forappropriate edoxaban dosage

Ritonavir is a strong P-gp inhibitor. recommendations forco-administration with P-gp

Potential P-gp inhibition by inhibitors.atazanavir is unknown and cannotbe excluded.

Warfarin Co-administration with atazanavir It is recommended that thehas the potential to increase or International Normaliseddecrease warfarin concentrations. Ratio (INR) be monitoredcarefully during treatmentwith atazanavir, especiallywhen commencing therapy.

ANTIEPILEPTICS

Carbamazepine Atazanavir may increase plasma Carbamazepine inlevels of carbamazepine due to combination with atazanavir

CYP3A4 inhibition. (with or without ritonavir) iscontraindicated due to the risk

Due to carbamazepine inducing for loss of virologic responseeffect, a reduction in atazanavir and development of resistanceexposure cannot be ruled out. (see section 4.3).

Close monitoring of thepatient's virologic responseshould be excercised.

Phenytoin, phenobarbital Ritonavir may decrease plasma Phenobarbital and phenytoin inlevels of phenytoin and/or combination with atazanavirphenobarbital due to CYP2C9 and (with or without ritonavir), are

CYP2C19 induction. Due tocontraindicated, due to the riskphenytoin/phenobarbital inducingeffect, a reduction in atazanavir for loss of virologic responseexposure cannot be ruled out. and development of resistance(see section 4.3)

Close monitoring of patient'svirologic response should beexercised.

Lamotrigine Co-administration of lamotrigine Lamotrigine should be usedand atazanavir /ritonavir may with caution in combinationdecrease lamotrigine plasma with atazanavir /ritonavir.concentrations due to UGT1A4induction. If necessary, monitorlamotrigine concentrationsand adjust the doseaccordingly.

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS

Antineoplastics

Apalutamide The mechanism of interaction is Co-administration with

CYP3A4 induction by apalutamide atazanavir (with or withoutand CYP3A4 inhibition by ritonavir) is contraindicatedatazanavir/ritonavir. due to the potential fordecreased atazanavir andritonavir plasma concentrationwith subsequent loss ofvirologic response andpossible resistance to the classof protease inhibitors (seesection 4.3). In addition,serum concentrations ofapalutamide may be increasedwhen coadministered withatazanavir/ritonavir, resultingin the potential for seriousadverse events includingseizure.

Encorafenib The mechanism of interaction is Co administration of

CYP3A4 inhibition by atazanavir encorafenib with atazanavirand/or ritonavir. (with or without ritonavir) iscontraindicated due to thepotential for loss of virologicresponse, development ofresistance, increase inencorafenib plasmaconcentration and subsequentrisk of serious adverse eventssuch as QT intervalprolongation (see section 4.3).

Ivosidenib The mechanism of interaction is Co administration of

CYP3A4 inhibition by atazanavir ivosidenib with atazanavirand/or ritonavir. (with or without ritonavir) iscontraindicated due topotential for loss of virologicresponse, development ofresistance, increase inivosidenib plasmaconcentration and subsequentrisk of serious adverse eventssuch as QT intervalprolongation (see section 4.3).

Irinotecan Atazanavir inhibits UGT and may If atazanavir is co-administeredinterfere with the metabolism of with irinotecan, patients shouldirinotecan, resulting in increased be closely monitored for adverseirinotecan toxicities. events related to irinotecan.

Immunosuppressants

Cyclosporin Concentrations of these More frequent therapeutic

Tacrolimus immunosuppressants may be concentration monitoring of

Sirolimus increased when co-administered these medicinal products iswith atazanavir due to CYP3A4 recommended until plasmainhibition. levels have been stabilised.

CARDIOVASCULAR AGENTS

Antiarrhythmics

Amiodarone, Concentrations of these Caution is warranted and

Systemic lidocaine, antiarrhythmics may be increased therapeutic concentration

Quinidine when co-administered with monitoring is recommendedatazanavir. The mechanism of when available. Theamiodarone or systemic concomitant use of quinidinelidocaine/atazanavir interaction is is contraindicated (see section

CYP3A inhibition. Quinidine has a 4.3).narrow therapeutic window and iscontraindicated due to potentialinhibition of CYP3A byatazanavir.

Calcium channel blockers

Bepridil Atazanavir should not be used in Co-administration with bepridilcombination with medicinal is contraindicated (see sectionproducts that are substrates of 4.3)

CYP3A4 and have a narrowtherapeutic index.

Diltiazem 180 mg once daily Diltiazem AUC: ↑125% (↑109% An initial dose reduction of(atazanavir 400 mg ↑141%) diltiazem by 50% isonce daily) Diltiazem cmax: ↑98% (↑78% recommended, with↑119%) subsequent titration as needed

Diltiazem cmin: ↑142% (↑114% and ECG monitoring.

↑173%)

Desacetyl-diltiazem AUC: ↑165%(↑145% ↑187%)

Desacetyl-diltiazem cmax: ↑172%(↑144% ↑203%)

Desacetyl-diltiazem cmin: ↑121%(↑102% ↑142%)

No significant effect on atazanavirconcentrations was observed.

There was an increase in themaximum PR interval compared toatazanavir alone. Co-administration of diltiazem andatazanavir /ritonavir has not beenstudied. The mechanism ofdiltiazem/atazanavir interaction is

CYP3A4 inhibition.

Verapamil Serum concentrations of verapamil Caution should be exercisedmay be increased by atazanavir when verapamil is co-due to CYP3A4 inhibition. administered with atazanavir.

CORTICOSTEROIDS

Dexamethasone and other Co-administration with Co-administration withcorticosteroids (all routes of dexamethasone or other corticosteroids (all routes ofadministration) corticosteroids that induce CYP3A administration) that aremay result in loss of therapeutic metabolized by CYP3A,effect of atazanavir and particularly for long-term use,development of resistance to may increase the risk foratazanavir and/or ritonavir. development of systemic

Alternative corticosteroids should be corticosteroid effects includingconsidered. Cushing’s syndrome and adrenalsuppression. The potential

The mechanism of interaction is benefit of treatment versus the

CYP3A4 induction by risk of systemic corticosteroiddexamethasone and CYP3A4 effects should be considered.inhibition by atazanavir and/orritonavir. For co-administration ofcutaneously administeredcorticosteroids sensitive to

CYP3A inhibition, consult the

Summary of Product

Characteristics of thecorticosteroid for condition oruses that augment its systemicabsorption.

Fluticasone propionate The fluticasone propionate plasma Co-administration ofintranasal 50 µg 4 times daily levels increased significantly, atazanavir/ritonavir and thesefor 7 days whereas the intrinsic cortisol levels glucocorticoids metabolised(ritonavir 100 mg capsules decreased by approximately 86% by CYP3A4 is nottwice daily) (90% confidence interval 82%- recommended unless the89%). Greater effects may be potential benefit of treatment

And expected when fluticasone outweighs the risk of systemicpropionate is inhaled. corticosteroid effects (see

Inhaled/Nasal Systemic corticosteroid effects section 4.4). A dose reduction

Corticosteroids including Cushing’s syndrome and of the glucocorticoid shouldadrenal suppression have been be considered with closereported in patients receiving monitoring of local andritonavir and inhaled or systemic effects or a switch tointranasally administered a glucocorticoid, which is notfluticasone propionate; this could a substrate for CYP3A4 (e.g.,also occur with other beclomethasone). Moreover,corticosteroids metabolised via the in case of withdrawal of

P450 3A pathway, e.g., glucocorticoids, progressivebudesonide. The effects of high dose reduction may have to befluticasone systemic exposure on performed over a longerritonavir plasma levels are yet period.unknown. The mechanism ofinteraction is CYP3A4 inhibition. Concomitant use of

Inhaled/Nasal Corticosteroids

Concomitant use of atazanavir and atazanavir (with or(with or without ritonavir) and without ritonavir) mayother Inhaled/Nasal increase plasma

Corticosteroids is expected to concentrations ofproduce the same effects. Inhaled/Nasal corticosteroids.

Use with caution. Consideralternatives to Inhaled/Nasal

Corticosteroids, particularlyfor long-term use.

ERECTILE DYSFUNCTION

PDE5 Inhibitors

Sildenafil, tadalafil, vardenafil Sildenafil, tadalafil and vardenafil Patients should be warnedare metabolised by CYP3A4. Co- about these possible sideadministration with atazanavir may effects when using PDE5result in increased concentrations inhibitors for erectileof the PDE5 inhibitor and an dysfunction with atazanavirincrease in PDE5-associated (see section 4.4). Also seeadverse events, including PULMONARY ARTERIALhypotension, visual changes, and HYPERTENSION in thispriapism. The mechanism of this table for futher informationinteraction is CYP3A4 inhibition. regarding co- administrationof atazanavir with sildenafil.

GONADOTROPIN RELEASING HORMONE (GnRH) RECEPTOR ANTAGONISTS

Elagolix The mechanism of interaction is Concomitant use of elagolixanticipated increase in elagolix 200 mg twice daily withexposure in the presence of atazanavir (with or without

CYP3A4 inhibition by atazanavir ritonavir) for more thanand/or ritonavir. 1 month is not recommendeddue to the potential risk ofadverse events such as boneloss and hepatic transaminaseelevations. Limit concomitantuse of elagolix 150 mg oncedaily with atazanavir (with orwithout ritonavir) to6 months.

KINASE INHIBITORS

Fostamatinib The mechanism of interaction is Concomitant use of

CYP3A4 inhibition by atazanavir fostamatinib with atazanavirand/or ritonavir. (with or without ritonavir)may increase the plasmaconcentration of R406, theactive metabolite offostamatinib. Monitor fortoxicities of R406 exposureresulting in dose-relatedadverse events such ashepatotoxicity andneutropenia. Fostamatinibdose reduction may berequired.

HERBAL PRODUCTS

St. John’s wort (Hypericum Concomitant use of St. John's wort Co-administration ofperforatum) with atazanavir may be expected to atazanavir with productsresult in significant reduction in containing St. John's wort isplasma levels of atazanavir. This contraindicated.effect may be due to an inductionof CYP3A4. There is a risk of lossof therapeutic effect anddevelopment of resistance (seesection 4.3).

HORMONAL CONTRACEPTIVES

Ethinyloestradiol 25 μg + Ethinyloestradiol AUC: ↓19% If an oral contraceptive isnorgestimate (↓25% ↓13%) administered with(atazanavir 300 mg once daily Ethinyloestradiol cmax: ↓16% atazanavir/ritonavir, it iswith ritonavir 100 mg once (↓26% ↓5%) recommended that the oraldaily) Ethinyloestradiol cmin: ↓37% contraceptive contain at least(↓45% ↓29%) 30 μg of ethinyloestradiol andthat the patient be reminded of

Norgestimate AUC: ↑85% (↑67% strict compliance with this↑105%) contraceptive dosing regimen.

Norgestimate cmax: ↑68% (↑51% Co-administration of↑88%) atazanavir /ritonavir with

Norgestimate cmin: ↑102% (↑77% other hormonal contraceptives↑131%) or oral contraceptivescontaining progestogens other

While the concentration of than norgestimate has notethinyloestradiol was increased been studied, and thereforewith atazanavir given alone, due to should be avoided. Anboth UGT and CYP3A4 inhibition alternate reliable method ofby atazanavir, the net effect of contraception isatazanavir/ritonavir is a decrease in recommended.ethinyloestradiol levels because ofthe inducing effect of ritonavir.

The increase in progestin exposuremay lead to related side-effects(e.g. insulin resistance,dyslipidemia, acne and spotting),thus possibly affecting thecompliance.

Ethinyloestradiol 35 µg + Ethinyloestradiol AUC: ↑48%norethindrone (↑31% ↑68%)(atazanavir 400 mg once daily) Ethinyloestradiol cmax: ↑15% (↓1%↑32%)

Ethinyloestradiol cmin: ↑91%(↑57% ↑133%)

Norethindrone AUC: ↑110%(↑68%↑162%)

Norethindrone cmax: ↑67% (↑42%↑196%)

Norethindrone cmin: ↑262%(↑157%↑409%)

The increase in progestin exposuremay lead to related side-effects(e.g. insulin resistance,dyslipidemia, acne and spotting),thus possibly affecting thecompliance.

LIPID-MODIFYING AGENTS

HMG-CoA reductase inhibitors

Simvastatin Simvastatin and lovastatin are Co-administration of

Lovastatin highly dependent on CYP3A4 for simvastatin or lovastatin withtheir metabolism and co- atazanavir is contraindicatedadministration with atazanavir may due to an increased risk ofresult in increased concentrations. myopathy includingrhabdomyolysis (see section4.3).

Atorvastatin The risk of myopathy including Co-administration ofrhabdomyolysis may also be atorvastatin with atazanavir isincreased with atorvastatin, which not recommended. If the useis also metabolised by CYP3A4. of atorvastatin is consideredstrictly necessary, the lowestpossible dose of atorvastatinshould be administered withcareful safety monitoring (seesection 4.4).

Pravastatin Although not studied, there is a Caution should be exercised.

Fluvastatin potential for an increase inpravastatin or fluvastatin exposurewhen co- administered withprotease inhibitors. Pravastatin isnot metabolised by CYP3A4.

Fluvastatin is partially metabolisedby CYP2C9.

Other lipid-modifying agents

Lomitapide Lomitapide is highly dependent on Co-administration of

CYP3A4 for metabolism and co- lomitapide and atazanaviradministration with atazanavir with ritonavir iswith ritonavir may result in contraindicated due to aincreased concentrations. potential risk of markedlyincreased transaminase levelsand hepatotoxicity (seesection 4.3).

INHALED BETA AGONISTS

Salmeterol Co-administration with atazanavir Co-administration ofmay result in increased salmeterol with atazanavir isconcentrations of salmeterol and not recommended (see sectionan increase in salmeterol- 4.4).associated adverse events.

The mechanism of interaction is

CYP3A4 inhibition by atazanavirand/or ritonavir.

OPIOIDS

Buprenorphine, once daily, Buprenorphine AUC: ↑67% Co-administration withstable maintenance dose Buprenorphine cmax: ↑37% atazanavir with ritonavir(atazanavir 300 mg once daily Buprenorphine cmin: ↑69% warrants clinical monitoringwith ritonavir 100 mg once for sedation and cognitivedaily) Norbuprenorphine AUC: ↑105% effects. A dose reduction of

Norbuprenorphine c : ↑61% buprenorphine may bemax

Norbuprenorphine cmin: ↑101% considered.

The mechanism of interaction is

CYP3A4 and UGT1A1 inhibition.

Concentrations of atazanavir(when given with ritonavir) werenot significantly affected.

Methadone, stable No significant effect on methadone No dosage adjustment ismaintenance dose concentrations was observed. necessary if methadone is co-(atazanavir 400 mg once daily) Given that low dose ritonavir (100 administered with atazanavir.

mg twice daily) has been shown tohave no significant effect onmethadone concentrations, nointeraction is expected ifmethadone is co- administeredwith atazanavir, based on thesedata.

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil Co-administration with atazanavir A safe and effective dose inmay result in increased combination with atazanavirconcentrations of the PDE5 has not been established forinhibitor and an increase in PDE5- sildenafil when used to treatinhibitor-associated adverse events. pulmonary arterialhypertension. Sildenafil, when

The mechanism of interaction is used for the treatment of

CYP3A4 inhibition by atazanavir pulmonary arterialand/or ritonavir. hypertension, iscontraindicated (see section4.3).

SEDATIVES

Benzodiazepines

Midazolam Midazolam and triazolam are Co-administration of

Triazolam extensively metabolised by atazanavir with triazolam or

CYP3A4. Co-administration with orally administeredatazanavir may cause a large midazolam is contraindicatedincrease in the concentration of (see section 4.3), whereasthese benzodiazepines. No drug caution should be used withinteraction study has been co- administration ofperformed for the co- atazanavir and parenteraladministration of atazanavir with midazolam. If atazanavir isbenzodiazepines. Based on data for co-administered withother CYP3A4 inhibitors, plasma parenteral midazolam, itconcentrations of midazolam are should be done in an intensiveexpected to be significantly higher care unit (ICU) or similarwhen midazolam is given orally. setting which ensures close

Data from concomitant use of clinical monitoring andparenteral midazolam with other appropriate medicalprotease inhibitors suggest a management in case ofpossible 3-4 fold increase in respiratory depression and/ormidazolam plasma levels. prolonged sedation. Dosageadjustment for midazolamshould be considered,especially if more than asingle dose of midazolam isadministered.

In case of withdrawal of ritonavir from the recommended atazanavir-boosted regimen (see section 4.4)

The same recommendations for drug interactions would apply except:

- that co-administration is not recommended with tenofovir, proton pump inhibitors, andbuprenorphine and contraindicated with carbamazepine, phenytoin and phenobarbital.

- that co-administration with famotidine is not recommended but if required, atazanavir withoutritonavir should be administered either 2 hours after famotidine or 12 hours before. No singledose of famotidine should exceed 20 mg, and the total daily dose of famotidine should notexceed 40 mg.

- the need to consider that

- co-administration of apixaban, dabigatran, or rivaroxaban and atazanavir withoutritonavir may affect apixaban, dabigatran, or rivaroxaban concentrations

- co-administration of voriconazole and atazanavir without ritonavir may affect atazanavirconcentrations

- co-administration of fluticasone and atazanavir without ritonavir may increase fluticasoneconcentrations relative to fluticasone given alone

- if an oral contraceptive is administered with atazanavir without ritonavir, it isrecommended that the oral contraceptive contain no more than 30 µg of ethinyloestradiol

- no dose adjustment of lamotrigine is required

Interaction studies have only been performed in adults.

A moderate amount of data in pregnant women (between 300-1000 pregnancy outcomes)indicate no malformative toxicity of atazanavir. Animal studies do not indicate reproductivetoxicity (see section 5.3). The use of Atazanavir Krka with ritonavir may be consideredduring 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 combinationwith zidovudine/lamivudine was administered to 41 pregnant women during the second or thirdtrimester. 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 notinclude atazanavir) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6months postpartum. Three of 20 infants (15%) born to women treated with atazanavir /ritonavir300/100 mg and four of 20 infants (20%) born to women treated with atazanavir /ritonavir 400/100mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40infants in this study received phototherapy for a maximum of 4 days. There were no reported cases ofkernicterus 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 willexacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In theprepartum period, additional monitoring should be considered.

Atazanavir has been detected in human milk. In order to avoid transmission of HIV to the infant it isrecommended that women living with HIV do not breast-feed their infants.

In a nonclinical fertility and early embryonic development study in rats, atazanavir altered oestruscycling with no effects on mating or fertility (see section 5.3).

Patients should be informed that dizziness has been reported during treatment with regimenscontaining atazanavir (see section 4.8).

Atazanavir has been evaluated for safety in combination therapy with other antiretroviral medicinalproducts 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 mgwith ritonavir 100 mg once daily (655 patients, 96 weeks median duration and 108 weeks maximumduration).

Adverse reactions were consistent between patients who received atazanavir 400 mg once daily andpatients who received atazanavir 300 mg with ritonavir 100 mg once daily, except that jaundice andelevated total bilirubin levels were reported more frequently with atazanavir plus ritonavir.

Among patients who received atazanavir 400 mg once daily or atazanavir 300 mg with ritonavir 100mg once daily, the only adverse reactions of any severity reported very commonly with at least apossible 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 100mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported within a fewdays 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, hasbeen reported during postmarketing surveillance. A large prospective observational study has shownan association between an increased incidence of chronic kidney disease and cumulative exposure toatazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. Thisassociation was observed independently of exposure to tenofovir disoproxil. Regular monitoring of therenal function of patients should be maintained throughout the treatment duration (see section 4.4).

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), veryrare (< 1/10 000). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness.

Immune system disorders: uncommon: hypersensitivity

Metabolism and nutrition uncommon: weight decreased, weight gain, anorexia, appetite increaseddisorders

Psychiatric disorders: uncommon: depression, disorientation, anxiety, insomnia, sleepdisorder, 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 pointesarare: QTc prolongationa, oedema, palpitation

Vascular disorders: uncommon: hypertension

Respiratory, thoracic and uncommon: dyspnoeamediastinal disorders

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

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

Skin and subcutaneous tissue common: rash;disorders: uncommon: erythema multiformea,b, toxic skin eruptionsa,b, drug rashwith eosinophilia and systemic symptoms (DRESS) syndromea,b,angioedemaa, urticaria, alopecia, pruritus;rare: Stevens-Johnson syndromea,b, vesiculobullous rash, eczema,vasodilatation

Musculoskeletal and connective uncommon: muscle atrophy, arthralgia, myalgia;tissue disorders rare: myopathy

Renal and urinary disorders: uncommon: nephrolithiasis, haematuria, proteinuria, pollakiuria,interstitial nephritis; chronic kidney diseasearare: kidney pain

Reproductive system and breast uncommon: gynaecomastiadisorders:

General disorders and common: fatigue;administration site conditions: uncommon: chest pain, malaise, pyrexia, asthenia;rare: gait disturbanceaThese adverse reactions were identified through post-marketing surveillance, however, the frequencies were estimated froma statistical calculation based on the total number of patients exposed to atazanavir in randomised controlled and otheravailable clinical trials (n = 2321).bSee description of selected adverse reactions for more details.

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections 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 canoccur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).

The frequency of this is unknown (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4).

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeksof starting therapy with atazanavir.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions, and drug rash witheosinophilia and systemic symptoms (DRESS) syndrome have been reported with the use ofatazanavir (see section 4.4).

The most frequently reported laboratory abnormality in patients receiving regimens containingatazanavir and one or more NRTIs was elevated total bilirubin reported predominantly as elevatedindirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubinwas noted in 37% (6% Grade 4). Among experienced patients treated with atazanavir 300 mg oncedaily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3-4 totalbilirubin elevations. Among naïve patients treated with atazanavir 300 mg once daily with 100 mgritonavir 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 receivingregimens containing atazanavir and one or more NRTIs included: elevated creatine kinase (7%),elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), lowneutrophils (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 Grade3-4 total bilirubin elevations.

In a clinical study AI424-020, paediatric patients 3 months to less than 18 years of age who receivedeither the oral powder or capsule formulation had a mean duration of treatment with atazanavir of115 weeks. The safety profile in this study was overall comparable to that seen in adults. Bothasymptomatic first-degree (23%) and second-degree (1%) atrioventricular block were reported inpaediatric patients. The most frequently reported laboratory abnormality in paediatric patientsreceiving atazanavir was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4) which occurred in45% of patients.

In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of agehad 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 adultstudies. The most frequently reported laboratory abnormalities in paediatric patients receivingatazanavir oral powder was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) andincreased amylase (Grade 3-4; 33%), generally of non-pancreatic origin. Elevation in ALT levels weremore frequently reported in paediatric patients in these studies than in adults.

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 withchronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily withritonavir 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 thosewithout chronic viral hepatitis. No differences in frequency of bilirubin elevations were observedbetween these patients and those without viral hepatitis. The frequency of treatment emergenthepatitis or transaminase elevations in co-infected patients was comparable between atazanavirand comparator regimens (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Human experience of acute overdose with atazanavir is limited. Single doses up to 1,200 mg havebeen taken by healthy volunteers without symptomatic untoward effects. At high doses that lead tohigh drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associatedliver 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, includingmonitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinicalstatus. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastriclavage. 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 extensivelymetabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significantremoval of this medicinal product.

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE08.

Atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits thevirus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formationof mature virions and infection of other cells.

Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2activity in cell culture.

Antiretroviral treatment naïve adult patients

In clinical trials of antiretroviral treatment naïve patients treated with unboosted atazanavir, the I50Lsubstitution, sometimes in combination with an A71V change, is the signature resistance substitutionfor atazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence ofphenotypic cross resistance to other PIs. In clinical trials of antiretroviral treatment naïve patientstreated 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 onatazanavir (with or without ritonavir). While it may contribute to decreased susceptibility toatazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself doesnot always lead to phenotypic resistance to atazanavir or have a consistent impact on clinicalefficacy.

Table 3: De novo substitutions in treatment naïve patients failing therapy with atazanavir +ritonavir (Study 138, 96 weeks)

Frequency de novo PI substitution (n=26)a>20% none10-20% nonea

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 virologicfailure patients, respectively.

Antiretroviral treatment experienced adult patients

In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates frompatients designated as virological failures on therapy that included either atazanavir, atazanavir +ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Ofthe 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%)displayed the I50L phenotype previously described in naïve 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, V8210-20% L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90a

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 cellculture 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-experiencedpopulation.

The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of themajor and minor resistance substitutions described previously to be involved in protease inhibitorresistance.

In antiretroviral naïve adult patients

Study 138 is an international randomised, open-label, multicenter, prospective trial of treatment naïvepatients comparing atazanavir /ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400mg/100 mg twice daily), each in combination with fixed-dose tenofovir disoproxilfumarate/emtricitabine (300 mg/200 mg tablets once daily). The atazanavir /ritonavir arm showedsimilar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by theproportion 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 138aatazanavir /ritonavirb (300 mg/100 mg Lopinavir/ritonavirc (400 mg/100 mgonce daily) n=440 twice daily) n=443

Week 48 Week 96 Week 48 Week 96

HIV RNA <50 copies/mL, %

All patientsd 78 74 76 68

Difference estimate Week 48: 1.7% [-3.8%, 7.1%][95% CI]d Week 96: 6.1% [0.3%, 12.0%]

Per protocol f 91 89 89e 86 (n=392 )analysis (n=352) (n=372) (n=331)

Difference Week 48: -3% [-7.6%, 1.5%]estimatee Week 96: 2.2% [-2.3%, 6.7%][95% CI]

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

HIV RNA<100,000 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218)copies/mL≥100,00074 (n=223) 74 (n=223) 72 (n=225) 66 (n=225)copies/mL

CD4 count78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48)<50 cells/mm350 to <1003 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29)cells/mm100 to <2003 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134)cells/mm≥ 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<100,000 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152)copies/mL≥100,000227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165)copies/mLa Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was4.94 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 withatazanavir 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted atazanavir 400 mg oncedaily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviralefficacy compared with atazanavir + ritonavir and two NRTIs (n=85) in HIV-infected subjects withfully suppressed HIV replication, as assessed by the proportion of subjects with HIV RNA < 50copies/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 + ritonavirgroup, had virologic rebound. Four subjects in the unboosted atazanavir group and 2 in theatazanavir + ritonavir group had HIV RNA > 500 copies/mL during the maintenance phase. Nosubject in either group showed emergence of protease inhibitor resistance. The M184V substitutionin reverse transcriptase, which confers resistance to lamivudine and emtricitabine, was detected in 2subjects 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 inthe atazanavir + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboostedatazanavir 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-dosecombination twice daily), each in combination with tenofovir disoproxil (see sections 4.5 and 4.8) andone 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 138weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients werereceiving 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 moreof the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty-two percent of patients in the studyhad a viral strain with fewer than two NRTI substitutions.

The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through48 weeks (Table 6).

Table 6: Efficacy Outcomes at Week 48a and at Week 96 (Study 045)

Parameter c

ATV/RTVb LPV/RTV (400 mg/(300 mg/ Time-averaged difference100 mg once daily 100 mg twice daily ATV/RTV-LPV/RTV(n=120) (n=123) [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 -2.29 -1.87 -2.08 0.13 0.14(n=90e) (n=64) (n=99) (n=65) [-0.12, 0.39] [-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 NA3 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 NAa 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 treatmentbefore Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/mL were53% 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 obtainedwith 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, theproportions 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 + ritonavirand lopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistentresults were obtained with the last observation carried forward method of analysis. By as-treatedanalysis, 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 were82% (72%). It is important to note that at time of the 96-week analysis, 48 % of patients overallremained on study.

Atazanavir + saquinavir was shown to be inferior to lopinavir + ritonavir.

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of atazanavir is based ondata from the open-label, multicenter clinical trial AI424-020 conducted in patients from 3months to 21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naïveand 101 antiretroviral-experienced) received once daily atazanavir (capsule or powderformulation), 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 receivedatazanavir capsules with ritonavir are presented in Table 7. For treatment-naïve paediatric patients, themean baseline CD4 cell count was 344 cells/mm3 (range: 2 to 800 cells/ mm3) and mean baselineplasma 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 to1157 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.09 log10 copies/mL (range: 3.28 to 5.00log10 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- Naïve atazanavir Treatment- Experienced

Capsules/ritonavir (300 mg/100 atazanavirmg once daily) Capsules/ritonavir (300 mg/100n=16 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.

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infectedpatients; significant differences were observed between the two groups. The pharmacokinetics ofatazanavir exhibit a non-linear disposition.

Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of atazanavir 300 mgonce daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) foratazanavir, cmax of 4466 (42%) ng/mL, with time to cmax of approximately 2.5 hours. The geometricmean (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 dailywith food produced a geometric mean (CV%) for atazanavir cmax of 2298 (71) ng/mL, with time to cmaxof 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.

Food effect: co-administration of atazanavir and ritonavir with food optimises the bioavailability ofatazanavir. Co-administration of a single 300 mg dose of atazanavir and 100 mg dose of ritonavir witha light meal resulted in a 33% increase in the AUC and a 40% increase in both the cmax and the 24 hourconcentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal did notaffect the AUC of atazanavir relative to fasting conditions and the cmax was within 11% of fastingvalues. The 24 hour concentration following a high fat meal was increased by approximately 33% dueto delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Administration of atazanavirwith ritonavir with either a light or a high fat meal decreased the coefficient of variation of AUC andcmax by approximately 25% compared to the fasting state. To enhance bioavailability and minimisevariability, atazanavir is to be taken with food.

Distribution: atazanavir was approximately 86% bound to human serum proteins over a concentrationrange of 100 to 10,000 ng/mL. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albuminto 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, atazanavirwas detected in the cerebrospinal fluid and semen.

Metabolism: studies in humans and in vitro studies using human liver microsomes have demonstratedthat atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolitesare then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolicpathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasmahave 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 radioactivitywas 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 ofunchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adultpatients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was 12hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a lightmeal.

Renal impairment: in healthy subjects, the renal elimination of unchanged atazanavir was approximately7% of the administered dose. There are no pharmacokinetic data available for atazanavir with ritonavirin patients with renal insufficiency. atazanavir (without ritonavir) has been studied in adult patientswith severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mgonce daily. Although this study presented some limitations (i.e., unbound drug concentrations notstudied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to50% in patients undergoing haemodialysis compared to patients with normal renal function. Themechanism 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. Themean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours inhealthy subjects. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavirare expected to be increased in patients with moderately or severely impaired hepatic function (seesections 4.2, pct. 4.3, and 4.4).

Age/Gender: a study of the pharmacokinetics of atazanavir was performed in 59 healthy male andfemale subjects (29 young, 30 elderly). There were no clinically important pharmacokineticdifferences based on age or gender.

Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated noeffect of race on the pharmacokinetics of atazanavir.

The pharmacokinetic data from HIV-infected pregnant women receiving atazanavir capsules withritonavir are presented in Table 8.

Table 8: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected

Pregnant Women in the Fed State

I I atazanavir 300 mg with ritonavir 100 mg I

Pharmacokinetic 2nd Trimester 3rd Trimester postpartuma

Parameter (n=9) (n=20) (n=36)

Cmax ng/mL 3729.09 3291.46 5649.10

Geometric mean (CV%) (39) (48) (31)

AUC ng*h/mL 34399.1 34251.5 60532.7

Geometric mean (CV%) (37) (43) (33)

Cmin ng/mLb663.78 668.48 1420.64

Geometric mean (CV%) (36) (50) (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 concentrationswere approximately 2-fold higher during the postpartum period when compared to those observed historically in HIV-infectednon-pregnant patients.b Cmin is concentration 24 hours post-dose

There is a trend toward a higher clearance in younger children when normalised for body weight. As aresult, greater peak to trough ratios are observed; however at recommended doses, geometric meanatazanavir exposures (cmin, cmax, and AUC) in paediatric patients are expected to be similar to thoseobserved in adults.

In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings weregenerally confined to the liver and included generally minimal to mild increases in serum bilirubin andliver 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 withhepatic changes were at least equal to that observed in humans given 400 mg once daily. In femalemice, atazanavir exposure at a dose that produced single-cell necrosis was 12 times the exposure inhumans given 400 mg once daily. Serum cholesterol and glucose were minimally to mildly increasedin rats but not in mice or dogs.

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at aconcentration (30 μM) of atazanavir corresponding to 30-fold the free drug concentration at cmax inhumans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90)in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PRinterval, prolongation of QT interval, and prolongation of QRS complex) were observed only in aninitial 2-week oral toxicity study performed in dogs. Subsequent 9-month oral toxicity studies in dogsshowed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical datais unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4and 4.8). The potential for PR prolongation should be considered in cases of overdose (see section4.9).

In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with noeffects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxicdoses. In pregnant rabbits, gross lesions of the stomach and intestines were observed in dead ormoribund 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 atransient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure toatazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than thatobserved in humans given 400 mg once daily.

Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrationsin vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavirdid 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 benignhepatic adenomas was seen in female mice only. The increased incidence of benign hepatic adenomasin female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis andis considered to have no relevance for humans at intended therapeutic exposures. There were notumorigenic findings in male mice or in rats.

Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it maybe an ocular irritant upon direct contact with the eye.

Capsule contentslactose monohydratecrospovidone (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)gelatineink:

shellacblack 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)gelatineink:

shellacblack ferric oxide (E172)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)gelatineink:

shellactitanium dioxide (E171)potassium hydroxide

Not applicable.

3 years

Shelf life after first opening is 2 months, stored below 25°C.

Store below 30°C.

Keep the container tightly closed in order to protect from moisture.

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 capsulesand 90 (3 x 30) hard capsules, in a box.

Not all pack sizes may be marketed.

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

150 mg hard capsules:60 hard capsules: EU/1/19/1353/001200 mg hard capsules:60 hard capsules: EU/1/19/1353/002300 mg hard capsules:30 hard capsules: EU/1/19/1353/00390 (3 x 30) hard capsules: EU/1/19/1353/004

Date of first authorisation: 25 March 2019

Detailed information on this medicinal product is available on the website of the European Medicines

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