ATAZANAVIR VIATRIS 300mg capsules medication leaflet

Atazanavir Viatris 150 mg hard capsules

Atazanavir Viatris 200 mg hard capsules

Atazanavir Viatris 300 mg hard capsules

150 mg capsules

Each capsule contains 150 mg atazanavir (as sulphate)200 mg capsules

Each capsule contains 200 mg atazanavir (as sulphate)300 mg capsules

Each capsule contains 300 mg atazanavir (as sulphate)

Excipient(s) with known effect150 mg capsules

Each capsule contains 84 mg lactose monohydrate200 mg capsules

Each capsule contains 112 mg lactose monohydrate300 mg capsules

Each capsule contains 168 mg lactose monohydrate

For the full list of excipients, see section 6.1.

Hard capsule150 mg capsules

Atazanavir Viatris 150 mg capsules are greenish-blue and blue opaque hard shell gelatin capsules filled withwhite to pale yellow powder and approximately 19.3 mm in length. The capsules are axially printed with‘MYLAN’ over ‘AR150’ in black ink on cap and body.

200 mg capsules

Atazanavir Viatris 200 mg capsules are blue and greenish-blue opaque hard shell gelatin capsules filled withwhite to pale yellow powder and approximately 21.4 mm in length. The capsules are axially printed with‘MYLAN’ over ‘AR200’ in black ink on cap and body.

300 mg capsules

Atazanavir Viatris 300 mg capsules are red and greenish-blue opaque hard shell gelatine capsules filled withwhite to pale yellow powder and approximately 23.5 mm in length. The capsules are axially printed with‘MYLAN’ over ‘AR300’ in black ink on cap and body.

Atazanavir Viatris, co-administered with low dose ritonavir, is indicated for the treatment of HIV-1-infectedadults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinalproducts (see section 4.2).

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

The choice of Atazanavir Viatris in treatment-experienced adult and paediatric patients should be based onindividual 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 is 300 mg once daily taken with ritonavir 100 mg once daily and withfood. Ritonavir is used as a booster of atazanavir pharmacokinetics (see sections 4.5 and 5.1). See alsosection 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 atazanavircapsules for paediatric patients is based on body weight as shown in Table 1 and should not exceed therecommended adult dose. Atazanavir Viatris capsules must be taken with ritonavir and have to be taken withfood.

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

Body Weight (kg) Atazanavir Viatris once daily ritonavir once daily doseadose15 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 medicinemay be available for paediatric patients at least 3 months of age and weighing at least 5 kg (see relevant

Summary of Product Characteristics for alternative forms). Switching to capsules from other formulations isencouraged as soon as patients are able to consistently swallow capsules.

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

No dosage adjustment is needed. Atazanavir Viatris with ritonavir is not recommended in patientsundergoing haemodialysis (see sections 4.4, and 5.2).

Atazanavir with ritonavir has not been studied in patients with hepatic impairment. Atazanavir Viatris withritonavir should be used with caution in patients with mild hepatic impairment. Atazanavir Viatris withritonavir must not be used in patients with moderate to severe hepatic impairment (see sections pct. 4.3, pct. 4.4, and5.2).

In case of withdrawal of ritonavir from the initial recommended ritonavir-boosted regimen (see section 4.4),unboosted atazanavir could be maintained in patients with mild hepatic impairment at a dose of 400 mg andin patients with moderate hepatic impairment with a reduced dose of 300 mg once daily with food (seesection 5.2). Unboosted atazanavir must not be used in patients with severe hepatic impairment.

During the second and third trimesters of pregnancy:

Atazanavir 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, especially whenthe activity of atazanavir or the whole regimen may be compromised due to drug resistance. Since there arelimited data available and due to inter-patient variability during pregnancy, Therapeutic Drug Monitoring(TDM) may be considered to ensure adequate exposure.

The risk of a further decrease in atazanavir exposure is expected when atazanavir is given with medicinalproducts known to reduce its exposure (e.g., tenofovir disoproxil or H2-receptor antagonists).

* If tenofovir disoproxil or an H2-receptor antagonist is needed, a dose increase to atazanavir 400 mg withritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2).

* It is not recommended to use atazanavir with ritonavir for pregnant patients who are receiving bothtenofovir 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, postpartumpatients should be closely monitored for adverse reactions.

* During this time, postpartum patients should follow the same dose recommendation as for non-pregnant patients, including those for co-administration of medicinal products known to affectatazanavir exposure (see section 4.5).

Paediatric patients (less than 3 months of age)

Atazanavir Viatris should not be used in children less than 3 months because of safety concerns especiallytaking 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 Viatris is contraindicated in patients with severe hepatic insufficiency (see sections 4.2, pct. 4.4 and5.2). Atazanavir Viatris with ritonavir is contraindicated in patients with moderate hepatic insufficiency (seesections 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 arterial hypertension(PAH) only (see section 4.5). For co-administration of sildenafil for the treatment of erectile dysfunction seesections 4.4 and 4.5.

Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450and have narrow therapeutic windows (e.g., quetiapine, lurasidone, alfuzosin, astemizole, terfenadine,cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution onparenterally 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 potential for lossof therapeutic effect and development of possible resistance (e.g., rifampicin, St. John's wort, apalutamide,encorafenib, ivosidenib, carbamazepine, phenobarbital and phenytoin) (see section 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 been clinicallyevaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects,hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir with ritonavir isco-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be considered. In thisinstance, close clinical monitoring is warranted (see Interaction with other Medicinal Products below).

Patients with coexisting conditions

Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed inpatients with hepatic impairment (see sections 4.2 and 4.3). The safety and efficacy of atazanavir has notbeen established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or Cand treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatalhepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also tothe relevant Summary of Product Characteristics for these medicinal products (see section 4.8).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequencyof liver function abnormalities during combination antiretroviral therapy and should be monitored accordingto standard practice. If there is evidence of worsening liver disease in such patients, interruption ordiscontinuation of treatment must be considered.

No dosage adjustment is needed in patients with renal impairment. However, Atazanavir Viatris is notrecommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).

Dose-related asymptomatic prolongations in PR interval with atazanavir have been observed in clinicalstudies. Caution should be used with medicinal products known to induce PR prolongations. In patients withpre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branchblock), Atazanavir Viatris should be used with caution and only if the benefits exceed the risk (see section5.1). Particular caution should be used when prescribing Atazanavir Viatris in association with medicinalproducts which have the potential to increase the QT interval and/or in patients with pre-existing risk factors(bradycardia, long congenital QT, electrolyte imbalances (see sections 4.8 and 5.3).

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses,in type A and B haemophiliac patients treated with protease inhibitors. In some patients additional factor

VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued orreintroduced if treatment had been discontinued. A causal relationship has been suggested, although themechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of thepossibility of increased bleeding.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Suchchanges may in part be linked to the disease control and life style. For lipids, there is in some cases evidencefor a treatment effect, while for weight gain there is no strong evidence relating this to any particulartreatment. For monitoring of blood lipids and glucose reference is made to established HIV treatmentguidelines. Lipid disorders should be managed as clinically appropriate.

In clinical studies, atazanavir with ritonavir has been shown to induce dyslipidaemia to a lesser extent thanlopinavir with ritonavir in either treatment-naïve patients (Study 138) or treatment experienced patients(Study 045), (see section 5.1).

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT) have occurred in patients receiving atazanavir (see section 4.8). Hepatic transaminaseelevations that occur with elevated bilirubin in patients receiving Atazanavir Viatris should be evaluated foralternative aetiologies. Alternative antiretroviral therapy to Atazanavir Viatris may be considered if jaundiceor scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not recommended because itmay result in a loss of therapeutic effect and development of resistance.

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

Combinations of atazanavir and indinavir have not been studied and co-administration of these medicinalproducts is not recommended (see section 4.5).

Withdrawal of ritonavir only under restrictive conditions

The recommended standard treatment is atazanavir boosted with ritonavir, ensuring optimal pharmacokineticparameters and level of virologic suppression.

The withdrawal of ritonavir from the boosted regimen of atazanavir is not recommended, but may beconsidered in adults patients at the dose of 400 mg once daily with food only under the following combinedrestrictive 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 given without ritonavir should not be considered in patients treated with a backbone regimencontaining tenofovir disoproxil and with other concomitant medications that reduce atazanavir bioavailability(see section 4.5 In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen) or incase of perceived challenging compliance.

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

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

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has beenreported during postmarketing surveillance. A large prospective observational study has shown anassociation 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 the renalfunction 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 patients requiredhospitalisation for additional management and some had complications. In some cases, nephrolithiasis hasbeen associated with acute renal failure or renal insufficiency. If signs or symptoms of 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, suchreactions have been observed within the first few weeks or months of initiation of CART. Relevant examplesare cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveciipneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occurin the setting of immune reactivation; however, the reported time to onset is more variable and these eventscan occur many months after initiation of treatment.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption,severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularlyin patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy(CART). Patients should be advised to seek medical advice if they experience joint aches and pain, jointstiffness or difficulty in movement.

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

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophiliaand systemic symptoms (DRESS) syndrome have been reported in patients receiving atazanavir. Patientsshould be advised of the signs and symptoms and monitored closely for skin reactions. Atazanavir should bediscontinued if severe rash develops.

The best results in managing these events come from early diagnosis and immediate interruption of anysuspect medicines. If the patient has developed SJS or DRESS associated with the use of atazanavir,atazanavir may not be restarted.

The combination of Atazanavir Viatris with atorvastatin is not recommended (see section 4.5).

Co-administration of Atazanavir Viatris with nevirapine or efavirenz is not recommended (see section 4.5).

If the co-administration of Atazanavir Viatris with an NNRTI is required, an increase in the dose of both

Atazanavir Viatris and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could beconsidered with close clinical monitoring.

Atazanavir is metabolised principally by CYP3A4. Co-administration of Atazanavir Viatris and medicinalproducts 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 erectile dysfunction inpatients receiving Atazanavir Viatris. Co-administration of Atazanavir Viatris with these medicinal productsis expected to substantially increase their concentrations and may result in PDE5-associated adversereactions such as hypotension, visual changes, and priapism (see section 4.5).

Co-administration of voriconazole and Atazanavir Viatris with ritonavir is not recommended, unless anassessment of the benefit/risk justifies the use of voriconazole.

In the majority of patients, a reduction in both voriconazole and atazanavir exposures are expected. In asmall number of patients without a functional CYP2C19 allele, significantly increased voriconazoleexposures are expected (see section 4.5).

Concomitant use of Atazanavir Viatris/ritonavir and fluticasone or other glucocorticoids that are metabolisedby CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemiccorticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section 4.5).

Concomitant use of salmeterol and Atazanavir Viatris may result in increased cardiovascular adverse eventsassociated with salmeterol. Co-administration of salmeterol and Atazanavir Viatris is not recommended (seesection 4.5).

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

Co-administration of Atazanavir Viatris with proton pump inhibitors is not recommended (see section 4.5). Ifthe combination of Atazanavir Viatris with a proton pump inhibitor is judged unavoidable, close clinicalmonitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not beexceeded.

Co-administration of atazanavir with other hormonal contraceptives or oral contraceptives containingprogestogens other than norgestimate or norethindrone has not been studied, and therefore should be avoided(see section 4.5).

Safety

Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults. Asymptomaticfirst- and second-degree AV block was reported in paediatric patients (see section 4.8). Caution should beused with medicinal products known to induce PR prolongations. In paediatric patients with pre-existingconduction problems (second degree or higher atrioventricular or complex bundle-branch block), Atazanavir

Viatris should be used with caution and only if the benefits exceed the risk. Cardiac monitoring isrecommended 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-galactosemalabsorption should not take this medicinal product.

When atazanavir and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir maypredominate 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 and ritonavir.

Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, atazanavir iscontraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index:

quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam,orally administered midazolam, lomitapide, and ergot alkaloids, particularly ergotamine anddihydroergotamine (see section 4.3).

Co-administration of atazanavir with grazoprevir-containing products, including elbasvir/grazoprevir fixed-dose combination is contraindicated because of the increase in grazoprevir and elbasvir plasmaconcentrations and potential for the increase in risk of ALT elevations associated with increased grazoprevirconcentrations (see section 4.3).

Co-administration of atazanavir with glecaprevir/pibrentasvir fixed-dose combination iscontraindicated because of the potential increase in the risk of ALT elevations due to a significantincrease in glecaprevir and pibrentasvir plasma concentrations (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) are shownin parentheses. The studies presented in Table 2 were conducted in healthy subjects unless otherwise noted.

Of importance, many studies were conducted with unboosted atazanavir, which is not the recommendedregimen 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 coadministration iscontraindicated, 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

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

Grazoprevir 200 mg once daily Atazanavir AUC: ↑43% (↑30% ↑57%) Co-administration of(atazanavir 300 mg/ritonavir Atazanavir Cmax: ↑12% (↑1% ↑24%) atazanavir and100 mg once daily) Atazanavir Cmin: ↑23% (↑13% ↑134%) elbasvir/grazoprevir iscontraindicated because

Grazoprevir AUC: ↑958% (↑678% ↑1339%) of a significant increase

Grazoprevir Cmax: ↑524% (↑342% ↑781%) in grazoprevir plasma

Grazoprevir Cmin: ↑1064% (↑696% ↑1602%) concentrations and anassociated potential

Grazoprevir concentrations were greatly increase in the risk ofincreased when co-administered with ALT elevationsatazanavir/ritonavir. (see section 4.3).

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

Elbasvir AUC: ↑376% (↑307% ↑456%)

Elbasvir Cmax: ↑315% (↑246% ↑397%)

Elbasvir Cmin: ↑545% (↑451% ↑654%)

Elbasvir concentrations were increased whenco-administered with atazanavir/ritonavir.

Sofosbuvir 400 mg/Sofosbuvir AUC: ↑40% (↑25% ↑57%) Co-administration ofvelpatasvir 100 Sofosbuvir Cmax: ↑29% (↑9% ↑52%) atazanavir withmg/voxilaprevir 100 mg single voxilaprevir-dose* Velpatasvir AUC: ↑93% (↑58%↑136%) containing products is(atazanavir 300 mg/ritonavir Velpatasvir Cmax: ↑29% (↑7% ↑56%) expected to increase100 mg once daily) the concentration of

Voxilaprevir AUC: ↑331% (↑276% voxilaprevir. Co-↑393%) administration of

Voxilaprevir C : ↑342% (↑265%↑435%) atazanavir withmaxvoxilaprevir-

*Lack of pharmacokinetics interaction containing regimens isbounds 70-143% not recommended.

Effect on atazanavir and ritonavir exposurehas not been studied.

Expected:

↔ Atazanavir↔ Ritonavir

The mechanism of interaction betweenatazanavir/ritonavir andsofosbuvir/velpatasvir/voxilaprevir isinhibition of OATP1B, P-gp, and CYP3A.

Glecaprevir 300 mg/Glecaprevir AUC: ↑553% (↑424%↑714%) Co-administration ofpibrentasvir 120 mg once daily Glecaprevir Cmax: ↑306% (↑215% ↑423%) atazanavir with(atazanavir 300 mg/ritonavir 100 Glecaprevir Cmin: ↑1330% (↑885% glecaprevir/pibrentasvirmg once daily*) ↑1970%) is contraindicatedbecause of the potential

Pibrentasvir AUC: ↑64% (↑48% ↑82%) increase in the risk of

Pibrentasvir Cmax: ↑29% (↑15% ↑45%) ALT elevations due to a

Pibrentasvir Cmin: ↑129% (↑95% ↑168%) significant increase in

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administrationglecaprevir and

*Effect of atazanavir and ritonavir on the pibrentasvir plasmafirst dose of glecaprevir and pibrentasvir concentrations (seeis reported. section 4.3)

ANTIPLATELETS

Ticagrelor The mechanism of the interaction is CYP3A4 Co-administration ofinhibition by atazanavir and/or ritonavir. atazanavir withticagrelor is notrecommended due topotential increase in theantiplatelet activity ofticagrelor.

Clopidogrel The mechanism of the interaction is CYP3A4 Co-administration withinhibition by atazanavir and or/ritonavir. clopidogrel is notrecommended due topotential reduction ofthe antiplatelet activityof clopidogrel.

Prasugrel The mechanism of the interaction is CYP3A4 No dose adjustment isinhibition by atazanavir and or/ritonavir. needed when prasugrelis co-administered withatazanavir (with orwithout ritonavir).

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, suchco-administration is not recommended.

Ritonavir 100 mg once daily Atazanavir AUC: ↑250% (↑144% ↑403%)* Ritonavir 100 mg once(atazanavir 300 mg once daily) Atazanavir Cmax: ↑120% (↑56% ↑211%)* daily is used as a

Studies conducted in HIV-infected Atazanavir Cmin: ↑713% (↑359% ↑1339%)* booster of atazanavirpatients. pharmacokinetics.

*In a combined analysis, atazanavir 300 mgand ritonavir 100 mg (n=33) was compared toatazanavir 400 mg without ritonavir (n=28).

The mechanism of interaction betweenatazanavir and ritonavir is CYP3A4inhibition.

Indinavir Indinavir is associated with indirect Co-administration ofunconjugated hyperbilirubinaemia due to atazanavir and indinavirinhibition of UGT. is not recommended(see section 4.4).

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

Lamivudine 150 mg twice daily No significant effect on lamivudine and Based on these data and+ zidovudine 300 mg twice daily zidovudine concentrations was observed. because ritonavir is not(atazanavir 400 mg once daily) expected to have asignificant impact onthe pharmacokinetics of

NRTIs, the co-administration of these

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administrationmedicinal products andatazanavir is notexpected to significantlyalter the exposure of theco-administeredmedicinal products.

Abacavir The co-administration of abacavir andatazanavir is not expected to significantly alterthe exposure of abacavir.

Didanosine (buffered tablets) Atazanavir, simultaneous administration with Didanosine should be200 mg/stavudine 40 mg, both ddI+d4T (fasted) taken at the fasted statesingle dose Atazanavir AUC: ↓87% (↓92% ↓79%) 2 hours after atazanavir(atazanavir 400 mg single dose) Atazanavir Cmax: ↓89% (↓94% ↓82%) taken with food. The co-

Atazanavir Cmin: ↓84% (↓90% ↓73%) administration ofstavudine with

Atazanavir, dosed 1 hr after ddI+d4T (fasted) atazanavir is not

Atazanavir AUC: ↔3% (↓36% ↑67%) expected to significantly

Atazanavir Cmax: ↑12% (↓33% ↑18%) alter the exposure of

Atazanavir Cmin: ↔3% (↓39% ↑73%) stavudine.

Atazanavir concentrations were greatlydecreased when co-administered withdidanosine (buffered tablets) and stavudine.

The mechanism of interaction is a reducedsolubility of atazanavir with increasing pHrelated to the presence of anti-acid agent indidanosine buffered tablets.

No significant effect on didanosine andstavudine concentrations was observed.

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

No significant effect on atazanavirconcentrations was observed whenadministered with enteric-coated didanosine,but administration with food decreaseddidanosine concentrations.

Tenofovir disoproxil fumarate Atazanavir AUC: ↓22% (↓35% ↓6%) * When co-administered300 mg once daily Atazanavir Cmax: ↓16% (↓30% ↔0%) * with tenofovir(atazanavir 300 mg once daily Atazanavir Cmin: ↓23% (↓43% ↑2%) * disoproxil fumarate, it iswith ritonavir 100 mg once daily) recommended that

*In a combined analysis from several clinical atazanavir 300 mg be300 mg tenofovir disoproxil studies, atazanavir/ritonavir 300/100 mg co- given with ritonavir 100fumarate is equivalent to 245 mg administered with tenofovir disoproxil mg and tenofovirtenofovir disoproxil. fumarate 300 mg (n=39) was compared to disoproxil fumarate 300atazanavir/ritonavir 300/100 mg (n=33). mg (all as a single dose

Studies conducted in HIV-infected with food).patients

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

The efficacy of atazanavir/ritonavir incombination with tenofovir disoproxilfumarate in treatment-experienced patientshas been demonstrated in clinical study 045and in treatment naïve patients in clinicalstudy 138 (see sections 4.8 and 5.1). Themechanism of interaction between atazanavirand tenofovir disoproxil fumarate is unknown.

Tenofovir disoproxil fumarate Tenofovir disoproxil fumarate AUC: ↑37% Patients should be300 mg once daily (↑30% ↑45%) closely monitored for(atazanavir 300 mg once daily Tenofovir disoproxil fumarate Cmax: ↑34% tenofovir disoproxilwith ritonavir 100 mg once daily) (↑20% ↑51%) fumarate-associated

Tenofovir disoproxil fumarate Cmin: ↑29% adverse reactions,300 mg tenofovir disoproxil (↑21% ↑36%) including renalfumarate is equivalent to 245 mg disorders.

tenofovir disoproxil.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz 600 mg once daily Atazanavir (pm): all administered with food Co-administration of(atazanavir 400 mg once daily Atazanavir AUC: ↔0% (↓9% ↑10%)* efavirenz and atazanavirwith ritonavir 100 mg once daily) Atazanavir Cmax: ↑17% (↑8% ↑27%)* is not recommended

Atazanavir Cmin: ↓42% (↓51% ↓31%)* (see section 4.4).

Efavirenz 600 mg once daily Atazanavir (pm): all administered with food(atazanavir 400 mg once daily Atazanavir AUC: ↔6% (↓10% ↑26%) */**with ritonavir 200 mg once daily) Atazanavir Cmax: ↔9% (↓5% ↑26%) */**

Atazanavir Cmin: ↔12% (↓16% ↑49%) */**

*When compared to Atazanavir300 mg/ritonavir 100 mg once daily in theevening without efavirenz. This decrease inatazanavir Cmin might negatively impact theefficacy of atazanavir. The mechanism ofefavirenz/atazanavir interaction is CYP3A4induction.

**Based on historical comparison.

Nevirapine 200 mg twice daily Nevirapine AUC: ↑26% (↑17% ↑36%) Co-administration of(atazanavir 400 mg once daily Nevirapine Cmax: ↑21% (↑11% ↑32%) nevirapine andwith ritonavir 100 mg once daily) Nevirapine Cmin : ↑35% (↑25% ↑47%) atazanavir is not

Study conducted in HIV-infected recommended (seepatients. Atazanavir AUC: ↓19% (↓35% ↑2%) * section 4.4).

Atazanavir Cmax: ↔2% (↓15% ↑24%) *

Atazanavir Cmin: ↓59% (↓73% ↓40%) *

*When compared to atazanavir 300 mg andritonavir 100 mg without nevirapine. Thisdecrease in atazanavir Cmin might negativelyimpact the efficacy of atazanavir. Themechanism of nevirapine/atazanavirinteraction is CYP3A4 induction.

Integrase Inhibitors

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

Raltegravir 400 mg twice daily Raltegravir AUC: ↑41% No dose adjustment(atazanavir/ritonavir) Raltegravir Cmax: ↑24% required for raltegravir.

Raltegravir C12hr: ↑77%

The mechanism is UGT1A1 inhibition.

ANTIBIOTICS

Clarithromycin 500 mg twice Clarithromycin AUC: ↑94% (↑75% ↑116%) No recommendationdaily Clarithromycin Cmax: ↑50% (↑32% ↑71%) regarding dose(atazanavir 400 mg once daily) Clarithromycin Cmin: ↑160% (↑135% ↑188%) reduction can be made;therefore, caution14-OH clarithromycin should be exercised if14-OH clarithromycin AUC: ↓70% (↓74% atazanavir is↓66%) co-administered with14-OH clarithromycin Cmax: ↓72% (↓76% clarithromycin.

↓67%)14-OH clarithromycin Cmin: ↓62% (↓66%↓58%)

Atazanavir AUC: ↑28% (↑16% ↑43%)

Atazanavir Cmax: ↔6% (↓7% ↑20%)

Atazanavir Cmin: ↑91% (↑66% ↑121%)

A dose reduction of clarithromycin may resultin subtherapeutic concentrations of 14-OHclarithromycin.

The mechanism of theclarithromycin/atazanavir interaction is

CYP3A4 inhibition.

ANTIFUNGALS

Ketoconazole 200 mg once daily No significant effect on atazanavir Ketoconazole and(atazanavir 400 mg once daily) concentrations was observed. itraconazole should be

Itraconazole Itraconazole, like ketoconazole, is a strong used cautiously withinhibitor as well as a substrate of CYP3A4. atazanavir/ritonavir.

Based on data obtained with other boosted PIs High doses ofand ketoconazole, where ketoconazole AUC ketoconazole andshowed a 3-fold increase, atazanavir/ritonavir itraconazoleis expected to increase ketoconazole or (>200 mg/day) are notitraconazole concentrations. recommended.

Voriconazole 200 mg twice daily Voriconazole AUC: ↓33% (↓42% ↓22%) Co-administration of(atazanavir 300 mg/ritonavir Voriconazole Cmax: ↓10% (↓22% ↓4%) voriconazole and100 mg once daily) Voriconazole Cmin: ↓39% (↓49% ↓28%) atazanavir with ritonavir

Subjects with at least one is not recommendedfunctional CYP2C19 allele. Atazanavir AUC: ↓12% (↓18% ↓5%) unless an assessment of

Atazanavir Cmax: ↓13% (↓20% ↓4%) the benefit/risk to the

Atazanavir Cmin: ↓ 20 % (↓28 % ↓10%) patient justifies the useof voriconazole (see

Ritonavir AUC: ↓12% (↓17% ↓7%) section 4.4).

Ritonavir Cmax: ↓9% (↓17% ↔0%) At the time

Ritonavir Cmin: ↓25% (↓35% ↓14%) voriconazole treatmentis required, a patient’s

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

In the majority of patients with at least one CYP2C19 genotypefunctional CYP2C19 allele, a reduction in should be performed ifboth voriconazole and atazanavir exposures feasible.

are expected. Therefore if the

Voriconazole 50 mg twice daily Voriconazole AUC: ↑561% (↑451% ↑699%) combination is(atazanavir 300 mg/ritonavir Voriconazole Cmax: ↑438% (↑355% ↑539%) unavoidable, the100 mg once daily) Voriconazole Cmin: ↑765% (↑571% ↑1,020%) following

Subjects without a functional recommendations are

CYP2C19 allele. Atazanavir AUC: ↓20% (↓35% ↓3%) made according to the

Atazanavir C : ↓19% (↓34% ↔0.2%) CYP2C19 status:max

Atazanavir C : ↓31 % (↓46 % ↓13%) - in patients with at leastminone functional

Ritonavir AUC: ↓11% (↓20% ↓1%) CYP2C19 allele, close

Ritonavir Cmax: ↓11% (↓24% ↑4%) clinical monitoring for a

Ritonavir Cmin: ↓19% (↓35% ↑1%) loss of bothvoriconazole (clinical

In a small number of patients without a signs) and atazanavirfunctional CYP2C19 allele, significantly (virologic response)increased voriconazole exposures are efficacy isexpected. recommended.

- in patients without afunctional CYP2C19allele, close clinical andlaboratory monitoringof voriconazole-associated adverseevents is recommended

If genotyping is notfeasible, full monitoringof safety and efficacyshould be performed.

Fluconazole 200 mg once daily Atazanavir and fluconazole concentrations No dosage adjustments(atazanavir 300 mg and ritonavir were not significantly modified when are needed for100 mg once daily) Atazanavir /ritonavir was co-administered fluconazole andwith fluconazole. atazanavir.

ANTIMYCOBACTERIAL

Rifabutin 150 mg twice weekly Rifabutin AUC: ↑48% (↑19% ↑84%)** When given with(atazanavir 300 mg and ritonavir Rifabutin Cmax: ↑149% (↑103% ↑206%)** atazanavir, the100 mg once daily) Rifabutin Cmin: ↑40% (↑5% ↑87%)** recommended dose ofrifabutin is 150 mg 325-O-desacetyl-rifabutin AUC: ↑990% times per week on set(↑714% ↑1361%)** days (for example25-O-desacetyl-rifabutin Cmax: ↑677% (↑513% Monday-Wednesday-↑883%)** Friday). Increased25-O-desacetyl-rifabutin Cmin: ↑1045% monitoring for(↑715% ↑1510%)** rifabutin-associatedadverse reactions

**When compared to rifabutin 150 mg once including neutropeniadaily alone. Total rifabutin and 25-O- and uveitis is warranteddesacetyl-rifabutin AUC: ↑119% (↑78% due to an expected↑169%). increase in exposure torifabutin. Further

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

In previous studies, the pharmacokinetics of dosage reduction ofatazanavir was not altered by rifabutin. rifabutin to 150 mgtwice weekly on setdays is recommendedfor patients in whom the150 mg dose 3 times perweek is not tolerated. Itshould be kept in mindthat the twice weeklydosage of 150 mg maynot provide an optimalexposure to rifabutinthus leading to a risk ofrifamycin resistance anda treatment failure. Nodose adjustment isneeded for atazanavir.

Rifampicin Rifampicin is a strong CYP3A4 inducer and The combination ofhas been shown to cause a 72% decrease in rifampicin andatazanavir AUC which can result in atazanavir isvirological failure and resistance contraindicated (seedevelopment. During attempts to overcome section 4.3).

the decreased exposure by increasing the doseof atazanavir or other protease inhibitors withritonavir, a high frequency of liver reactionswas seen.

ANTIPSYCHOTICS

Quetiapine Due to CYP3A4 inhibition by atazanavir, Co-administration ofconcentrations of quetiapine are expected to quetiapine withincrease. atazanavir iscontraindicated asatazanavir may increasequetiapine-relatedtoxicity. Increasedplasma concentrationsof quetiapine may leadto coma (see section4.3).

Lurasidone Atazanavir is expected to increase plasma Co-administration oflevels of lurasidone due to CYP3A4 lurasidone withinhibition. atazanavir iscontraindicated as thismay increaselurasidone-relatedtoxicity(see section 4.3).

ACID REDUCING AGENTS

H2-Receptor antagonists

Without tenofovir

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

In HIV-infected patients with atazanavir/ritonavir at the recommended dose For patients not taking300/100 mg once daily tenofovir, if atazanavir

Famotidine 20 mg twice daily Atazanavir AUC: ↓18% (↓25% ↑1%) 300 mg/ritonavir

Atazanavir Cmax: ↓20% (↓32% ↓7%) 100 mg and H2-receptor

Atazanavir Cmin: ↔1% (↓16% ↑18%) antagonists areco-administered, a dose

Famotidine 40 mg twice daily Atazanavir AUC: ↓23% (↓32% ↓14%) equivalent to famotidine

Atazanavir Cmax: ↓23% (↓33% ↓12%) 20 mg twice daily

Atazanavir Cmin: ↓20% (↓31% ↓8%) should not be exceeded.

In healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg If a higher dose of anonce daily H2-receptor antagonistis required (e.g.,

Famotidine 40 mg twice daily Atazanavir AUC: ↔3% (↓14% ↑22%)famotidine 40 mg twice

Atazanavir Cmax: ↔2% (↓13% ↑8%)daily or equivalent) an

Atazanavir Cmin: ↓14% (↓32% ↑8%)increase of theatazanavir/ritonavirdose from 300/100 mgto 400/100 mg can beconsidered.

With tenofovir disoproxil fumarate 300 mg once daily (equivalent to 245 mg tenofovir disoproxil)

In HIV-infected patients with atazanavir/ritonavir at the recommended dose of For patients who are300/100 mg once daily taking tenofovir

Famotidine 20 mg twice daily Atazanavir AUC: ↓21% (↓34% ↓4%)* disoproxil fumarate,

If atazanavir/ritonavirwith both tenofovir

Atazanavir Cmax: ↓21% (↓36% ↓4%)*disoproxil fumarate and

Atazanavir Cmin: ↓19% (↓37% ↑5%)*an H2-receptor

Famotidine 40 mg twice daily Atazanavir AUC: ↓24% (↓36% ↓11%)* antagonist are

Atazanavir Cmax: ↓23% (↓36% ↓8%)* co-administered, a dose

Atazanavir Cmin: ↓25% (↓47% ↑7%)* increase of atazanavir to

In HIV-infected patients with atazanavir/ritonavir at an increased dose of 400 mg with 100 mg of400/100 mg once daily ritonavir isrecommended. A dose

Famotidine 20 mg twice daily Atazanavir AUC: ↑18% (↑6.5% ↑30%)*equivalent to famotidine

Atazanavir Cmax: ↑18% (↑6.7% ↑31%)*40 mg twice daily

Atazanavir Cmin: ↑24 % (↑10% ↑39%)*should not be exceeded.

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 atazanavir 300 mg oncedaily with ritonavir 100 mg once daily andtenofovir disoproxil fumarate 300 mg all as asingle dose with food.

When compared to atazanavir 300 mg withritonavir 100 mg without tenofovir disoproxilfumarate, atazanavir concentrations areexpected to be additionally decreased byabout 20%.

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

The mechanism of interaction is decreasedsolubility of atazanavir as intra-gastric pHincreases with H2-blockers.

Omeprazole 40 mg once daily Atazanavir (am): 2 hr after omeprazole Co-administration of(atazanavir 400 mg once daily Atazanavir AUC: ↓61% (↓65% ↓55%) atazanavir with ritonavirwith ritonavir 100 mg once daily) Atazanavir Cmax: ↓66% (↓62% ↓49%) and proton pump

Atazanavir Cmin: ↓65% (↓71% ↓59%) inhibitors is not

Omeprazole 20 mg once daily Atazanavir (am): 1 hr after omeprazole recommended. If the(atazanavir 400 mg once daily Atazanavir AUC: ↓30% (↓43% ↓14%)* combination is judgedwith ritonavir 100 mg once daily) Atazanavir Cmax: ↓31% (↓42% ↓17%)* unavoidable, close

Atazanavir C : ↓31% (↓46% ↓12%)* clinical monitoring isminrecommended in

*When compared to atazanavir 300 mg once combination with andaily with ritonavir 100 mg once daily. increase in the dose ofatazanavir to 400 mg

The decrease in AUC, Cmax, and Cmin was not with 100 mg ofmitigated when an increased dose of ritonavir; doses ofatazanavir /ritonavir (400/100 mg once daily) proton pump inhibitorswas temporally separated from omeprazole by comparable to12 hours. Although not studied, similar results omeprazole 20 mgare expected with other proton pump should not be exceededinhibitors. This decrease in atazanavir (see section 4.4).

exposure might negatively impact the efficacyof atazanavir. The mechanism of interaction isdecreased solubility of atazanavir as intra-gastric pH increases with proton pumpinhibitors.

Antacids

Antacids and medicinal Reduced plasma concentrations of atazanavir Atazanavir should beproducts containing buffers may be the consequence of increased gastric administered 2 hourspH if antacids, including buffered medicinal before or 1 hour afterproducts, are administered with atazanavir. antacids or bufferedmedicinal products.

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Potential for increased alfuzosin Co-administration ofconcentrations which can result in alfuzosin withhypotension. The mechanism of interaction is atazanavir is

CYP3A4 inhibition by atazanavir and/or contraindicated (seeritonavir. section 4.3)

ANTICOAGULANTS

Direct-acting oral anticoagulants (DOACs)

Apixaban Potential for increased apixaban and Co-administration of

Rivaroxaban rivaroxaban concentrations which can result in apixaban or rivaroxabana higher risk of bleeding. and atazanavir withritonavir is not

The mechanism of interaction is inhibition of recommended.

CYP3A4/and P-gp by atazanavir/ritonavir.

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

Ritonavir is a strong inhibitor of both

CYP3A4 and P-gp.

Atazanavir is an inhibitor of CYP3A4. Thepotential inhibition of P-gp by atazanavir isunknown and cannot be excluded.

Dabigatran Potential for increased dabigatran Co-administration ofconcentrations which can result in a higher dabigatran andrisk of bleeding. The mechanism of atazanavir with ritonavirinteraction is P-gp inhibition. is not recommended.

Ritonavir is a strong P-gp inhibitor.

Potential P-gp inhibition by atazanavir isunknown and cannot be excluded.

Edoxaban Potential for increased edoxaban Exercise caution whenconcentrations which can result in a higher edoxaban is used withrisk of bleeding. The mechanism of atazanavir.

interaction is P-gp inhibition by atazanavir/ritonavir. Please refer to theedoxaban SmPC

Ritonavir is a strong P-gp inhibitor. sections 4.2 and 4.5 forappropriate edoxaban

Potential P-gp inhibition by atazanavir is dosageunknown and cannot be excluded. recommendations forco-administration with

Warfarin Co-administration with atazanavir has the It is recommended thatpotential to increase or decrease warfarin the Internationalconcentrations. Normalised Ratio (INR)be monitored carefullyduring treatment withatazanavir, especiallywhen commencingtherapy.

ANTIEPILEPTICS

Carbamazepine Atazanavir may increase plasma levels of Carbamazepine incarbamazepine due to CYP3A4 inhibition. combination with

Due to carbamazepine inducing effect, a atazanavir (with orreduction in atazanavir exposure cannot be without ritonavir) isruled out. contraindicated due tothe risk for loss ofvirologic response anddevelopment ofresistance (seesection 4.3).

Close monitoring of thepatient's virologicresponse should beexercised.

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

Phenytoin, phenobarbital Ritonavir may decrease plasma levels of Phenobarbital andphenytoin and/or phenobarbital due to phenytoin in

CYP2C9 and CYP2C19 induction. combination withatazanavir (with or

Due to phenytoin/phenobarbital inducing without ritonavir) areeffect, a reduction in atazanavir exposure contraindicated, due tocannot be ruled out the risk for loss ofvirologic response anddevelopment ofresistance (seesection 4.3).

Close monitoring ofpatient’s virologicresponse should beexercised.

Lamotrigine Co-administration of lamotrigine and Lamotrigine should beatazanavir/ritonavir may decrease lamotrigine used with caution inplasma concentrations due to UGT1A4 combination withinduction. atazanavir/ritonavir.

If necessary, monitorlamotrigineconcentrations andadjust the doseaccordingly.

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS

Antineoplastics

Apalutamide The mechanism of interaction is CYP3A4 Co-administration withinduction by apalutamide and CYP3A4 atazanavir (with orinhibition by atazanavir/ritonavir. without ritonavir) iscontraindicated due tothe potential fordecreased atazanavirand ritonavir plasmaconcentration withsubsequent loss ofvirologic response andpossible resistance tothe class of proteaseinhibitors (see section4.3). In addition, serumconcentrations ofapalutamide may beincreased when co-administered withatazanavir/ritonavir,resulting in the potentialfor serious adverseevents includingseizure.

Encorafenib The mechanism of interaction is CYP3A4 Co-administration ofinhibition by atazanavir and/or ritonavir. encorafenib with

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administrationatazanavir (with orwithout ritonavir) iscontraindicated due tothe potential for loss ofvirologic response,development ofresistance, increase inencorafenib plasmaconcentration andsubsequent risk ofserious adverse eventssuch as QT intervalprolongation (seesection 4.3).

Ivosidenib The mechanism of interaction is CYP3A4 Co-administration ofinhibition by atazanavir and/or ritonavir. ivosidenib withatazanavir (with orwithout ritonavir) iscontraindicated due topotential for loss ofvirologic response,development ofresistance, increase inivosidenib plasmaconcentration andsubsequent risk ofserious adverse eventssuch as QT intervalprolongation (seesection 4.3).

Irinotecan Atazanavir inhibits UGT and may interfere If atazanavir iswith the metabolism of irinotecan, resulting in co-administered withincreased irinotecan toxicities. irinotecan, patientsshould be closelymonitored for adverseevents related toirinotecan.

Immunosuppressants

Cyclosporin Concentrations of these immunosuppressants More frequent

Tacrolimus may be increased when co-administered with therapeutic

Sirolimus atazanavir due to CYP3A4 inhibition. concentrationmonitoring of thesemedicinal products isrecommended untilplasma levels have beenstabilised.

CARDIOVASCULAR AGENTS

Antiarrhythmics

Amiodarone, Systemic lidocaine, Concentrations of these antiarrhythmics may Caution is warranted

Quinidine be increased when co-administered with and therapeuticatazanavir. The mechanism of amiodarone or concentration

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administrationsystemic lidocaine/atazanavir interaction is monitoring is

CYP3A inhibition. Quinidine has a narrow recommended whentherapeutic window and is contraindicated due available. Theto potential inhibition of CYP3A by concomitant use ofatazanavir. quinidine iscontraindicated (seesection 4.3).

Calcium channel blockers

Bepridil Atazanavir should not be used in combination Co-administration withwith medicinal products that are substrates of bepridil is

CYP3A4 and have a narrow therapeutic index. contraindicated (seesection 4.3)

Diltiazem 180 mg once daily Diltiazem AUC: ↑125% (↑109% ↑141%) An initial dose(atazanavir 400 mg once daily) Diltiazem Cmax: ↑98% (↑78% ↑119%) reduction of diltiazem

Diltiazem Cmin: ↑142% (↑114% ↑173%) by 50% isrecommended, with

Desacetyl-diltiazem AUC: ↑165% (↑145% subsequent titration as↑187%) needed and ECG

Desacetyl-diltiazem Cmax: ↑172% (↑144% monitoring.

↑203%)

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

No significant effect on atazanavirconcentrations was observed. There was anincrease in the maximum PR intervalcompared to atazanavir alone. Co-administration of diltiazem and atazanavir/ritonavir has not been studied.

The mechanism of diltiazem/atazanavirinteraction is CYP3A4 inhibition.

Verapamil Serum concentrations of verapamil may be Caution should beincreased by atazanavir due to CYP3A4 exercised wheninhibition. verapamil isco-administered withatazanavir.

CORTICOSTEROIDS

Dexamethasone and other Co-administration with dexamethasone or Co-administration withcorticosteroids (all routes of other corticosteroids that induce CYP3A may corticosteroids (alladministration) result in loss of therapeutic effect of routes ofatazanavir and development of resistance to administration) that areatazanavir and/or ritonavir. Alternative metabolised by CYP3A,corticosteroids should be considered. particularly for longterm use, may increase

The mechanism of interaction is CYP3A4 the risk for developmentinduction by dexamethasone and CYP3A4 of systemicinhibition by atazanavir and/or ritonavir. corticosteroid effectsincluding Cushing’ssyndrome and adrenalsuppression. The

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administrationpotential benefit oftreatment versus the riskof systemiccorticosteroid effectsshould be considered.

For co-administration ofcutaneouslyadministeredcorticosteroids sensitiveto CYP3A inhibition,consult the Summary of

Product Characteristicsof the corticosteroid forcondition or uses thataugment its systemicabsorption.

Fluticasone propionate The fluticasone propionate plasma levels Co-administration ofintranasal 50 µg 4 times daily increased significantly, whereas the intrinsic atazanavir /ritonavir andfor 7 days cortisol levels decreased by approximately these glucocorticoids(ritonavir 100 mg capsules twice 86% (90% confidence interval 82%- 89%). metabolised bydaily) Greater effects may be expected when CYP3A4 is notfluticasone propionate is inhaled. Systemic recommended unless

And corticosteroid effects including Cushing's the potential benefit ofsyndrome and adrenal suppression have been treatment outweighs the

Inhaled/Nasal Corticosteroids reported in patients receiving ritonavir and risk of systemicinhaled or intranasally administered corticosteroid effectsfluticasone propionate; this could also occur (see section 4.4). A dosewith other corticosteroids metabolised via the reduction of the

P450 3A pathway, e.g., budesonide. The glucocorticoid shouldeffects of high fluticasone systemic exposure be considered with closeon ritonavir plasma levels are yet unknown. monitoring of local and

The mechanism of interaction is CYP3A4 systemic effects or ainhibition. switch to aglucocorticoid, which is

Concomitant use of atazanavir (with or not a substrate forwithout ritonavir) and other Inhaled/Nasal CYP3A4 (e.g.,

Corticosteroids is expected to produce the beclomethasone).

same effects. Moreover, in case ofwithdrawal ofglucocorticoids,progressive dosereduction may have tobe performed over alonger period.

Concomitant use of

Inhaled/Nasal

Corticosteroids andatazanavir (with orwithout ritonavir) mayincrease plasmaconcentrations of

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

Inhaled/Nasalcorticosteroids. Usewith caution. Consideralternatives to

Inhaled/Nasal

Corticosteroids,particularly for long-term use.

ERECTILE DYSFUNCTION

PDE5 Inhibitors

Sildenafil, tadalafil, vardenafil Sildenafil, tadalafil, and vardenafil are Patients should bemetabolised by CYP3A4. Co-administration warned about thesewith atazanavir may result in increased possible side effectsconcentrations of the PDE5 inhibitor and an when using PDE5increase in PDE5-associated adverse events, inhibitors for erectileincluding hypotension, visual changes, and dysfunction withpriapism. The mechanism of this interaction is atazanavir (see section

CYP3A4 inhibition. 4.4).

Also see

PULMONARY

ARTERIAL

HYPERTENSION inthis table for furtherinformation regardingco-administration ofatazanavir withsildenafil.

GONADOTROPIN RELEASING HORMONE (GnRH) RECEPTOR ANTAGONISTS

Elagolix The mechanism of interaction is anticipated Concomitant use ofincrease in elagolix exposure in the presence elagolix 200 mg twiceof CYP3A4 inhibition by atazanavir and/or daily with atazanavirritonavir. (with or withoutritonavir) for more than1 month is notrecommended due to thepotential risk of adverseevents such as bone lossand hepatictransaminase elevations.

Limit concomitant useof elagolix 150 mg oncedaily with atazanavir(with or withoutritonavir) to 6 months.

KINASE INHIBITORS

Fostamatinib The mechanism of interaction is CYP3A4 Concomitant use ofinhibition by atazanavir and/or ritonavir. fostamatinib withatazanavir (with orwithout ritonavir) mayincrease the plasmaconcentration of R406,

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administrationthe active metabolite offostamatinib. Monitorfor toxicities of R406exposure resulting indose-related adverseevents such ashepatotoxicity andneutropenia.

Fostamatinib dosereduction may berequired.

HERBAL PRODUCTS

St. John’s wort (Hypericum Concomitant use of St. John’s wort with Co-administration ofperforatum) atazanavir may be expected to result in atazanavir with productssignificant reduction in plasma levels of containing St. John’satazanavir. This effect may be due to an wort is contraindicated.

induction of CYP3A4. There is a risk of lossof therapeutic effect and development ofresistance (see section 4.3).

HORMONAL CONTRACEPTIVES

Ethinyloestradiol 25 μg + Ethinyloestradiol AUC: ↓19% (↓25% ↓13%) If an oral contraceptivenorgestimate Ethinyloestradiol Cmax: ↓16% (↓26% ↓5%) is administered with(atazanavir 300 mg once daily Ethinyloestradiol Cmin: ↓37% (↓45% ↓29%) atazanavir /ritonavir, itwith ritonavir 100 mg once daily) is recommended that the

Norgestimate AUC: ↑85% (↑67% ↑105%) oral contraceptive

Norgestimate Cmax: ↑68% (↑51% ↑88%) contain at least 30 μg of

Norgestimate Cmin: ↑102% (↑77% ↑131%) ethinyloestradiol andthat the patient be

While the concentration of ethinyloestradiol reminded of strictwas increased with atazanavir given alone, compliance with thisdue to both UGT and CYP3A4 inhibition by contraceptive dosingatazanavir, the net effect of regimen. Co-atazanavir/ritonavir is a decrease in administration ofethinyloestradiol levels because of the atazanavir /ritonavirinducing effect of ritonavir. with other hormonalcontraceptives or oral

The increase in progestin exposure may lead contraceptivesto related side-effects (e.g., insulin resistance, containing progestogensdyslipidemia, acne and spotting), thus other than norgestimatepossibly affecting the compliance. has not been studied,

Ethinyloestradiol 35 µg + Ethinyloestradiol AUC: ↑48% (↑31% ↑68%) and therefore should benorethindrone Ethinyloestradiol C : ↑15% (↓1% ↑32%) avoided. An alternatemax(atazanavir 400 mg once daily) Ethinyloestradiol Cmin: ↑91% (↑57% ↑133%) reliable method ofcontraception is

Norethindrone AUC: ↑110% (↑68% ↑162%) recommended.

Norethindrone Cmax: ↑67% (↑42% ↑196%)

Norethindrone Cmin: ↑262% (↑157% ↑409%)

The increase in progestin exposure may leadto related side effects (e.g., insulin resistance,

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administrationdyslipidemia, acne and spotting), thuspossibly affecting the compliance.

LIPID MODIFYING AGENTS

HMG- CoA reductase inhibitors

Simvastatin Simvastatin and lovastatin are highly Co-administration of

Lovastatin dependent on CYP3A4 for their metabolism simvastatin or lovastatinand co-administration with atazanavir may with atazanavir isresult in increased concentrations. contraindicated due toan increased risk ofmyopathy includingrhabdomyolysis (seesection 4.3).

Atorvastatin The risk of myopathy including Co-administration ofrhabdomyolysis may also be increased with atorvastatin withatorvastatin, which is also metabolised by atazanavir is not

CYP3A4. recommended. If theuse of atorvastatin isconsidered strictlynecessary, the lowestpossible dose ofatorvastatin should beadministered withcareful safetymonitoring (see section4.4).

Pravastatin Although not studied, there is a potential for Caution should be

Fluvastatin an increase in pravastatin or fluvastatin exercised.exposure when co-administered with proteaseinhibitors. Pravastatin is not metabolised by

CYP3A4. Fluvastatin is partially metabolisedby CYP2C9.

Other lipid-modifying agents

Lomitapide Lomitapide is highly dependent on CYP3A4 Co-administration offor metabolism and co-administration with lomitapide andatazanavir with ritonavir may result in atazanavir with ritonavirincreased concentrations. is contraindicated due toa potential risk ofmarkedly increasedtransaminase levels andhepatotoxicity (seesection 4.3).

INHALED BETA AGONISTS

Salmeterol Co-administration with atazanavir may result Co-administration ofin increased concentrations of salmeterol and salmeterol withan increase in salmeterol- associated adverse atazanavir is notevents. recommended (seesection 4.4).

The mechanism of interaction is CYP3A4inhibition by atazanavir and/or ritonavir.

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administration

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 clinicalwith ritonavir 100 mg once daily) monitoring for sedation

Norbuprenorphine AUC:↑105% and cognitive effects. A

Norbuprenorphine Cmax:↑61% dose reduction of

Norbuprenorphine Cmin:↑101% buprenorphine may beconsidered

The mechanism of interaction is CYP3A4 and

UGT1A1 inhibition.

Concentrations of atazanavir (when givenwith ritonavir) were not significantly affected.

Methadone, stable maintenance No significant effect on methadone No dosage adjustment isdose concentrations was observed. Given that low necessary if methadone(atazanavir 400 mg once daily) dose ritonavir (100 mg twice daily) has been is co-administered withshown to have no significant effect on atazanavir.

methadone concentrations, no interaction isexpected if methadone is co-administered withatazanavir, based on these data.

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil Co-administration with atazanavir may result A safe and effectivein increased concentrations of the PDE5 dose in combinationinhibitor and an increase in with atazanavir has not

PDE5-inhibitor-associated adverse events. been established forsildenafil when used to

The mechanism of interaction is CYP3A4 treat pulmonary arterialinhibition by atazanavir and/or ritonavir. hypertension. Sildenafil,when used for thetreatment of pulmonaryarterial hypertension, iscontraindicated (seesection 4.3).

SEDATIVES

Benzodiazepines

Midazolam Midazolam and triazolam are extensively Co-administration of

Triazolam metabolised by CYP3A4. Co-administration atazanavir withwith atazanavir may cause a large increase in triazolam or orallythe concentration of these benzodiazepines. administered midazolam

No drug interaction study has been performed is contraindicated (seefor the co-administration of atazanavir with section 4.3), whereasbenzodiazepines. Based on data for other caution should be used

CYP3A4 inhibitors, plasma concentrations of with co-administrationmidazolam are expected to be significantly of atazanavir andhigher when midazolam is given orally. Data parenteral midazolam. Iffrom concomitant use of parenteral atazanavir is co-midazolam with other protease inhibitors administered withsuggest a possible 3-4-fold increase in parenteral midazolam, itmidazolam plasma levels. should be done in an

Medicinal products by Interaction Recommendationstherapeutic area concerning co-administrationintensive care unit(ICU) or similar settingwhich ensures closeclinical monitoring andappropriate medicalmanagement in case ofrespiratory depressionand/or prolongedsedation. Dosageadjustment formidazolam should beconsidered, especially ifmore than a single doseof midazolam isadministered.

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

The same recommendations for drug drug interactions would apply except:

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

- that co-administration with famotidine is not recommended but if required, atazanavir without ritonavirshould be administered either 2 hours after famotidine or 12 hours before. No single dose of famotidineshould exceed 20 mg, and the total daily dose of famotidine should not exceed 40 mg.

- the need to consider that:

- co-administration of apixaban, dabigatran, or rivaroxaban and atazanavir without ritonavir mayaffect 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 is recommended thatthe 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 nomalformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of Atazanavir Viatris with ritonavir may be considered during pregnancy only if the potential benefitjustifies the potential risk.

In clinical trial AI424-182 atazanavir/ritonavir (300/100 mg or 400/100 mg) in combination withzidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Six of20 (30%) women on atazanavir/ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir /ritonavir400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no cases of lactic acidosis observedin the clinical trial AI424-182.

The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not includeatazanavir) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 monthspostpartum. Three of 20 infants (15%) born to women treated with atazanavir/ritonavir 300/100 mg and fourof 20 infants (20%) born to women treated with atazanavir/ritonavir 400/100 mg experienced grade 3-4bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study receivedphototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.

For dosing recommendations see section 4.2 and for pharmacokinetic data see section 5.2.

It is not known whether Atazanavir Viatris 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 oestrus cyclingwith no effects on mating or fertility (see section 5.3).

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

Atazanavir has been evaluated for safety in combination therapy with other antiretroviral medicinal productsin controlled clinical trials in 1,806 adult patients receiving atazanavir 400 mg once daily (1,151 patients, 52weeks median duration and 152 weeks maximum duration) or atazanavir 300 mg with ritonavir 100 mg oncedaily (655 patients, 96 weeks median duration and 108 weeks maximum duration).

Adverse reactions were consistent between patients who received atazanavir 400 mg once daily and patientswho received atazanavir 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated totalbilirubin levels were reported more frequently with atazanavir plus ritonavir.

Among patients who received atazanavir 400 mg once daily or atazanavir 300 mg with ritonavir 100 mgonce daily, the only adverse reactions of any severity reported very commonly with at least a possiblerelationship to regimens containing atazanavir and one or more NRTIs were nausea (20%), diarrhoea (10%),and jaundice (13%). Among patients receiving atazanavir 300 mg with ritonavir 100 mg, the frequency ofjaundice was 19%. In the majority of cases, jaundice was reported within a few days to a few months afterthe initiation of treatment (see section 4.4).

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has beenreported during postmarketing surveillance. A large prospective observational study has shown anassociation 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 the renalfunction 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), very rare (< 1/10,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders: uncommon: hypersensitivity

Metabolism and nutrition disorders: uncommon: weight decreased, weight gain, anorexia, appetiteincreased

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 mediastinal uncommon: dyspnoeadisorders:

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

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

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

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

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

Reproductive system and breast disorders: uncommon: gynaecomastia

General disorders and administration site common: fatigue;conditions: uncommon: chest pain, malaise, pyrexia, asthenia;rare: gait disturbancea These adverse reactions were identified through post-marketing surveillance, however, the frequencies were estimated from astatistical calculation based on the total number of patients exposed to atazanavir in randomised controlled and other availa bleclinical trials (n = 2321).b See description of selected adverse reactions for more details.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviraltherapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported;however, the reported time to onset is more variable and these events can occur many months after initiationof treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors,advanced HIV disease or long- term exposure to combination antiretroviral therapy (CART). The frequencyof this is unknown (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

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

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

The most frequently reported laboratory abnormality in patients receiving regimens containing atazanavirand one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect[unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 37%(6% Grade 4). Among experienced patients treated with atazanavir 300 mg once daily with 100 mg ritonavironce daily for a median duration of 95 weeks, 53% had Grade 3-4 total bilirubin elevations. Among naïvepatients treated with atazanavir 300 mg once daily with 100 mg ritonavir once daily for a median duration of96 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%), elevatedalanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), low neutrophils (5%),elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) (3%), andelevated lipase (3%).

Two percent of patients treated with atazanavir experienced concurrent Grade 3-4 ALT/AST and Grade 3-4total bilirubin elevations.

In clinical study AI424-020, paediatric patients 3 months to less than 18 years of age who received either theoral powder or capsule formulation had a mean duration of treatment with atazanavir of 115 weeks. Thesafety profile in this study was overall comparable to that seen in adults. Both asymptomatic first-degree(23%) and second-degree (1%) atrioventricular block were reported in paediatric patients. The mostfrequently reported laboratory abnormality in paediatric patients receiving atazanavir was elevation of totalbilirubin (≥ 2.6 times ULN, Grade 3-4) which occurred in 45% of patients.

In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of age had amean duration of treatment with atazanavir oral powder of 80 weeks. No deaths were reported. The safetyprofile in these studies was overall comparable to that seen in previous paediatric and adult studies. The mostfrequently reported laboratory abnormalities in paediatric patients receiving atazanavir oral powder waselevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) and increased amylase (Grade 3-4; 33%),generally of non-pancreatic origin. Elevation in ALT levels were more frequently reported in paediatricpatients 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 with chronichepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily with ritonavir 100 mg oncedaily, 97 patients were co-infected with chronic hepatitis B or C. Co-infected patients were more likely tohave baseline hepatic transaminase elevations than those without chronic viral hepatitis. No differences infrequency of bilirubin elevations were observed between these patients and those without viral hepatitis. Thefrequency of treatment emergent hepatitis or transaminase elevations in co-infected patients was comparablebetween atazanavir and comparator regimens (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

Human experience of acute overdose with atazanavir is limited. Single doses up to 1,200 mg have been takenby healthy volunteers without symptomatic untoward effects. At high doses that lead to high drug exposures,jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associated liver function test changes)or PR interval prolongations may be observed (see sections 4.4 and 4.8).

Treatment of overdose with atazanavir should consist of general supportive measures, including monitoringof vital signs and electrocardiogram (ECG), and observations of the patient’s clinical status. If indicated,elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration ofactivated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote foroverdose with atazanavir. Since atazanavir is extensively metabolised by the liver and is highly proteinbound, dialysis is unlikely to be beneficial in significant removal 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 the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of maturevirions and infection of other cells.

Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 activityin 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 substitution foratazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence of phenotypic crossresistance to other PIs. In clinical trials of antiretroviral treatment naïve patients treated with boostedatazanavir, the I50L substitution did not emerge in any patient without baseline PI substitutions. The N88Ssubstitution has been rarely observed in patients with virologic failure on atazanavir (with or withoutritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with otherprotease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance toatazanavir or have a consistent impact on clinical efficacy.

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 from patientsdesignated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, oratazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates f rompatients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotypepreviously 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). FCsusceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram

Biosciences, South San Francisco, California, USA)

None of the de novo substitutions (see Table 4) are specific to atazanavir and may reflect re-emergence ofarchived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population.

The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the majorand minor resistance substitutions described previously to be involved in protease inhibitor resistance.

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 (400 mg/100 mgtwice daily), each in combination with fixed-dose tenofovir disoproxil fumarate/emtricitabine(300 mg/200 mg tablets once daily). The atazanavir/ritonavir arm showed similar (non-inferior) antiviralefficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA <50 copies/mL at Week 48 (Table 5).

Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 5).

Table 5: Efficacy Outcomes in Study 138 a

Parameter Atazanavir/ritonavirb Lopinavir/ritonavirc(300 mg/100 mg once daily) (400 mg/100 mg twice daily)n=440 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 analysise 86 91 89 89(n=392f) (n=352) (n=372) (n=331)

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

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

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

CD4 count 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48)<50 cells/mm350 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29)100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134)≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228)

HIV RNA Mean Change from Baseline, log10 copies/mL

All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340)

CD4 Mean Change from Baseline, cells/mm3

All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317)

CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic

HIV RNA 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152)<100,000 copies/mL≥100,000 copies/mL 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165)a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma

HIV-1 RNA was 4.94 log10 copies/mL (range 2.6 to 5.88 log10 copies/mL)b Atazanavir/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed-dose 300 mg/200 mg tablets oncedaily).c Lopinavir/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed-dose 300 mg/200 mg tablets oncedaily).d Intent-to-treat analysis, with missing values considered as failures.e Per protocol analysis: Excluding non-completers and patients with major protocol deviations.f Number of patients evaluable.

Data on withdrawal of ritonavir from atazanavir boosted regimen (see also section 4.4)

Study 136 (INDUMA)

In an open-label, randomised, comparative study following a 26- to 30-week induction phase with atazanavir300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted atazanavir 400 mg once daily and two

NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral efficacy comparedwith atazanavir + ritonavir and two NRTIs (n=85) in HIV-infected subjects with fully suppressed HIVreplication, as assessed by the proportion of subjects with HIV RNA < 50 copies/mL: 78% of subjects onunboosted atazanavir and two NRTIs compared with 75% on atazanavir + ritonavir and two NRTIs.

Eleven subjects (13%) in the unboosted atazanavir group and 6 (7%) in the atazanavir + ritonavir group, hadvirologic rebound. Four subjects in the unboosted atazanavir group and 2 in the atazanavir + ritonavir grouphad HIV RNA > 500 copies/mL during the maintenance phase. No subject in either group showedemergence of protease inhibitor resistance. The M184V substitution in reverse transcriptase, which confersresistance to lamivudine and emtricitabine, was detected in 2 subjects in the unboosted atazanavir and 1subject in the atazanavir + ritonavir group.

There were fewer treatment discontinuations in the unboosted atazanavir group (1 vs. 4 subjects in theatazanavir + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboosted atazanavirgroup 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) andatazanavir/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed-dosecombination twice daily), each in combination with tenofovir disoproxil fumarate (see sections 4.5 and 4.8)and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI,

NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeksfor PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PIand 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the atazanavir + ritonavir treatment armand 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10,

M46, I54, V82, I84, and L90. Thirty-two percent of patients in the study had a viral strain with fewer thantwo NRTI substitutions.

The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through 48weeks (Table 6).

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

Parameter ATV/RTVb (300 mg/ 100 mg LPV/RTVc (400 mg/ 100 mg Time-averaged differenceonce daily) twice daily) ATV/RTV-LPV/RTVn=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 -1.93 -2.29 -1.87 -2.08 0.13 0.14patients (n=90 e) (n=64) (n=99) (n=65) [-0.12, 0.39] [-0.13, 0.41]

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

All 36 (43/120) 32 (38/120) 42 (52/123) 35 (41/118) NA NApatients

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 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NApatientsa The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baselineplasma 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 whocompleted treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with

HIV RNA < 400 copies/mL were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at Weeks 48and 96 respectively.g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54,

L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline.

NA = not applicable.

Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for atazanavir +ritonavir and lopinavir + ritonavir were similar (non-inferior). Consistent results were obtained with the lastobservation carried forward method of analysis (time-averaged difference of 0.11, 97.5% confidence interval[-0.15, 0.36]). By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/mL (< 50 copies/mL) in the atazanavir + ritonavir arm and the lopinavir + ritonavir arm were55% (40%) and 56% (46%), respectively.

Through 96 weeks of treatment, mean HIV RNA changes from baseline for atazanavir + ritonavir andlopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistent results wereobtained with the last observation carried forward method of analysis. By as-treated analysis, excludingmissing values, the proportions of patients with HIV RNA <400 copies/mL (<50 copies/mL) for atazanavir +ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at t imeof the 96-week analysis, 48 % of patients overall remained on study.

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

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of atazanavir is based on data from theopen- label, multicenter clinical trial AI424-020 conducted in patients from 3 months to 21 years of age.

Overall in this study, 182 paediatric patients (81 antiretroviral-naïve and 101 antiretroviral-experienced)received once daily atazanavir (capsule or powder formulation), with or without ritonavir, in combinationwith two NRTIs.

The clinical data derived from this study are inadequate to support the use of atazanavir (with or withoutritonavir) in children below 6 years of age.

Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received

Atazanavir capsules with ritonavir are presented in Table 7. For treatment-naïve paediatric patients, the meanbaseline CD4 cell count was 344 cells/mm3 (range: 2 to 800 cells/ mm3) and mean baseline plasma HIV 1

RNA was 4.67 log10 copies/mL (range: 3.70 to 5.00 log10 copies/mL). For treatment-experienced paediatricpatients, the mean baseline CD4 cell count was 522 cells/mm3 (range: 100 to 1157 cells/mm3) and meanbaseline plasma HIV 1 RNA was 4.09 log10 copies/mL (range: 3.28 to 5.00 log10 copies/mL).

Table 7: Efficacy Outcomes (paediatric patients 6 years to less than 18 years of age) at Week 48 (Study

AI424-020)

Parameter Treatment-Naïve Treatment-Experienced

Atazanavir Atazanavir

Capsules/ritonavir Capsules/ritonavir(300 mg/100 mg once (300 mg/100 mg oncedaily) daily)n=16 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-infected patients;significant differences were observed between the two groups. The pharmacokinetics of atazanavir exhibit anon-linear disposition.

In HIV-infected patients (n=33, combined studies), multiple dosing of atazanavir 300 mg once daily withritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, Cmax of 4466 (42%)ng/mL, with time to Cmax of approximately 2.5 hours. The geometric mean (CV%) for atazanavir Cmin and

AUC was 654 (76%) ng/mL and 44185 (51%) ng*h/mL, respectively.

In HIV-infected patients (n=13), multiple dosing of atazanavir 400 mg (without ritonavir) once daily withfood produced a geometric mean (CV%) for atazanavir Cmax of 2298 (71) ng/mL, with time to Cmax ofapproximately 2.0 hours. The geometric mean (CV%) for atazanavir Cmin and AUC were 120 (109) ng/mLand 14874 (91) ng*h/mL, respectively.

Co-administration of atazanavir and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300-mg dose of atazanavir and 100-mg dose of ritonavir with a light meal resultedin a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration ofatazanavir relative to the fasting state. Co-administration with a high-fat meal did not affect the AUC ofatazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hourconcentration following a high fat meal was increased by approximately 33% due to delayed absorption; themedian Tmax increased from 2.0 to 5.0 hours. Administration of atazanavir with ritonavir with either a light ora high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared tothe fasting state. To enhance bioavailability and minimise variability, atazanavir is to be taken with food.

Atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to10,000 ng/mL. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent(89% and 86%, respectively, at 1,000 ng/mL). In a multiple-dose study in HIV-infected patients dosed with400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinalfluid and semen.

Studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir isprincipally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are then excreted in thebile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of

N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised.

Neither metabolite demonstrated in vitro antiviral activity.

Following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered inthe faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of theadministered dose in the faeces and urine, respectively. Mean urinary excretion of unchanged drug was 7%following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult patients (n=33, combined studies)the mean half-life within a dosing interval for atazanavir was 12 hours at steady state following a dose of300 mg daily with ritonavir 100 mg once daily with a light meal.

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administereddose. There are no pharmacokinetic data available for atazanavir with ritonavir in patients with renalinsufficiency. Atazanavir (without ritonavir) has been studied in adult patients with severe renal impairment(n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this studypresented some limitations (i.e., unbound drug concentrations not studied), results suggested that theatazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysiscompared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections4.2 and 4.4.)

Atazanavir is metabolised and eliminated primarily by the liver. Atazanavir (without ritonavir) has beenstudied 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 withimpaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impairedsubjects was 12.1 hours compared to 6.4 hours in healthy subjects. The effects of hepatic impairment on thepharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied. Concentrations ofatazanavir with or without ritonavir are expected to be increased in patients with moderately or severelyimpaired hepatic function (see sections 4.2, pct. 4.3, and 4.4).

Age/gender

A study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female subjects (29young, 30 elderly). There were no clinically important pharmacokinetic differences based on age or gender.

A population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race onthe pharmacokinetics of atazanavir.

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

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

Women in the Fed Stateatazanavir 300 mg with ritonavir 100 mg

Pharmacokinetic Parameter 2nd Trimester 3rd Trimester postpartuma(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)

C bmin ng/mL 663.78 668.48 1420.64

Geometric mean (CV%) (36) (50) (47)a Atazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during thepostpartum period (4-12 weeks) than those observed historically in HIV-infected, non-pregnant patients.

Atazanavir plasma trough concentrations were approximately 2-fold higher during the postpartum periodwhen compared to those observed historically in HIV-infected non-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 a result,greater peak to trough ratios are observed, however at recommended doses, geometric mean atazanavirexposures (Cmin, Cmax, and AUC) in paediatric patients are expected to be similar to those observed in adults.

In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were generallyconfined to the liver and included generally minimal to mild increases in serum bilirubin and liver enzymes,hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic single-cell necrosis. Systemicexposures of atazanavir in mice (males), rats, and dogs at doses associated with hepatic changes were at leastequal to that observed in humans given 400 mg once daily. In female mice, atazanavir exposure at a dose thatproduced single-cell necrosis was 12 times the exposure in humans given 400 mg once daily. Serumcholesterol and glucose were minimally to mildly increased in rats but not in mice or dogs.

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at aconcentration (30 μM) of atazanavir corresponding to 30-fold the free drug concentration at Cmax in humans.

Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) in rabbit

Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval,prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2-week oraltoxicity study performed in dogs. Subsequent 9-month oral toxicity studies in dogs showed no drug-relatedelectrocardiographic changes. The clinical relevance of these non-clinical data is unknown. Potential cardiaceffects of this product in humans cannot be ruled out (see sections 4.4 and 4.8). The potential for PRprolongation should be considered in cases of overdose (see section 4.9).

In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with 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 or moribunddoes at maternal doses 2 and 4 times the highest dose administered in the definitive embryo-developmentstudy. In the pre- and postnatal development assessment in rats, atazanavir produced a transient reduction inbody weight in the offspring at a maternally toxic dose. Systemic exposure to atazanavir at doses thatresulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given400 mg once daily.

Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitroin both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not inducemicronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liverat plasma and tissue concentrations exceeding those that were clastogenic in vitro.

In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign hepaticadenomas was seen in female mice only. The increased incidence of benign hepatic adenomas in femalemice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and is considered tohave no relevance for humans at intended therapeutic exposures. There were no tumorigenic findings in malemice or in rats.

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

Lactose monohydrate

Crospovidone

Magnesium stearate

Capsule shell cap 150 mg

Iron oxide red (E172)

Titanium dioxide (E171)

Patent blue V (E131)

Gelatin

Capsule shell body 150 mg

Titanium dioxide (E171)

Patent blue V (E131)

Gelatin

Capsule shell cap 200 mg

Titanium dioxide (E171)

Indigo Carmine (E132)

Gelatin

Capsule shell body 200 mg

Iron oxide yellow (E172)

Titanium dioxide (E171)

Patent blue V (E131)

Gelatin

Capsule shell cap 300 mg

Iron oxide yellow (E172)

Iron oxide red (E172)

Titanium dioxide (E171)

Gelatin

Capsule shell body 300 mg

Iron oxide red (E172)

Titanium dioxide (E171)

Patent blue V (E131)

Gelatin

Shellac

Ammonia solution, concentrated

Iron oxide black (E172)

Potassium hydroxide

Not applicable.

3 years

For bottles: Use within 90 days of first opening

Store below 25°C. Store in the original package in order to protect from moisture.

150 mg

OPA/Aluminium/PVC - Aluminium blisters containing 60, 60 x 1 (unit dose) capsules.

PVC/PVDC/Aluminium blisters containing 60, 60 x 1 (unit dose) capsules.

HDPE bottle with polypropylene screw cap containing 60 capsules.

200 mg

OPA/Aluminium/PVC - Aluminium blisters containing 60, 60 x 1 (unit dose) capsules.

PVC/PVDC/Aluminium blisters containing 30, 60, 60 x 1 (unit dose) capsules.

HDPE bottle with polypropylene screw cap containing 60 capsules.

300 mg

OPA/Aluminium/PVC - Aluminium blisters containing 30, 30 x 1 (unit dose) capsules.

PVC/PVDC/Aluminium blisters containing 30, 30 x 1 (unit dose) capsules.

HDPE bottle with polypropylene screw cap containing 30, 90 capsules.

Not all pack sizes may be marketed.

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

Viatris Limited

Damastown Industrial Park,

Mulhuddart,

Dublin 15,

DUBLIN,

Ireland

EU/1/16/1091/001

EU/1/16/1091/002

EU/1/16/1091/003

EU/1/16/1091/004

EU/1/16/1091/005

EU/1/16/1091/006

EU/1/16/1091/007

EU/1/16/1091/008

EU/1/16/1091/009

EU/1/16/1091/010

EU/1/16/1091/011

EU/1/16/1091/012

EU/1/16/1091/013

EU/1/16/1091/014

EU/1/16/1091/015

EU/1/16/1091/016

EU/1/16/1091/017

Date of first authorisation: 22 August 2016

Date of latest renewal: 26 April 2021

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

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