Leaflet EVOTAZ 300mg / 150mg film-coated tablets

EVOTAZ 300 mg/150 mg film-coated tablets

Each film-coated tablet contains atazanavir sulphate corresponding to 300 mg atazanavir and 150 mgof cobicistat.

For the full list of excipients, see section 6.1.

Film-coated tablet

Pink, oval, biconvex, film-coated tablet of approximate dimensions of 19 mm x 10.4 mm, debossedwith '3641' on one side and plain on the other side.

EVOTAZ is indicated in combination with other antiretroviral medicinal products for the treatment of

HIV-1 infected adults and adolescents (aged 12 years and older weighing at least 35 kg) withoutknown mutations associated with resistance to atazanavir (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 EVOTAZ for adults and adolescents (aged 12 years and older weighing atleast 35 kg) is one tablet once daily taken orally with food (see section 5.2).

If EVOTAZ is missed within 12 hours of the time it is usually taken, patients should be instructed totake the prescribed dose of EVOTAZ with food as soon as possible. If this is noticed later than12 hours of the time it is usually taken, the missed dose should not be taken and the patient shouldresume the usual dosing schedule.

Based on the very limited renal elimination of cobicistat and atazanavir, no special precautions or doseadjustments of EVOTAZ are required for patients with renal impairment.

EVOTAZ is not recommended for patients undergoing haemodialysis (see sections 4.4 and 5.2).

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubularsecretion of creatinine without affecting actual renal glomerular function. EVOTAZ should not beinitiated in patients with creatinine clearance less than 70 mL/min if any co-administered medicinalproduct (e.g. emtricitabine, lamivudine, tenofovir disoproxil or adefovir) requires dose adjustmentbased on creatinine clearance (see sections 4.4, pct. 4.8 and 5.2).

There are no pharmacokinetic data regarding the use of EVOTAZ in patients with hepatic impairment.

Atazanavir and cobicistat are metabolised by the hepatic system. Atazanavir should be used withcaution in patients with mild (Child-Pugh Class A) hepatic impairment. However, atazanavir must notbe used in patients with moderate (Child-Pugh Class B) to severe (Child-Pugh Class C) hepaticimpairment. No dose adjustment of cobicistat is required in patients with mild or moderate hepaticimpairment. Cobicistat has not been studied in patients with severe hepatic impairment and is notrecommended in these patients.

EVOTAZ should be used with caution in patients with mild hepatic impairment. EVOTAZ must notbe used in patients with moderate to severe hepatic impairment (see section 4.3).

EVOTAZ should not be used in children less than 3 months of age because of safety concernsespecially taking into account the potential risk of kernicterus associated with the atazanavircomponent.

Children from 3 months to < 12 years of age or weighing < 35 kg

The safety and efficacy of EVOTAZ in children less than 12 years of age or weighing less than 35 kghave not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but norecommendation on a posology can be made.

Treatment with EVOTAZ during pregnancy results in low atazanavir exposure. Therefore, therapywith EVOTAZ should not be initiated during pregnancy, and women who become pregnant duringtherapy with EVOTAZ should be switched to an alternative regimen (see sections 4.4 and 4.6).

EVOTAZ is to be taken orally with food (see section 5.2). The film-coated tablet should be swallowedwhole and must not be chewed, broken, cut or crushed.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Co-administration with the following medicinal products that are strong inducers of the CYP3A4isoform of cytochrome P450 due to the potential for loss of therapeutic effect (see section 4.5): carbamazepine, phenobarbital, phenytoin (antiepileptics) St John's wort (Hypericum perforatum) (herbal product) rifampicin (antimycobacterial)

Co-administration with the following medicinal products due to the potential for serious and/or life-threatening adverse reactions (see section 4.5): colchicine, when used in patients with renal and/or hepatic impairment (antigout) (seesection 4.5) sildenafil - when used for the treatment of pulmonary arterial hypertension (see sections 4.4and 4.5 for co-administration for the treatment of erectile dysfunction), avanafil (PDE5inhibitors) dabigatran (anticoagulant) simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5) lomitapide (lipid-modifying agent) grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used totreat chronic hepatitis C infection) (see section 4.5) glecaprevir/pibrentasvir fixed dose combination (see section 4.5) substrates of CYP3A4 or the UGT1A1 isoform of UDP-glucuronyltransferase and have narrowtherapeutic windows: alfuzosin (alpha-1-adrenoreceptor antagonist) amiodarone, bepridil, dronedarone, quinidine, systemic lidocaine(antiarrhythmics/antianginals) astemizole, terfenadine (antihistamines) cisapride (gastrointestinal motility agent) ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine) pimozide, quetiapine, lurasidone (antipsychotics/neuroleptics) (see section 4.5) ticagrelor (platelet aggregation inhibitor) triazolam, midazolam administered orally (sedatives/hypnotics) (for caution onparenterally administered midazolam, see section 4.5).

Moderate to severe hepatic impairment.

The choice of EVOTAZ in patients should be based on individual viral resistance testing and thepatient’s treatment history (see section 5.1).

Treatment with atazanavir/cobicistat 300/150 mg during the second and third trimester has beenshown to result in low atazanavir exposure. Cobicistat levels decrease and may not provide sufficientboosting. The substantial reduction in atazanavir exposure may result in virological failure and anincreased risk of mother to child transmission of HIV infection. Therefore, therapy with EVOTAZshould not be initiated during pregnancy, and women who become pregnant during therapy with

EVOTAZ should be switched to an alternative regimen (see sections 4.2 and 4.6).

The use of EVOTAZ is contraindicated in patients with moderate to severe hepatic impairment.

EVOTAZ should be used with caution in patients with mild hepatic impairment (see sections 4.2, pct. 4.3and 5.2).

Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed inpatients with hepatic impairment (see sections 4.2 and 5.2). The safety and efficacy of atazanavir havenot been established in patients with significant underlying liver disorders. Patients with chronichepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severeand potentially fatal hepatic adverse reactions (see section 4.8). In case of concomitant antiviraltherapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics forthese medicinal products.

Patients with previous liver dysfunction or patients with chronic active hepatitis have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, interruption or discontinuation of treatment must be considered.

Cobicistat has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

EVOTAZ is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubularsecretion of creatinine. This effect on serum creatinine, leading to a decrease in the estimated creatineclearance, should be taken into consideration when EVOTAZ is administered to patients in whom theestimated creatinine clearance is used to guide aspects of their clinical management, includingadjusting doses of co-administered medicinal products. For more information consult the cobicistat

Summary of Product Characteristics.

EVOTAZ should not be initiated in patients with creatinine clearance less than 70 mL/min if one ormore co-administered medicinal product requires dose adjustment based on creatinine clearance (e.g.emtricitabine, lamivudine, tenofovir disoproxil or adefovir; see sections 4.2, pct. 4.8 and 5.2).

As atazanavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will besignificantly removed by haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil andcobicistat is associated with a greater risk of renal adverse reactions compared with regimens thatinclude tenofovir disoproxil without cobicistat.

Dose related asymptomatic prolongations in PR interval with atazanavir, a component of EVOTAZhave been observed in clinical studies. Caution should be used with medicinal products known toinduce PR prolongations. In patients with pre-existing conduction problems (second degree or higheratrioventricular or complex bundle-branch block), EVOTAZ should be used with caution and only ifthe benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing

EVOTAZ in association with medicinal products which have the potential to increase the QT intervaland/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyteimbalances (see sections 4.8 and 5.3).

There have been reports of increased bleeding, including spontaneous skin haematomas andhaemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In somepatients additional factor VIII was given. In more than half of the reported cases, treatment withprotease inhibitors was continued or reintroduced if treatment had been discontinued. A causalrelationship has been suggested, although the mechanism of action has not been elucidated.

Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.

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

In clinical studies, atazanavir has been shown to induce dyslipidaemia to a lesser extent thancomparators.

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT) have occurred in patients receiving atazanavir (see section 4.8). Hepatictransaminase elevations that occur with elevated bilirubin in patients receiving EVOTAZ should beevaluated for alternative aetiologies. Alternative antiretroviral therapy to EVOTAZ may be consideredif jaundice or scleral icterus is unacceptable to a patient.

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

UGT. Combinations of EVOTAZ and indinavir have not been studied and co-administration of thesemedicinal products is not recommended (see section 4.5).

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

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

Nephrolithiasis has been reported in patients receiving atazanavir (see section 4.8). Some patientsrequired hospitalisation for additional management and some had complications. In some cases,nephrolithiasis has been associated with acute renal failure or renal insufficiency. If signs or symptomsof nephrolithiasis occurs, temporary interruption or discontinuation of treatment may be considered.

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

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

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

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

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash witheosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receivingatazanavir. Patients should be advised of the signs and symptoms and monitored closely for skinreactions. EVOTAZ or any other medicinal product containing atazanavir should be discontinued ifsevere rash develops.

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

EVOTAZ, EVOTAZ may not be restarted.

EVOTAZ is indicated for use with other antiretrovirals for the treatment of HIV-1 infection. EVOTAZshould not be used in combination with products containing the same active components includingatazanavir, cobicistat or with fixed-dose products that contain cobicistat. EVOTAZ should not be usedin combination with another antiretroviral that requires pharmacokinetic enhancement (i.e., anotherprotease inhibitor or elvitegravir) since dosing recommendations for such combinations have not beenestablished and may result in decreased plasma concentrations of atazanavir and/or the otherantiretroviral leading to loss of therapeutic effect and development of resistance. Co-administration of

EVOTAZ with other protease inhibitors is not recommended. Because atazanavir is a component of

EVOTAZ, co-administration of EVOTAZ with nevirapine or efavirenz is not recommended (seesection 4.5).

EVOTAZ should not be used in combination with ritonavir or medicinal products containing ritonavirdue to similar pharmacological effects of cobicistat and ritonavir on CYP3A (see section 4.5).

Atazanavir is metabolised principally by CYP3A4. Cobicistat is a strong mechanism-based CYP3Ainhibitor and is a CYP3A substrate. Co-administration of EVOTAZ and medicinal products thatinduce CYP3A4 is contraindicated or not recommended (see sections 4.3 and 4.5) because, in additionto decreased plasma concentrations of atazanavir due to induction of CYP3A4, decreased plasmaconcentrations of cobicistat could result in cobicistat plasma levels that are insufficient to achieveadequate pharmacoenhancement of atazanavir.

Increased plasma concentrations of medicinal products that are metabolised by CYP3A (includingatazanavir) are observed on co-administration with cobicistat. Higher plasma concentrations of co-administered medicinal products can result in increased or prolonged therapeutic effects or adversereactions. For medicinal products metabolised by CYP3A these higher plasma concentrations maypotentially lead to severe, life-threatening or fatal events (see sections 4.3 and 4.5).

Co-administration of EVOTAZ with medicinal products that inhibit CYP3A may decrease theclearance of atazanavir and cobicistat, resulting in increased atazanavir and cobicistat plasmaconcentrations (see section 4.5).

Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or

UGT1A1. If switching from atazanavir boosted with ritonavir to EVOTAZ, caution is required duringthe first two weeks of treatment with EVOTAZ, particularly if doses of any concomitantlyadministered medicinal products have been titrated or adjusted during use of ritonavir as apharmacoenhancer (see section 4.5).

Cobicistat is a weak CYP2D6 inhibitor and is metabolised to a minor extent by CYP2D6.

Co-administration with EVOTAZ can increase plasma concentrations of medicinal products that aremetabolised by CYP2D6 (see sections 4.3 and 4.5).

Because atazanavir is a component of EVOTAZ, the combination of EVOTAZ with atorvastatin is notrecommended (see section 4.5).

Particular caution should be used when prescribing PDE5-inhibitors (sildenafil, tadalafil, vardenafil, oravanafil) for the treatment of erectile dysfunction in patients receiving EVOTAZ. Co-administration of

EVOTAZ with these medicinal products is expected to substantially increase their concentrations andmay result in PDE5-associated adverse reactions such as hypotension, visual changes and priapism(see section 4.5).

Co-administration of voriconazole and EVOTAZ is not recommended unless an assessment of thebenefit/risk justifies the use of voriconazole (see section 4.5).

Concomitant use of EVOTAZ and fluticasone or other glucocorticoids that are metabolized by

CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemiccorticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5).

Co-administration of EVOTAZ with warfarin has the potential to produce serious and/orlife-threatening bleeding due to increased warfarin plasma concentrations, and it is recommended thatthe International Normalized Ratio (INR) be monitored (see section 4.5).

Co-administration of EVOTAZ with proton pump inhibitors (PPIs) is not recommended due to thedecreased solubility of atazanavir as intra-gastric pH increase with PPIs (see section 4.5).

Plasma concentrations of drospirenone are increased following administration ofdrospirenone/ethinyloestradiol with atazanavir/cobicistat. If drospirenone/ethinyloestradiol is co-administered with atazanavir/cobicistat, clinical monitoring is recommended due to the potential forhyperkalemia.

Data are not available to make recommendations regarding the use of EVOTAZ with other oralcontraceptives. Alternative forms of contraception (non-hormonal) should be considered (seesection 4.5).

Drug interaction trials were not conducted for EVOTAZ. As EVOTAZ contains atazanavir andcobicistat, any interactions that have been identified with these active substances individually mayoccur with EVOTAZ.

Complex or unknown mechanisms of drug interaction preclude extrapolation of ritonavir druginteractions to certain cobicistat drug interactions. The recommendations given for concomitant use ofatazanavir and other medicinal products may, therefore, differ depending on whether atazanavir isboosted with ritonavir or cobicistat. In particular, atazanavir boosted with cobicistat is more sensitivefor CYP3A induction (see section 4.3 and the interaction table). Caution is also required during thefirst time of treatment if switching the pharmacoenhancer from ritonavir to cobicistat (see section 4.4).

Atazanavir is metabolised in the liver through CYP3A4.

Cobicistat is a CYP3A substrate and is metabolised to a minor extent by CYP2D6.

Co-administration of EVOTAZ with medicinal products that are strong inducers of CYP3A (such ascarbamazepine, phenobarbital, phenytoin, rifampicin, and St. John’s wort [Hypericum perforatum])may result in decreased plasma concentrations of atazanavir and/or cobicistat, leading to loss oftherapeutic effect and possible development of resistance to atazanavir (see section 4.3 and Table 1).

Co-administration of EVOTAZ with medicinal products containing ritonavir or cobicistat, which arestrong inhibitors of CYP3A, may result in additional boosting and increased plasma concentration ofatazanavir.

Co-administration of EVOTAZ with medicinal products that inhibit CYP3A may result in increasedplasma concentration of atazanavir and/or cobicistat. Some examples include, but are not limited to,itraconazole, ketoconazole and voriconazole (see Table 1).

Co-administration of EVOTAZ with medicinal products that are moderate to weak inducers of

CYP3A may result in decreased plasma concentration of atazanavir and/or cobicistat, leading to lossof therapeutic effect and possible development of resistance to atazanavir. Some examples include, butare not limited to etravirine, nevirapine, efavirenz, fluticasone and bosentan (see Table 1).

Atazanavir is an inhibitor of CYP3A4 and UGT1A1. Atazanavir is a weak to moderate inhibitor of

CYP2C8. Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase thebiotransformation of some medicinal products metabolised by CYP3A4.

Cobicistat is a strong mechanism-based CYP3A inhibitor and a weak CYP2D6 inhibitor. Cobicistatinhibits the transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3.

Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19.

Cobicistat is not expected to induce CYP3A4 or P-gp. Unlike ritonavir, cobicistat is not an inducer of

CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1.

Co-administration of medicinal products that are substrates of CYP3A and have narrow therapeuticindeces and for which elevated plasma concentrations are associated with serious and/orlife-threatening events are contraindicated with EVOTAZ. These medicinal products includealfuzosin, amiodarone, astemizole, bepridil, cisapride, colchicine, dronedarone, ergot deriviatives (e.g.dihydroergotamine, ergometrine, ergotamine, methylergonovine), lomitapide, lovastatin, orallyadministered midazolam, pimozide, quetiapine, quinidine, lurasidone, simvastatin, sildenafil (whenused to treat pulmonary arterial hypertension), avanafil, systemic lidocaine, ticagrelor, terfenadine andtriazolam.

Co-administration of EVOTAZ with grazoprevir-containing products, including elbasvir/grazoprevirfixed dose combination (used to treat chronic hepatitis C infection) is contraindicated because of theincrease in grazoprevir and elbasvir plasma concentrations and potential for the increase in risk of

ALT elevations associated with the increase in grazoprevir concentrations (see section 4.3 and

Table 1). Co-administration of EVOTAZ with glecaprevir/pibrentasvir fixed dose combination 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).

Increased plasma concentrations of medicinal products that are metabolised by CYP3A, CYP2C8,

CYP2D6 and/or UGT1A1 are expected when co-administered with EVOTAZ. Co-administration of

EVOTAZ in patients receiving medicinal products that are substrates of the transporters P-gp, BCRP,

MATE1, OATP1B1 and OATP1B3 may result in increased plasma concentrations of theco-administered medicinal products (see section 4.4). Co-administration with dabigatran, a substrate of

P-gp, is contraindicated. Clinically significant interactions between EVOTAZ and substrates of

CYP1A2, CYP2B6, CYP2C9 or CYP2C19 are not expected.

Interactions between EVOTAZ and other medicinal products are listed in Table 1 below (increase isindicated as “↑”, decrease as “↓”, no change as “↔”). The recommendations shown in Table 1 arebased on either drug interaction trials of unboosted atazanavir, atazanavir boosted with ritonavir,cobicistat or predicted interactions due to the expected magnitude of the interaction and potential forserious adverse reactions or loss of therapeutic effect of EVOTAZ. If available, 90% confidenceintervals (CI) are shown in parentheses. The studies presented in Table 1 were conducted in healthysubjects unless otherwise noted.

Table 1: Interactions between EVOTAZ and other medicinal products

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

ANTI-HCV AGENTS

Grazoprevir 200 mg once Atazanavir AUC ↑43% Co-administration of EVOTAZ anddaily (↑30% ↑57%) elbasvir/grazoprevir is(atazanavir 300 mg/ritonavir Atazanavir Cmax ↑12% (↑1% contraindicated because of the100 mg once daily) ↑24%) expected increase in grazoprevir

Atazanavir Cmin ↑23% (↑13% plasma concentrations and the↑134%) associated potential increase in therisk of ALT elevations

Grazoprevir AUC: ↑958% (see section 4.3).(↑678% ↑1339%)

Grazoprevir Cmax: ↑524%(↑342% ↑781%)

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

Grazoprevir concentrationswere greatly increased whenco-administered withatazanavir/ritonavir.

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

Atazanavir Cmin ↑15% (↑2%↑29%)

Elbasvir AUC: ↑376%(↑307% ↑456%)

Elbasvir Cmax: ↑315%(↑246% ↑397%)

Elbasvir Cmin: ↑545%(↑451% ↑654%)

Elbasvir concentrations wereincreased whenco-administered withatazanavir/ritonavir

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Sofosbuvir Sofosbuvir AUC: ↑40% Co-administration of EVOTAZ400 mg/velpatasvir, (↑25% ↑57%) with voxilaprevir-containing100 mg/voxilaprevir 100 mg Sofosbuvir Cmax:↑29% (↑9% products is expected to increase thesingle dose* ↑52%) concentration of voxilaprevir. Co-(atazanavir 300 mg with administration of EVOTAZ withritonavir 100 mg once daily) Velpatasvir AUC: ↑93% voxilaprevir-containing regimens is(↑58% ↑136%) not recommended.

Velpatasvir Cmax: ↑29%(↑7% ↑56%)

Voxilaprevir AUC: ↑331%(↑276% ↑393%)

Voxilaprevir Cmax: ↑342%(↑265% ↑435%)

*Lack of pharmacokineticsinteraction bounds 70-143%

Effect on atazanavir andritonavir exposure has notbeen studied.

Expected:↔ Atazanavir↔ Ritonavir

The mechanism ofinteraction betweenatazanavir/ritonavir andsofosbuvir/velpatasvir/voxilaprevir is inhibition of

OATP1B, Pgp, and CYP3A.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Glecaprevir Glecaprevir AUC: ↑553% Contraindicated because of the300 mg/pibrentasvir 120 mg (↑424% ↑714%) potential increase in the risk ofonce daily Glecaprevir Cmax: ↑306% ALT elevations due to a significant(atazanavir 300 mg with (↑215% ↑423%) increase in glecaprevir andritonavir 100 mg once daily*) Glecaprevir Cmin: ↑1330% pibrentasvir plasma concentrations(↑885% ↑1970%) (see section 4.3)

Pibrentasvir AUC: ↑64%(↑48% ↑82%)

Pibrentasvir Cmax: ↑29%(↑15% ↑45%)

Pibrentasvir Cmin: ↑129%(↑95% ↑168%)

Atazanavir AUC: ↑11%(↑3% ↑19%)

Atazanavir Cmax: ↔ 0% (↓10% ↑10%)

Atazanavir Cmin: ↑16% (↑7%↑25%)

* Effect of atazanavir andritonavir on the first dose ofglecaprevir and pibrentasviris reported.

ANTI-RETROVIRALS

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

Indinavir Indinavir is associated with Co-administration of EVOTAZ andindirect unconjugated indinavir is not recommendedhyperbilirubinaemia due to (see section 4.4).inhibition of UGT.

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

Lamivudine 150 mg No significant effect on Based on these data and becausetwice daily + zidovudine lamivudine and zidovudine cobicistat is not expected to have a300 mg twice daily concentrations was observed significant impact on the(atazanavir 400 mg once daily) when co-administered with pharmacokinetics of NRTIs, theatazanavir. co-administration of EVOTAZwith these medicinal products isnot expected to significantly alterthe exposure of the co-administeredmedicinal products.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Didanosine (buffered tablets) Atazanavir, simultaneous Didanosine should be taken in the200 mg/stavudine 40 mg, both administration with ddI+d4T fasted state 2 hours after EVOTAZsingle dose (fasted) taken with food. The(atazanavir 400 mg single dose) Atazanavir AUC ↓87% co-administration of EVOTAZ(↓92% ↓79%) with stavudine is not expected to

Atazanavir Cmax ↓89% significantly alter the exposure of(↓94% ↓82%) stavudine.

Atazanavir Cmin ↓84% (↓90%↓73%)

Atazanavir, dosed 1 hr afterddI+d4T (fasted)

Atazanavir AUC ↔3%(↓36% ↑67%)

Atazanavir Cmax ↑12%(↓33% ↑18%)

Atazanavir Cmin ↔3% (↓39%↑73%)

Atazanavir concentrationswere greatly decreased whenco-administered withdidanosine (buffered tablets)and stavudine.

The mechanism ofinteraction is a reducedsolubility of atazanavir withincreasing pH related to thepresence of anti-acid agent indidanosine buffered tablets.

No significant effect ondidanosine and stavudineconcentrations was observed.

Didanosine (enteric-coated Didanosine (with food)capsules) 400 mg single dose Didanosine AUC ↓34%(atazanavir 400 mg once daily) (↓40% ↓26%)

Didanosine Cmax ↓36%(↓45% ↓26%)

Didanosine Cmin ↑13% (↓9%↑41%)

No significant effect onatazanavir concentrationswas observed whenadministered withenteric-coated didanosine,but administration with fooddecreased didanosineconcentrations.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Tenofovir disoproxil fumarate Atazanavir AUC ↓25% Tenofovir DF may decrease the(tenofovir DF) 300 mg (↓30% ↓19%) AUC and Cmin of atazanavir. Whenonce daily Atazanavir Cmax ↓21% co-administered with tenofovir DF,(atazanavir 400 mg once daily) (↓27% ↓14%) it is recommended that EVOTAZ

Atazanavir Cmin ↓40% (↓48% and tenofovir DF 300 mg be given300 mg tenofovir disoproxil ↓32%) together with food. Atazanavirfumarate is equivalent to increases tenofovir concentrations.245 mg tenofovir disoproxil. Tenofovir: Higher concentrations could

AUC: ↑24% (↑21% ↑28%) potentiate tenofovir-associated

Cmax: ↑14% (↑8% ↑20%) adverse reactions, including renal

Cmin: ↑22% (↑15% ↑30%) disorders. Patients receivingtenofovir disoproxil should be

Co-administration of monitored for tenofovir-associatedtenofovir DF with cobicistat adverse reactions.is expected to increasetenofovir plasmaconcentrations.

Tenofovir:

AUC: ↑23%

Cmin: ↑55%

The mechanism ofinteraction betweenatazanavir and tenofovir DFis unknown.

Tenofovir alafenamide 10 mg Tenofovir alafenamide When co-administering tenofovironce daily/emtricitabine AUC ↑75% (↑55% ↑98%) alafenamide/emtricitabine and200 mg once daily Cmax ↑80% (↑48% ↑118%) EVOTAZ, the recommended dose(atazanavir 300 mg once daily of tenofovirwith cobicistat 150 mg once Tenofovir: alafenamide/emtricitabine isdaily) AUC ↑247% (↑229% 10/200 mg once daily.

Tenofovir alafenamide 10 mg ↑267%) Co-administration of EVOTAZ andonce daily Cmax ↑216% (↑200% ↑233%) tenofovir alafenamide 25 mg for(atazanavir 300 mg once daily Cmin ↑273% (↑254% ↑293%) treatment of HBV infection is notwith cobicistat 150 mg once recommendeddaily) Cobicistat:

AUC ↑5% (↔0% ↑9%)

Cmax ↓4% (↓8% ↔0%)

Cmin ↑35% (↑21% ↑51%)

Co-administration oftenofovir alafenamide withcobicistat is expected toincrease tenofoviralafenamide and tenofovirplasma concentrations.

AUC ↑6% (↑1% ↑11%)

Cmax ↓2% (↓4% ↑2%)

Cmin ↑18% (↑6% ↑31%)

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz 600 mg once daily Atazanavir EVOTAZ is not recommended for(atazanavir 400 mg once daily) Atazanavir AUC ↓74% co-administration with efavirenz.

(↓78% ↓68%) Efavirenz decreases atazanavir

Atazanavir Cmax ↓59% concentrations and is expected to(↓77% ↓49%) decrease cobicistat plasma

Atazanavir Cmin ↓93% (↓95% concentrations. This may result in↓90%) loss of therapeutic effect of

Efavirenz 600 mg single dose Efavirenz: EVOTAZ and development of(cobicistat 150 mg once daily) AUC: ↔7% (↓11% ↓3%) resistance to atazanavir (see

Cmax: ↓13% (↓20% ↓6%) section 4.4).

Cmin: Not determined

The mechanism ofinteraction betweenefavirenz and atazanavir, orefavirenz and cobicistat is

CYP3A4 induction byefavirenz.

Etravirine Co-administration of EVOTAZ is not recommended foretravirine and EVOTAZ is co-administration with etravirineexpected to decrease because it may result in the loss ofatazanavir and cobicistat therapeutic effect and developmentplasma concentrations. of resistance to atazanavir.

The mechanism ofinteraction is CYP3A4induction by etravirine.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Nevirapine 200 mg twice daily Nevirapine AUC ↑25% Co-administration of EVOTAZ and(atazanavir 300 mg once daily (↑17% ↑34%) nevirapine is not recommended andwith ritonavir 100 mg Nevirapine Cmax ↑17% (↑9% may result in a loss of therapeuticonce daily) ↑25%) effect of EVOTAZ and

Nevirapine Cmin ↑32% development of resistance to

Study conducted in (↑22% ↑43%) atazanavir. Co-administration of

HIV-infected patients nevirapine and EVOTAZ is

Atazanavir AUC ↓42% expected to increase nevirapine(↓52% ↓29%) plasma concentrations which may

Atazanavir Cmax ↓28% increase the risk of(↓40% ↓14%) nevirapine-associated toxicity (see

Atazanavir Cmin ↓72% (↓80% section 4.4).↓60%)

Co-administration ofnevirapine and cobicistat isexpected to decreasecobicistat plasmaconcentrations whilenevirapine plasmaconcentrations may beincreased.

The mechanism ofinteraction is CYP3A4induction by nevirapine and

CYP3A4 inhibition byatazanavir and cobicistat.

Rilpivirine EVOTAZ is expected to Co-administration of EVOTAZ andincrease rilpivirine plasma rilpivirine can be used without doseconcentrations. adjustments, as the expectedincrease in rilpivirine

The mechanism of concentrations is not consideredinteraction is CYP3A clinically relevant.inhibition.

Integrase Inhibitors

Dolutegravir Co-administration with EVOTAZ and dolutegravir can be

EVOTAZ is expected to used without dose adjustments.increase dolutegravir plasmaconcentrations. Dolutegraviris not expected to affect thepharmacokinetics of

EVOTAZ.

The mechanism ofinteraction is inhibition of

UGT1A1 by atazanavir.

Raltegravir 400 mg Raltegravir AUC ↑72% No dose adjustment is required fortwice daily Raltegravir Cmax ↑53% raltegravir if co-administered with(atazanavir 400 mg) Raltegravir C12hr ↑95% EVOTAZ.

The mechanism is UGT1A1inhibition by atazanavir.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

CCR5 Antagonists

Maraviroc Maraviroc is a substrate of When co-administering maraviroc

CYP3A and its plasma and EVOTAZ, patients shouldconcentration increases when receive maraviroc 150 mgco-administered with potent twice daily. For further details,

CYP3A inhibitors. consult the Summary of Product

Characteristics for maraviroc.

Maraviroc is not expected tohave an impact onconcentrations of atazanavirand cobicistat.

The mechanism ofinteraction is CYP3A4inhibition by atazanavir andcobicistat.

ANTIBIOTICS

Clarithromycin 500 mg Clarithromycin AUC ↑94% Alternative antibiotics should betwice daily (↑75% ↑116%) considered.(atazanavir 400 mg once daily) Clarithromycin Cmax ↑50%(↑32% ↑71%)

Clarithromycin Cmin ↑160%(↑135% ↑188%)14-OH clarithromycin14-OH clarithromycin AUC↓70% (↓74% ↓66%)14-OH clarithromycin Cmax↓72% (↓76% ↓67%)14-OH clarithromycin Cmin↓62% (↓66% ↓58%)

Atazanavir AUC ↑28%(↑16% ↑43%)

Atazanavir Cmax ↔6% (↓7%↑20%)

Atazanavir Cmin ↑91% (↑66%↑121%)

Clarithromycin may increaseconcentrations of atazanavirand cobicistat. Exposure toclarithromycin is expected toincrease if co-administeredwith EVOTAZ.

The mechanism ofinteraction is CYP3A4inhibition by atazanavirand/or cobicistat andclarithromycin.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

ANTIDIABETICS

Metformin Cobicistat reversibly inhibits Careful patient monitoring and

MATE1, and concentrations dose adjustment of metformin isof metformin may be recommended in patients who areincreased when taking EVOTAZ.co-administered with

EVOTAZ.

ANTIFUNGALS

Ketoconazole 200 mg No significant effect on Caution is warranted. Specificonce daily atazanavir concentrations dosing recommendations are not(atazanavir 400 mg once daily) was observed. available for co-administration of

Itraconazole Itraconazole, like EVOTAZ with either ketoconazoleketoconazole, is a potent or itraconazole.inhibitor as well as a If co-administration is required, thesubstrate of CYP3A4. daily dose of ketoconazole oritraconazole should not exceed

Concentrations of 200 mg.ketoconazole, itraconazole,and/or cobicistat may beincreased withco-administration ofketoconazole or itraconazolewith EVOTAZ.

The mechanism ofinteraction is CYP3A4inhibition by atazanavir,cobicistat and ketoconazoleor itraconazole.

Voriconazole Effects unknown Voriconazole should not beco-administered with EVOTAZunless the benefit/risk assessmentjustifies the use of voriconazole(see section 4.4). Clinicalmonitoring may be needed uponco-administration with EVOTAZ.

Fluconazole 200 mg once daily Atazanavir and fluconazole Clinical monitoring is(atazanavir 300 mg and concentrations were not recommended uponritonavir 100 mg once daily) significantly modified when co-administration with EVOTAZ.

atazanavir/ritonavir wasco-administered withfluconazole.

Concentration of fluconazolemay be increased ifco-administered withcobicistat.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

ANTIGOUT

Colchicine Colchicine plasma EVOTAZ must not beconcentrations may be co-administered with colchicine toincreased when patients with renal or hepaticco-administered with impairment.

EVOTAZ. Recommended dosage ofcolchicine when administered

The mechanism of with EVOTAZ in patientsinteraction is CYP3A4 without renal or hepaticinhibition by atazanavir and impairment: a dose reduction incobicistat. colchicine dosage or aninterruption of colchicine treatmentis recommended in patients withnormal renal or hepatic function iftreatment with EVOTAZ isrequired.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

ANTIMYCOBACTERIALS

Rifabutin 150 mg Rifabutin AUC ↑48% (↑19% Co-administration of EVOTAZ andtwice weekly ↑84%)* rifabutin is not recommended. If(atazanavir 300 mg once daily Rifabutin Cmax ↑149% the combination is needed, thewith ritonavir 100 mg (↑103% ↑206%)* recommended dose of rifabutin isonce daily) Rifabutin Cmin ↑40% (↑5% 150 mg 3 times per week on set↑87%)* days (for example

Monday-Wednesday-Friday).25-O-desacetyl-rifabutin Increased monitoring for

AUC ↑990% (↑714% rifabutin-associated adverse↑1361%)* reactions including neutropenia and25-O-desacetyl-rifabutin uveitis is warranted due to an

Cmax ↑677% (↑513% expected increase in exposure to↑883%)* rifabutin. Further dosage reduction25-O-desacetyl-rifabutin Cmin of rifabutin to 150 mg twice↑1045% (↑715% ↑1510%)* weekly on set days isrecommended for patients in whom

*When compared to the 150 mg dose 3 times per weekrifabutin 150 mg once daily is not tolerated. It should be kept inalone. Total rifabutin and mind that the twice weekly dosage25-O-desacetyl-rifabutin of 150 mg may not provide an

AUC ↑119% (↑78% ↑169%). optimal exposure to rifabutin thus

Rifabutin 150 mg every other Cobicistat: leading to a risk of rifamycinday/elvitegravir 150 mg AUC: ↔ resistance and a treatment failure.once daily/cobicistat 150 mg Cmax: ↔ Consideration should be given toonce daily Cmin: ↓66% official guidance on the appropriatetreatment of tuberculosis in

Rifabutin: HIV-infected patients.

AUC: ↔8%

Cmax: ↔9%

Cmin: ↔6%25-O-desacetyl-rifabutin:

AUC: ↑525%

Cmax: ↑384%

Cmin: ↑394%

The mechanism ofinteraction is CYP3A4inhibition by atazanavir andcobicistat.

Rifampicin 600 mg once daily Rifampicin is a strong Rifampicin substantially decreases(atazanavir 300 mg once daily CYP3A4 inducer and has plasma concentrations ofwith ritonavir 100 mg been shown to cause a 72% atazanavir, which may result in lossonce daily) decrease in atazanavir AUC of therapeutic effect of EVOTAZwhich can result in and development of resistance tovirological failure and atazanavir. The combination ofresistance development. rifampicin and EVOTAZ iscontraindicated (see section 4.3).

The mechanism ofinteraction is CYP3A4induction by rifampicin.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

ACID-REDUCING AGENTS

H2-Receptor antagonists

Without Tenofovir

Famotidine 20 mg twice daily Atazanavir AUC ↓18% For patients not taking tenofovir,(atazanavir 300 mg/ritonavir (↓25% ↑1%) EVOTAZ once daily with food100 mg once daily) in Atazanavir Cmax ↓20% should be administered

HIV-infected patients (↓32% ↓7%) simultaneously with, and/or at least

Atazanavir Cmin ↔1% (↓16% 10 hours after, a dose of the↑18%) H2-receptor antagonist. The dose ofthe H2-receptor antagonist shouldnot exceed a dose comparable tofamotidine 20 mg twice daily.

With Tenofovir DF 300 mg once daily

Famotidine 20 mg twice daily Atazanavir AUC ↓10% For patients who are taking(atazanavir 300 mg/ritonavir (↓18% ↓2%) tenofovir DF, it is not100 mg/tenofovir DF 300 mg Atazanavir Cmax ↓9% (↓16% recommended to co-administeronce daily, simultaneous ↓1%) EVOTAZ with an H2-receptoradministration) Atazanavir Cmin ↓19% (↓31% antagonist.

↓6%)

The mechanism ofinteraction is decreasedsolubility of atazanavir asintra-gastric pH increaseswith H2 blockers.

Omeprazole 40 mg once daily Atazanavir AUC ↓94% Co-administration of EVOTAZ(atazanavir 400 mg once daily, (↓95% ↓93%) with proton pump inhibitors is not2 hours after omeprazole) Atazanavir Cmax ↓96% recommended.

(↓96% ↓95%)

Atazanavir Cmin ↓95% (↓97%↓93%)

Omeprazole 40 mg once daily Atazanavir AUC ↓76%(atazanavir 300 mg once daily (↓78% ↓73%)with ritonavir 100 mg Atazanavir Cmax ↓72%once daily, 2 hours after (↓76% ↓68%)omeprazole) Atazanavir Cmin ↓78% (↓81%↓74%)

Omeprazole 20 mg once daily Atazanavir AUC ↓42%am (↓66% ↓25%)(atazanavir 300 mg once daily Atazanavir Cmax ↓39%with ritonavir 100 mg (↓64% ↓19%)once daily pm, 12 hours after Atazanavir Cmin ↓46% (↓59%omeprazole) ↓29%)

The mechanism ofinteraction is decreasedsolubility of atazanavir asintra-gastric pH increaseswith proton pump inhibitors.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Antacids

Antacids and medicinal Reduced plasma EVOTAZ should be administeredproducts containing buffers concentrations of atazanavir 2 hours before or 1 hour aftermay be the consequence of antacids or buffered medicinalincreased gastric pH if products.antacids, including bufferedmedicinal products, areadministered with EVOTAZ.

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Potential for increased Co-administration of EVOTAZalfuzosin concentrations with alfuzosin is contraindicatedwhich can result in (see section 4.3)hypotension.

The mechanism ofinteraction is CYP3A4inhibition by atazanavir andcobicistat.

ANTICOAGULANTS

Dabigatran Co-administration with Co-administration of EVOTAZ

EVOTAZ may increase with dabigatran is contraindicateddabigatran plasma levels (see section 4.3).with similar effects as seenwith other strong P-gpinhibitors.

The mechanism ofinteraction is P-gp inhibitionby cobicistat.

Warfarin Co-administration with Co-administration with EVOTAZ

EVOTAZ has the potential has the potential to produce seriousto increase warfarin plasma and/or life-threatening bleedingconcentrations. due to increased exposure towarfarin and has not been studied.

The mechanism of It is recommended that the INR beinteraction is CYP3A4 monitored.inhibition by atazanavir andcobicistat.

Apixaban Co-administration with Co-administration of apixaban,

Edoxaban EVOTAZ may result in edoxaban or rivaroxaban is not

Rivaroxaban increased plasma recommended with EVOTAZ.

concentrations of the

DOACs, which may lead toan increased risk of bleeding.

The mechanism ofinteraction is CYP3A4and/or P-gp inhibition bycobicistat.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

ANTIPLATELETS

Ticagrelor Co-administration of Concomitant administration of

EVOTAZ and ticagrelor may EVOTAZ with ticagrelor isincrease concentrations of contraindicated.the antiplatelet agent.

Use of other antiplatelets not

The mechanism of affected by CYP inhibition orinteraction is CYP3A and/or induction (e.g., prasugrel) is

P-gp inhibition by atazanavir recommended (see section 4.3).and cobicistat.

Clopidogrel Co-administration of Concomitant administration of

EVOTAZ with clopidogrel EVOTAZ with clopidogrel is notmay lead to potential recommended.reduction of the antiplateletactivity of clopidogrel. Use of other antiplatelets notaffected by CYP inhibition or

The mechanism of induction (e.g., prasugrel) isinteraction is CYP3A4 recommended.inhibition by atazanavirand/or cobicistat.

Prasugrel The mechanism of No dose adjustment of prasugrel isinteraction is CYP3A4 required.inhibition by atazanavirand/or cobicistat.

Antiplatelet activity isexpected to be adequate.

ANTIEPILEPTICS

Carbamazepine These antiepileptics are Co-administration of EVOTAZ and

Phenobarbital expected to decrease these antiepileptics is

Phenytoin atazanavir and/or cobicistat contraindicated (see section 4.3).

plasma concentrations.

The mechanism ofinteraction is CYP3Ainduction by theantiepileptic.

ANTIHISTAMINE AGENTS

Astemizole EVOTAZ must not be used Co-administration of EVOTAZ

Terfenadine in combination with with astemizole and terfenadine ismedicinal products that are contraindicated (see section 4.3).substrates of CYP3A4 andhave a narrow therapeuticindex.

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS

Antineoplastics

Irinotecan Atazanavir inhibits UGT and If EVOTAZ is co-administered withmay interfere with the irinotecan, patients should be closelymetabolism of irinotecan, monitored for adverse reactionsresulting in increased related to irinotecan.irinotecan toxicities.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Dasatinib Concentrations of these Concentrations of these medicinal

Nilotinib medicinal products may be products may be increased when

Vinblastine increased when co-administered with EVOTAZ

Vincristine co-administered with resulting in the potential for

EVOTAZ. increased adverse events usuallyassociated with these anticancer

The mechanism of medicinal products.interaction is CYP3A4inhibition by cobicistat.

Immunosuppressants

Ciclosporin Concentrations of these More frequent therapeutic

Tacrolimus immunosuppressants may be concentration monitoring is

Sirolimus increased when recommended forco-administered with immunosuppressant agents when

EVOTAZ. co-administered with EVOTAZ.

The mechanism ofinteraction is inhibition of

CYP3A4 by atazanavir andcobicistat.

ANTIPSYCHOTICS

Pimozide Concentrations of these The combination of pimozide,

Quetiapine medicinal products may be quetiapine or lurasidone and

Lurasidone increased when EVOTAZ is contraindicated (seeco-administered with section 4.3).

EVOTAZ.

The mechanism ofinteraction is CYP3Ainhibition by atazanavir andcobicistat.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

CARDIOVASCULAR AGENTS

Antiarrhythmics

Disopyramide Concentrations of these Co-administration with EVOTAZ

Flecainide antiarrhythmics may be has the potential to produce serious

Mexiletine increased when and/or life-threatening adverse

Propafenone co-administered with reactions. Caution is warranted and

EVOTAZ. therapeutic concentrationmonitoring of these medicinal

The mechanism of products is recommended if theyinteraction is CYP3A are used concomitantly withinhibition by atazanavir and EVOTAZ.cobicistat.

Amiodarone Concentrations of these Amiodarone, dronedarone,

Dronedarone antiarrhythmics may be quinidine and systemic lidocaine

Quinidine increased when have a narrow therapeutic window

Systemic lidocaine co-administered with and are contraindicated due to

EVOTAZ. potential inhibition of CYP3A by

EVOTAZ (see section 4.3).

The mechanism ofinteraction is CYP3Ainhibition by atazanavir andcobicistat.

Digoxin (0.5 mg Plasma concentrations of The peak concentration of digoxinsingle dose)/cobicistat digoxin may be increased is increased when co-administered(150 mg multiple doses) when co-administered with with cobicistat. When

EVOTAZ. co-administering with EVOTAZ,titrate the digoxin dose and monitor

Digoxin: digoxin concentrations. The lowest

AUC: ↔ dose of digoxin should initially be

Cmax: ↑41% prescribed.

Cmin: not determined

The mechanism ofinteraction is inhibition of

P-gp by cobicistat.

Metoprolol Concentrations of Clinical monitoring is

Timolol beta-blockers may be recommended whenincreased when co-administered with EVOTAZco-administered with and a dose reduction of the

EVOTAZ. beta-blocker may be necessary.

The mechanism ofinteraction is inhibition of

CYP2D6 by cobicistat.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Calcium channel blockers

Bepridil EVOTAZ must not be used Co-administration with bepridil isin combination with contraindicated (see section 4.3).medicinal products that aresubstrates of CYP3A4 andhave a narrow therapeuticindex.

Diltiazem 180 mg once daily Diltiazem AUC ↑125% Exposure to diltiazem and a(atazanavir 400 mg once daily) (↑109% ↑141%) metabolite, desacetyl-diltiazem, is

Diltiazem Cmax ↑98% (↑78% increased when diltiazem is↑119%) co-administered with atazanavir, a

Diltiazem Cmin ↑142% component of EVOTAZ. An initial(↑114% ↑173%) dose reduction of diltiazem by 50%should be considered, and

Desacetyl-diltiazem AUC electrocardiogram monitoring is↑165% (↑145% ↑187%) recommended.

Desacetyl-diltiazem Cmax↑172% (↑144% ↑203%)

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

No significant effect onatazanavir concentrationswas observed. There was anincrease in the maximum PRinterval compared toatazanavir alone.

The mechanism ofinteraction is CYP3A4inhibition by atazanavir andcobicistat.

Amlodipine Concentrations of these Caution is warranted. Dose titration

Felodipine calcium channel blockers of the calcium channel blockers

Nicardipine may be increased when should be considered.

Nifedipine co-administered with Electrocardiogram monitoring is

Verapamil EVOTAZ. recommended.

The mechanism of Clinical monitoring of therapeuticinteraction is inhibition of effect and adverse events is

CYP3A4 by atazanavir and recommended when thesecobicistat. medicinal products areco-administered with EVOTAZ.

Endothelin Receptor Antagonists

Bosentan Co-administration of Atazanavir plasma concentrationsbosentan with cobicistat may may decrease as a consequence of alead to decreased cobicistat reduction in cobicistat plasmaplasma concentrations. concentrations, which may result inloss of therapeutic effect and

The mechanism of development of resistance.interaction is induction of

CYP3A4 by bosentan. Co-administration is notrecommended (see section 4.4).

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

CORTICOSTEROIDS

Dexamethasone and other Co-administration with Co-administration withcorticosteroids metabolized by dexamethasone or other corticosteroids that are metabolized

CYP3A. corticosteroids (all routes of by CYP3A, particularly foradministration) that induce long-term use, may increase the risk

CYP3A may result in loss of for development of systemictherapeutic effect of corticosteroid effects including

EVOTAZ and development Cushing’s syndrome and adrenalof resistance to atazanavir. suppression. The potential benefit oftreatment versus the risk of systemic

The mechanism of corticosteroid effects should beinteraction is CYP3A4 considered.induction by dexamethasoneand CYP3A4 inhibition by For co-administration ofatazanavir and/or cobicistat. cutaneously administeredcorticosteroids sensitive to CYP3A4inhibition, consult the Summary of

Product Characteristics of thecorticosteroid for condition or usesthat augment its systemicabsorption.

Corticosteroids primarily Interaction not studied with Concomitant use of EVOTAZ andmetabolised by CYP3A any of the components of corticosteroids that are metabolised(including betamethasone, EVOTAZ. by CYP3A (e.g. fluticasonebudesonide, fluticasone, propionate or other inhaled or nasalmometasone, prednisone, Plasma concentrations of corticosteroids) may increase thetriamcinolone). these medicinal products risk of development of systemicmay be increased when co- corticosteroid effects, includingadministered with EVOTAZ, Cushing’s syndrome and adrenalresulting in reduced serum suppression.cortisol concentrations.

Co-administration with CYP3A-metabolised corticosteroids is notrecommended unless the potentialbenefit to the patient outweighs therisk, in which case patients shouldbe monitored for systemiccorticosteroid effects. Alternativecorticosteroids which are lessdependent on CYP3A metabolism,e.g. beclomethasone for intranasalor inhalational use, should beconsidered, particularly forlong-term use.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

ANTIDEPRESSANTS

Other antidepressants:

Trazodone Plasma concentrations of If trazodone is co-administeredtrazodone may be increased with EVOTAZ, the combinationwhen co-administered with should be used with caution and a

EVOTAZ. lower dose of trazodone should beconsidered.

The mechanism ofinteraction is CYP3A4inhibition by atazanavir andcobicistat.

ERECTILE DYSFUNCTION

PDE5 Inhibitors

Sildenafil Sildenafil, tadalafil, and Patients should be warned about

Tadalafil vardenafil are metabolised these possible side effects when

Vardenafil by CYP3A4. using PDE5 inhibitors for erectile

Avanafil Co-administration with dysfunction with EVOTAZ (see

EVOTAZ may result in section 4.4).increased concentrations ofthe PDE5 inhibitor and an For the treatment of erectileincrease in PDE5-associated dysfunction, it is recommendedadverse events, including that when co-administered withhypotension, visual changes, EVOTAZ, sildenafil should beand priapism. used with caution at reduced dosesof 25 mg every 48 hours; tadalafil

The mechanism of this should be used with caution atinteraction is CYP3A4 reduced doses of 10 mg everyinhibition by atazanavir and 72 hours; vardenafil should be usedcobicistat. with caution at reduced doses of nomore than 2.5 mg every 72 hours.

Increase monitoring for adversereactions.

The combination of avanafil and

EVOTAZ is contraindicated (seesection 4.3).

Also see PULMONARY

ATERIAL HYPERTENSION inthis table for further informationregarding co-administration of

EVOTAZ with sildenafil.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

HERBAL PRODUCTS

St. John’s wort Concomitant use of St. Co-administration of EVOTAZ(Hypericum perforatum) John's wort with EVOTAZ with products containing St. John'smay be expected to result in wort is contraindicated (seesignificant reduction in section 4.3).plasma levels of cobicistatand atazanavir. This effectmay be due to an inductionof CYP3A4. There is a riskof loss of therapeutic effectand development ofresistance to atazanavir (seesection 4.3).

HORMONAL CONTRACEPTIVES

Progestin/estrogen Concentrations of ethinyl Co-administration of EVOTAZ andestradiol and norethindrone hormonal contraceptives should beare increased when a avoided. An alternatecombined oral contraceptive (non-hormonal) reliable method ofcontaining those agents is contraception is recommended.co-administered withatazanavir. The mechanismof interaction is inhibition ofmetabolism by atazanavir.

Effects of co-administrationof EVOTAZ on progestinand estrogen are unknown.

Drospirenone/ethinyloestradio Drospirenone AUC: ↑ 130% Plasma concentrations ofl 3 mg/0.02 mg single dose Drospirenone Cmax: ↔ drospirenone are increased(atazanavir 300 mg once daily Drospirenone Cmin: Not following co-administration ofwith cobicistat 150 mg once calculated drospirenone/ethinyloestradiol withdaily) atazanavir/cobicistat. If

Ethinyloestradiol AUC: ↔ drospirenone/ethinyloestradiol is

Ethinyloestradiol Cmax: ↔ co-administered with

Ethinyloestradiol C : Not atazanavir/cobicistat clinicalmincalculated monitoring is recommended due tothe potential for hyperkalemia.

LIPID-MODIFYING AGENTS

Lomitapide The co-administration of There is a potential for risk oflomitapide with any of the markedly increased transaminasecomponents of EVOTAZ has levels and hepatotoxicitynot been studied. associated with increased plasmaconcentrations of lomitapide.

Lomitapide is highlydependent on CYP3A4 for Co-administration of lomitapideits metabolism and with EVOTAZ is contraindicatedco-administration with (see section 4.3).

EVOTAZ may result inincreased concentrations oflomitapide.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

HMG-CoA reductase inhibitors

Simvastatin Simvastatin and lovastatin Co-administration of simvastatin or

Lovastatin are highly dependent on lovastatin with EVOTAZ is

CYP3A4 for their contraindicated due to an increasedmetabolism and risk of myopathy includingco-administration with rhabdomyolysis (see section 4.3).

EVOTAZ may result inincreased concentrations.

Atorvastatin 10 mg single dose Atorvastatin AUC: ↑ 822% Plasma concentrations of(atazanavir 300 mg once daily Atorvastatin Cmax: ↑ 1785% atorvastatin are increased when co-with cobicistat 150 mg once Atorvastatin Cmin: Not administered withdaily) calculated atazanavir/cobicistat

Atazanavir AUC ↓5% Co-administration of atorvastatin

Atazanavir Cmax ↓7% with EVOTAZ is not

Atazanavir Cmin ↓10% recommended.

Pravastatin Although not studied, there Caution should be exercised.

Fluvastatin is a potential for an increase

Pitavastatin in pravastatin or fluvastatinexposure whenco-administered withprotease inhibitors.

Pravastatin is notmetabolised by CYP3A4.

Fluvastatin is partiallymetabolised by CYP2C9.

Plasma concentrations ofpitavastatin may beincreased if co-administeredwith EVOTAZ.

Rosuvastatin (10 mg single Rosuvastatin AUC: ↑ 242% Plasma concentrations ofdose) Rosuvastatin Cmax: ↑ 958% rosuvastatin are increased when co-(atazanavir 300 mg once daily Rosuvastatin Cmin: Not administered withwith cobicistat 150 mg once calculated atazanavir/cobicistat.daily)

Atazanavir AUC: ↔ When co-administration is

Atazanavir Cmax:↔ necessary, do not exceed 10 mg

Atazanavir Cmin: ↑ 6% rosuvastatin daily, and clinicalmonitoring for safety (e.g.,myopathy) is recommended.

INHALED BETA AGONISTS

Salmeterol Co-administration with Co-administration of salmeterol

EVOTAZ may result in with EVOTAZ is notincreased concentrations of recommended (see section 4.4).salmeterol and an increase insalmeterol-associatedadverse events.

The mechanism ofinteraction is CYP3A4inhibition by atazanavir andcobicistat.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

ERGOT DERIVATES

Dihydroergotamine EVOTAZ must not be used Co-administration of EVOTAZ and

Ergometrine in combination with these ergot derivates is

Ergotamine medicinal products that are contraindicated (see section 4.3).

Methylergonovine substrates of CYP3A4 andhave a narrow therapeuticindex.

NEUROLEPTICS

Perphenazine Co-administration of A decrease in the dose of

Risperidone neuroleptics with EVOTAZ neuroleptics metabolized by

Thioridazine may result in increased CYP3A or CYP2D6 may beplasma concentrations of required when co-administeredneuroleptics. with EVOTAZ.

The mechanism ofinteraction is inhibition of

CYP3A4 and/or CYP2D6 byatazanavir and/or cobicistat.

OPIOIDS

Buprenorphine, once daily, Buprenorphine AUC ↑67% Co-administration warrants clinicalstable maintenance dose Buprenorphine Cmax ↑37% monitoring for sedation and(atazanavir 300 mg once daily Buprenorphine Cmin ↑69% cognitive effects. A dose reductionwith ritonavir 100 mg of buprenorphine may beonce daily) Norbuprenorphine AUC considered.

↑105%

Norbuprenorphine Cmax↑61%

Norbuprenorphine Cmin↑101%

The mechanism ofinteraction is CYP3A4 and

UGT1A1 inhibition byatazanavir.

Concentrations of atazanavirwere not significantlyaffected.

Buprenorphine/naloxone in Buprenorphine AUC: ↑35%combination with cobicistat Buprenorphine Cmax: ↔

Buprenorphine Cmin: ↑66%

Naloxone AUC: ↓28%

Naloxone Cmax: ↓28%

The mechanism ofinteraction is CYP3A4inhibition by cobicistat.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Methadone, stable No significant effect on No dosage adjustment is necessarymaintenance dose methadone concentrations if methadone is co-administered(atazanavir 400 mg once daily) was observed when with EVOTAZ.

co-administered withatazanavir. Given thatcobicistat has been shown tohave no significant effect onmethadone concentrations,no interaction is expected ifmethadone isco-administered with

EVOTAZ.

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil Co-administration with A safe and effective dose in

EVOTAZ may result in combination with EVOTAZ hasincreased concentrations of not been established for sildenafilthe PDE5 inhibitor and an when used to treat pulmonaryincrease in arterial hypertension. Sildenafil,

PDE5 inhibitor-associated when used for the treatment ofadverse events. pulmonary arterial hypertension, iscontraindicated (see section 4.3).

The mechanism ofinteraction is CYP3A4inhibition by atazanavir andcobicistat.

SEDATIVES/HYPNOTICS

Midazolam Midazolam and triazolam are EVOTAZ should not be

Triazolam extensively metabolized by co-administered with triazolam or

CYP3A4. Co-administration orally administered midazolam (seewith EVOTAZ may cause a section 4.3), whereas cautionlarge increase in the should be used withconcentration of these co-administration of EVOTAZ andbenzodiazepines. Based on parenteral midazolam. If EVOTAZdata for other CYP3A4 is co-administered with parenteralinhibitors, plasma midazolam, it should be done in anconcentrations of midazolam intensive care unit (ICU) or similarare expected to be setting which ensures close clinicalsignificantly higher when monitoring and appropriatemidazolam is given orally. medical management in case of

Data from concomitant use respiratory depression and/orof parenteral midazolam prolonged sedation. Dosagewith other protease inhibitors adjustment for midazolam shouldsuggest a possible 3-4-fold be considered, especially if moreincrease in midazolam than a single dose of midazolam isplasma levels. administered.

Medicinal products by Interaction Recommendations concerningtherapeutic area co-administration

Buspirone Concentrations of these For these sedatives/hypnotics, dose

Clorazepate sedatives/hypnotics may be reduction may be necessary and

Diazepam increased when concentration monitoring is

Estazolam co-administered with recommended.

Flurazepam EVOTAZ.

Zolpidem

The mechanism ofinteraction is inhibition of

CYP3A4 by cobicistat.

GASTROINTESTINAL MOTILITY AGENTS

Cisapride EVOTAZ must not be used Co-administration of EVOTAZ andin combination with cisapride is contraindicated (seemedicinal products that are section 4.3).substrates of CYP3A4 andhave a narrow therapeuticindex.

Interaction studies have only been performed in adults.

EVOTAZ is not recommended during pregnancy nor should it be initiated in pregnant patients; analternative regimen is recommended (see sections 4.2 and 4.4). This is due to substantially lowerexposures of cobicistat and consequently, lower exposures of co-administered antiretroviral agents,including atazanavir, during the second and third trimesters, compared to postpartum.

Animal studies with EVOTAZ are insufficient with respect to reproductive toxicity (see section 5.3).

Atazanavir, an active component of EVOTAZ, has been detected in human milk. It is unknown ifcobicistat/metabolites are excreted in human milk. Studies in animals have shown excretion ofcobicistat/metabolites in milk. Because of both the potential for HIV transmission and the potential forserious adverse reactions in breast-feeding infants, women should be instructed not to breast-feed ifthey are receiving EVOTAZ.

The effect of EVOTAZ on fertility in humans has not been studied. In a nonclinical fertility and earlyembryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating orfertility (see section 5.3). No human data on the effect of cobicistat on fertility are available. Animalstudies do not indicate harmful effects of cobicistat on fertility.

EVOTAZ has a minor influence on the ability to drive or use machines. Dizziness may occurfollowing administration of regimens containing atazanavir and cobicistat (see section 4.8).

The overall safety profile of EVOTAZ is based on available data from clinical trials conducted withatazanavir, atazanavir boosted with either cobicistat or ritonavir, and post-marketing data.

As EVOTAZ contains atazanavir and cobicistat, the adverse reactions associated with each of theindividual components may be expected.

In a Phase III study (GS-US-216-0114), the most frequently reported adverse reactions in theatazanavir boosted with cobicistat group were associated with elevated bilirubin levels (see Table 2).

In two controlled clinical trials, where subjects received atazanavir alone (400 mg once daily) oratazanavir (300 mg daily) boosted with ritonavir (100 mg daily), the most frequently reported adversereactions were nausea, diarrhoea and jaundice. In the majority of cases, jaundice was reported within afew days to a few months after the initiation of treatment (see section 4.4).

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, hasbeen reported during postmarketing surveillance (see section 4.4).

Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to 1/1,000). Within eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2: Tabulated summary of adverse reactions

System Organ Class

Frequency Adverse Reactions

Immune system disordersuncommon hypersensitivity

Metabolism and nutrition disorderscommon increased appetiteuncommon weight decreased, weight gain, anorexia

Psychiatric disorderscommon insomnia, abnormal dreamsuncommon depression, sleep disorder, disorientation, anxiety

Nervous system disorderscommon headache, dizziness, somnolence, dysgeusiauncommon peripheral neuropathy, syncope, amnesia

Eye disordersvery common ocular icterus

Cardiac disordersuncommon torsades de pointesarare QTc prolongationa, oedema, palpitation

Vascular disordersuncommon hypertension

Respiratory, thoracic and mediastinal disordersuncommon dyspnoea

System Organ Class

Frequency Adverse Reactions

Gastrointestinal disordersvery common nauseacommon vomiting, diarrhoea, dyspepsia, abdominal pain, abdominal distension,flatulence, dry mouthuncommon pancreatitis, gastritis, stomatitis aphthous

Hepatobiliary disordersvery common jaundicecommon hyperbilirubinaemiauncommon hepatitis, cholelithiasisa, cholestasisarare hepatosplenomegaly, cholecystitisa

Skin and subcutaneous tissue disorderscommon rashuncommon pruritus, erythema multiformea,b, toxic skin eruptionsa,b, drug rash witheosinophilia and systemic symptoms (DRESS) syndromea,b, angioedemaa,urticaria, alopeciarare Stevens-Johnson syndromea,b, vesiculobullous rash, eczema, vasodilatation

Musculoskeletal and connective tissue disordersuncommon myalgia, muscle atrophy, arthralgiarare myopathy

Renal and urinary disordersuncommon nephrolithiasisa, haematuria, proteinuria, pollakiuria, interstitial nephritis,chronic kidney diseasearare kidney pain

Reproductive system and breast disordersuncommon gynaecomastia

General disorders and administration site conditionscommon fatigueuncommon pyrexia, asthenia, chest pain, malaiserare gait disturbancea These adverse reactions were identified through post-marketing surveillance; however, the frequencies wereestimated from a statistical calculation based on the total number of patients exposed to atazanavir (with andwithout ritonavir) in randomised controlled and other available clinical trials (n = 2321).b See section Description of selected adverse reactions for more details.

Immune reactivation syndrome and autoimmune disorders

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (see section 4.4).

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

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

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

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

Cobicistat, a component of EVOTAZ, has been shown to decrease estimated creatinine clearance dueto inhibition of tubular secretion of creatinine. An increase from baseline in serum creatinine solelydue to cobicistat’s inhibitory effect generally does not exceed 0.4 mg/dL.

In study GS-US-216-0114, decreases in estimated creatinine clearance occurred early in treatmentwith cobicistat, after which they stabilised. The mean (± SD) change in estimated glomerular filtrationrate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was -15.1 ± 16.5 mL/min in theatazanavir boosted with cobicistat plus emtricitabine and tenofovir DF fixed-dose combination groupand -8.0 ± 16.8 mL/min in the atazanavir boosted with ritonavir plus emtricitabine and tenofovir DFfixed-dose combination group.

Effects on the liver

In study GS-US-216-0114, through 144 weeks of treatment hyperbilirubinaemia (> 1 x ULN) wascommon: 97.7% in the atazanavir boosted with cobicistat plus emtricitabine and tenofovir DFfixed-dose combination group, and 97.4% in the atazanavir boosted with ritonavir plus emtricitabineand tenofovir DF fixed-dose combination group. However, a higher percentage of subjects in theatazanavir boosted with cobicistat group had increases in total bilirubin > 2 x ULN than those in theatazanavir boosted with ritonavir group (88.0% versus 80.9%). The rates of study drug discontinuationdue to bilirubin-related adverse events were low and similar in both groups (4.9% in thecobicistat-boosted group and 4.0% in the ritonavir-boosted group). An increase of > 3 x ULN inalanine aminotransferase or aspartate aminotransferase was recorded in 12.8% of subjects in thecobicistat-boosted group and 9.0% in the ritonavir-boosted group.

The most frequently reported laboratory abnormality in patients receiving regimens containingatazanavir and one or more NRTIs was elevated total bilirubin reported predominantly as elevatedindirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubinwas noted in 37% (6% Grade 4). Among experienced patients treated with atazanavir 300 mg oncedaily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3-4 totalbilirubin elevations. Among naïve patients treated with atazanavir 300 mg once daily with 100 mgritonavir once daily for a median duration of 96 weeks, 48% had Grade 3-4 total bilirubin elevations(see section 4.4).

Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receivingregimens containing atazanavir and one or more NRTIs included: elevated creatine kinase (7%),elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), lowneutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase(AST/SGOT) (3%), and elevated lipase (3%).

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

Grade 3-4 total bilirubin elevations.

Paediatric patients aged 3 months to < 12 years

In clinical studies, paediatric patients 3 months to less than 18 years of age had a mean duration oftreatment with atazanavir of 115 weeks. The safety profile in these studies was overall comparable tothat seen in adults. Both asymptomatic first-degree (23%) and second-degree (1%) atrioventricularblock were reported in paediatric patients. The most frequently reported laboratory abnormality inpaediatric patients receiving atazanavir was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4)which occurred in 45% of patients.

Paediatric patients aged 12 to < 18 years and weighing more than 35 kg

The safety of atazanavir administered with cobicistat plus two NRTIs (N = 14) was evaluated in

HIV-1 infected virologically suppressed paediatric patients between the ages of 12 to < 18 yearsthrough 48 weeks in an open-label clinical study (GS-US-216-0128). In this study, the safety profile ofatazanavir and cobicistat was similar to that in adults.

Patients co-infected with hepatitis B and/or hepatitis C virus

Co-infected patients with hepatitis B and/or C were more likely to have baseline hepatic transaminaseelevations than those without chronic viral hepatitis. No differences in frequency of bilirubinelevations were observed between these patients and those without viral hepatitis. The frequency oftreatment emergent hepatitis or transaminase elevations in co-infected patients was comparablebetween atazanavir and comparator regimens (see section 4.4).

Patients with chronic hepatitis B or hepatitis C virus co-infection:

In GS-US-216-0114, 3.6% of subjects were hepatitis B virus surface antigen positive and 5.3% werehepatitis C virus seropositive. Subjects with significant liver function test abnormalities generally hadabnormal baseline transaminases (AST or ALT), underlying chronic or acute hepatitis B or Cco-infection, concomitant hepatotoxic medicinal products (e.g., isoniazid), or a medical history ofalcoholism or alcohol abuse.

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

Human experience of acute overdose with EVOTAZ is limited.

There is no specific antidote for overdose with EVOTAZ. If overdose occurs with EVOTAZ, thepatient must be monitored for evidence of toxicity. Treatment should consist of general supportivemeasures including monitoring of vital signs and ECG as well as observation of the patient’s clinicalstatus. Since atazanavir and cobicistat are extensively metabolised by the liver and highly proteinbound, dialysis is unlikely to be beneficial in significant removal of this medicinal product.

Pharmacotherapeutic group: Antivirals for systemic use; antivirals for treatment of HIV infections,combinations. ATC code: J05AR15

EVOTAZ is a fixed-dose combination of the antiviral drug atazanavir boosted by the pharmacokineticenhancer cobicistat.

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

Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily.

Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3Asubstrates, such as atazanavir, where bioavailability is limited and half-life is shortened by

CYP3A-dependent metabolism.

Atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 activity in cell culture.

Cobicistat has no antiviral activity.

Effect of cobicistat on atazanavir pharmacokinetics

The antiretroviral effect of EVOTAZ is due to the atazanavir component. The activity of cobicistat asa pharmacokinetic enhancer to atazanavir has been demonstrated in pharmacokinetic trials. In thesepharmacokinetic trials, the exposure of atazanavir 300 mg with cobicistat 150 mg was consistent withthat observed when boosted with ritonavir 100 mg. EVOTAZ is bioequivalent to atazanavir 300 mgonce daily in combination with cobicistat 150 mg once daily coadministered as single agents (seesection 5.2).

In treatment-naïve HIV-1 infected patients

The safety and efficacy of atazanavir with cobicistat in HIV-1 infected patients were evaluated in therandomised, double-blind, active-controlled phase 3 study GS-US-216-0114 in HIV-1 infectedpatients with baseline estimated creatinine clearance above 70 mL/min who were treatment-naïve(n = 692).

Patients were randomised in a 1:1 ratio to receive either atazanavir 300 mg with cobicistat 150 mgonce daily or atazanavir 300 mg with ritonavir 100 mg once daily, each administered with a fixedbackground regimen containing tenofovir DF 300 mg and emtricitabine 200 mg administered as afixed-dose combination tablet. Randomisation was stratified by screening HIV-1 RNA level(≤ 100,000 copies/mL or > 100,000 copies/mL). Virologic response rate was evaluated in bothtreatment arms and virologic response was defined as achieving an undetectable viral load(< 50 HIV-1 RNA copies/mL). Viruses were known to be susceptible to atazanavir, emtricitabine andtenofovir DF at baseline.

The demographic and baseline characteristics were similar between the atazanavir with cobicistat andatazanavir with ritonavir groups. The median age of subjects was 36 years (range: 19-70). The medianbaseline plasma HIV-1 RNA was 4.81 log10 copies/mL (range: 3.21-6.44). The median baseline CD4+cell count was 352 cells/mm3 (range: 1-1455) and 16.9% had CD4+ cell counts ≤ 200 cells/mm3. Thepercentage of subjects with baseline viral loads > 100,000 copies/mL was 39.7%. Treatment outcomesat Weeks 48 and 144 for study GS-US-216-0114 are presented in Table 3.

Table 3: Virologic outcome of randomised treatment of study GS-US-216-0114 at

Weeks 48a and 144b

Week 48 Week 144

Atazanavir Atazanavir Atazanavir Atazanavirwith with with withcobicistatf ritonavirf cobicistatf ritonavirf(n = 344) (n = 348) (n = 344) (n = 348)

Virologic success 85% 87% 72% 74%

HIV-1 RNA < 50 copies/mL

Treatment difference -2.2% (95% CI = -7.4%, 3.0%) -2.1% (95% CI = -8.7%, 4.5%)

Virologic failurec 6% 4% 8% 5%

No virologic data in 9% 9% 20% 21%

Week 48 or Week 144window

Discontinued study drug 6% 7% 11% 11%due to AE or deathd

Discontinued study drug 3% 2% 8% 10%due to other reasons and lastavailable HIV-1 RNA< 50 copies/mLe

Missing data during 0% 0% < 1% < 1%window but on study druga Week 48 window is between Day 309 and 378 (inclusive)b Week 144 window is between Day 967 and 1,050 (inclusive)c Includes subjects who had ≥ 50 copies/mL in the Week 48 or 144 windows, subjects who discontinued earlydue to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lackor loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.d Includes patients who discontinued due to adverse event (AE) or death at any time point from Day 1 throughthe time window if this resulted in no virologic data on treatment during the specified window.e Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy,e.g., withdrew consent, loss to follow-up.f Plus background regimen of emtricitabine 200 mg and tenofovir DF 300 mg fixed-dose combination.

Atazanavir with cobicistat and emtricitabine and tenofovir DF fixed-dose combination wasnon-inferior in achieving HIV-1 RNA < 50 copies/mL when compared to atazanavir with ritonavir andemtricitabine and tenofovir DF fixed-dose combination.

In study GS-US-216-0114, the mean increase from baseline in CD4+ cell count at Weeks 48 and 144were 213 and 310 cells/mm3 in patients receiving atazanavir boosted with cobicistat and 219 and332 cells/mm3 in patients receiving atazanavir boosted with ritonavir, respectively.

The resistance profile of EVOTAZ is driven by atazanavir. Cobicistat does not select any HIVresistance mutations, due to its lack of antiviral activity.

In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50Lsubstitution, sometimes in combination with an A71V change, is the signature resistance substitutionfor atazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence ofphenotypic cross resistance to other PIs. For more information consult the REYATAZ Summary of

Product Characteristics.

Atazanavir with cobicistat

Limited data are available on the development of resistance to atazanavir boosted with cobicistat.

In an analysis of treatment-failure subjects who received atazanavir 300 mg co-administered withcobicistat 150 mg in study GS-US-216-0114 through Week 144, evaluable genotypic data from pairedbaseline and treatment-failure isolates were available for all 21 virologic failures in this group (6%,21/344). Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution

M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E or anyprimary resistance substitution associated with protease inhibitors. In the group receiving atazanavir300 mg co-administered with ritonavir 100 mg, evaluable genotypic data was available for all19 virologic failures (5%, 19/348). Among the 19 patients, 1 developed the emtricitabine-associatedresistance substitution M184V with no tenofovir or protease inhibitor associated resistancesubstitutions.

Paediatric patients aged 3 months to < 12 years or weighing less than 35 kg

The European Medicines Agency has deferred the obligation to submit the results of studies with

EVOTAZ in the treatment of HIV-1 infection (see section 4.2 for information on paediatric use).

Paediatric patients aged 12 to < 18 years and weighing more than 35 kg

The safety and efficacy of atazanavir with cobicistat were evaluated in an open-label phase 2/3 Study

GS-US-216-0128 in HIV-1 infected virologically suppressed paediatric patients between the ages of12 and < 18 years with baseline estimated creatinine clearance ≥ 90 mL/min. Fourteen patientsreceived atazanavir 300 mg once daily with cobicistat 150 mg once daily administered with abackground regimen containing two NRTIs.

The median age of patients was 14 years (range: 12 to 17); median weight of patients was 52.7 kg(range: 46.5 to 63.3); 71% were male; 57% were Asian, 29% were White, and 14% were Black. Atbaseline, 13/14 subjects had plasma HIV-1 RNA < 50 copies/mL and 1 subject had plasma HIV-1

RNA = 50 copies/mL.

In patients treated with atazanavir + cobicistat, the median baseline CD4+ cell count and CD4+% was770 cells/mm3 (range: 486 to 1765) and 33% (range: 23% to 45%), respectively. At Week 48, 93%(13/14) of patients retained HIV-1 RNA < 50 copies/mL and the median change from baseline in

CD4+ cell count and CD4+% was -60 cells/mm3 and -0.3%, respectively. Three out of 14 patientsqualified for resistance analysis: 1 patient showed no resistance in protease or reverse transcriptase and2 had missing data due to assay failure.

One EVOTAZ tablet is bioequivalent to one atazanavir capsule (300 mg) plus one cobicistat tablet(150 mg) following single oral dose administration with a light meal in healthy subjects (n = 62).

The following statements reflect the pharmacokinetic properties of atazanavir in combination withcobicistat or the individual components of EVOTAZ.

In a trial where HIV-infected subjects (n = 22) were instructed to take atazanavir 300 mg withcobicistat 150 mg once daily with food, the steady-state atazanavir Cmax, AUCtau and Ctau (mean ± SD)values were 3.9 ± 1.9 mcg/mL, 46.1 ± 26.2 mcg*hr/mL and 0.80 ± 0.72 mcg/mL, respectively.

Steady-state cobicistat Cmax, AUCtau and Ctau (mean ± SD) values were 1.5 ± 0.5 mcg/mL,11.1 ± 4.5 mcg*hr/mL and 0.05 ± 0.07 mcg/mL, respectively (n = 22).

Administration of a single dose of EVOTAZ with a light meal (336 kcal, 5.1 g fat, 9.3 g protein)resulted in a 42% increase in atazanavir Cmax, a 28% increase in atazanavir AUC, a 31% increase incobicistat Cmax, and a 24% increase in cobicistat AUC relative to the fasting state. Administration of asingle dose of EVOTAZ with a high-fat meal (1,038 kcal, 59 g fat, 37 g protein) resulted in a 14%reduction in atazanavir Cmax with no change in atazanavir AUC or cobicistat exposures (Cmax, AUC)relative to the fasting state. The 24-hour atazanavir concentration following a high-fat meal wasincreased approximately 23% due to delayed absorption; the median Tmax increased from 2.0 to3.5 hours. Cmax and AUCs after a high-fat meal decreased 36% and 25% in comparison to a light meal,respectively; however, the 24-hour atazanavir concentration was similar when EVOTAZ was givenwith a light meal and a high-fat meal. To enhance bioavailability, EVOTAZ is to be taken with food.

Atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100to 10,000 ng/mL. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similarextent (89% and 86%, respectively, at 1,000 ng/mL). In a multiple-dose study in HIV-infected patientsdosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected inthe cerebrospinal fluid and semen.

Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drugconcentration ratio was 2.

Studies in humans and in vitro studies using human liver microsomes have demonstrated thatatazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites arethen excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolicpathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasmahave been characterised. Neither metabolite demonstrated in vitro antiviral activity.

Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does notundergo glucuronidation. Following oral administration of [14C]cobicistat, 99% of circulatingradioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine andfaeces and do not contribute to the CYP3A inhibitory activity of cobicistat.

Following a single 400 mg dose of [14C]atazanavir, 79% and 13% of the total radioactivity wasrecovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion ofunchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adultpatients (n = 33, combined studies), the mean half-life within a dosing interval for atazanavir was12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a lightmeal.

Following oral administration of [14C]cobicistat, 86% and 8.2% of the dose were recovered in faecesand urine, respectively. The median terminal plasma half-life of cobicistat following administration ofcobicistat is approximately 3-4 hours.

Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in

AUC and Cmax values over the dose range of 200 mg to 800 mg once daily.

Cobicistat exposures are non-linear and greater than dose-proportional over the range of 50 mg to400 mg, consistent with a mechanism-based CYP3A inhibitor.

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of theadministered dose. There are no pharmacokinetic data available for atazanavir in combination withcobicistat in patients with renal insufficiency. Atazanavir has been studied in adult patients with severerenal impairment (n = 20), including those on haemodialysis, at multiple doses of 400 mg once daily.

Although this study presented some limitations (i.e., unbound drug concentrations not studied), resultssuggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patientsundergoing haemodialysis compared to patients with normal renal function. The mechanism of thisdecrease is unknown (see sections 4.2 and 4.4.)

A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects withsevere renal impairment (estimated creatinine clearance below 30 mL/min). No meaningfuldifferences in cobicistat pharmacokinetics were observed between subjects with severe renalimpairment and healthy subjects, consistent with low renal clearance of cobicistat.

Atazanavir is metabolised and eliminated primarily by the liver. The effects of hepatic impairment onthe pharmacokinetics of atazanavir given with cobicistat have not been studied. Concentrations ofatazanavir given with cobicistat are expected to be increased in patients with impaired hepatic function(see sections 4.2 and 4.4).

Cobicistat is primarily metabolised and eliminated by the liver. A study of the pharmacokinetics ofcobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment(Child-Pugh Class B). No clinically relevant differences in cobicistat pharmacokinetics were observedbetween subjects with moderate impairment and healthy subjects. The effect of severe hepaticimpairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

The pharmacokinetics of atazanavir and cobicistat, alone or in combination, have not been evaluatedin an elderly population (65 years of age and older).

Paediatric Patients aged 3 months to < 12 years

For paediatric patients aged 3 months to < 12 years, no data are available on the pharmacokinetics ofatazanavir and cobicistat in combination.

Paediatric Patients aged 12 to < 18 years and weighing more than 35 kg

In paediatric patients aged 12 to < 18 years who received cobicistat-boosted atazanavir (n = 14) in

Study GS-US-216-0128, exposures of atazanavir and cobicistat (AUCtau, Cmax, and Ctrough) were higher(24% to 180%) than in adults; however, the increases were not considered clinically significant as thesafety profiles were similar in adult and paediatric patients.

No clinically relevant pharmacokinetic differences due to gender have been identified for atazanavir orcobicistat.

No clinically relevant pharmacokinetic differences due to ethnicity have been identified for atazanaviror cobicistat.

In a 3-month combination oral toxicity study of atazanavir and cobicistat in rats, there were notoxicologic interactions apparent as no additive or synergistic toxicities were observed. Whencompared to their single-agent profiles all findings could be attributed to either atazanavir orcobicistat.

In an ex vivo rabbit pharmacology study, isolated hearts were exposed to atazanavir, cobicistat, oratazanavir and cobicistat in combination. Each single agent produced effects on left ventricularcontractility and PR prolongation at concentrations at least 35-fold higher than the free atazanavir andcobicistat concentrations at the recommended human dose (RHD) Cmax. When administered incombination, no clear additive or synergistic cardiovascular effects were observed at atazanavir andcobicistat concentrations at least 2-fold higher than the free atazanavir and cobicistat concentrations atthe RHD Cmax.

The following statements reflect the preclinical safety results of the individual active substances of

EVOTAZ.

In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings weregenerally confined to the liver and included generally minimal to mild increases in serum bilirubin andliver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepaticsingle-cell necrosis. Systemic exposures of atazanavir in mice (males), rats, and dogs at dosesassociated with hepatic changes were at least equal to that observed in humans given 400 mgonce daily. In female mice, atazanavir exposure at a dose that produced single-cell necrosis was12 times the exposure in humans given 400 mg once daily. Serum cholesterol and glucose wereminimally 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 inhumans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90)in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PRinterval, prolongation of QT interval, and prolongation of QRS complex) were observed only in aninitial 2-week oral toxicity study performed in dogs. Subsequent 9-month oral toxicity studies in dogsshowed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical datais unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4and 4.8). The potential for PR prolongation should be considered in cases of overdose(see 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 ormoribund does at maternal doses 2 and 4 times the highest dose administered in the definitiveembryo-development study. In the pre- and postnatal development assessment in rats, atazanavirproduced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemicexposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightlygreater than that observed in humans given 400 mg once daily.

Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrationsin vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavirdid not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled

DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.

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

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

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dosetoxicity, genotoxicity, and toxicity to reproduction and development. No teratogenic effects wereobserved in rats and rabbit developmental toxicity studies. In rats, ossification changes in the spinalcolumn and sternebra of foetuses occurred at a dose that produced significant maternal toxicity.

Ex vivo rabbit studies and in vivo dog studies suggest that cobicistat has a low potential for QTprolongation, and may slightly prolong the PR interval and decrease left ventricular function at meanconcentrations at least 10-fold higher than the human exposure at the recommended 150 mg dailydose.

A long-term carcinogenicity study of cobicistat in rats revealed tumourigenic potential specific for thisspecies that is regarded as of no relevance for humans. A long-term carcinogenicity study in mice didnot show any carcinogenic potential.

Tablet corecellulose, microcrystalline (E460(i))croscarmellose sodium (E468)sodium starch glycolatecrospovidone (E1202)stearic acid (E570)magnesium stearate (E470b)hydroxypropylcellulose (E463)silica (E551)

Film-coatinghypromellose (hydroxypropyl methyl cellulose, E464)titanium dioxide (E171)talc (E553b)triacetin (E1518)red iron oxide (E172)

Not applicable.

2 years

Do not store above 30 °C.

High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure. Each bottlecontains 30 film-coated tablets and a silica gel dessicant.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets andouter cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

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

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/15/1025/001-002

Date of first authorisation: 13 July 2015

Date of latest renewal: 27 March 2020

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

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