REYATAZ 200mg capsules medication leaflet

REYATAZ 100 mg hard capsules

REYATAZ 150 mg hard capsules

REYATAZ 200 mg hard capsules

REYATAZ 300 mg hard capsules

REYATAZ 100 mg hard capsules

Each capsule contains 100 mg of atazanavir (as sulphate).

Excipient with known effect: 54.79 mg of lactose per capsule.

REYATAZ 150 mg hard capsules

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

Excipient with known effect: 82.18 mg of lactose per capsule.

REYATAZ 200 mg hard capsules

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

Excipient with known effect: 109.57 mg of lactose per capsule.

REYATAZ 300 mg hard capsules

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

Excipient with known effect: 164.36 mg of lactose per capsule.

For the full list of excipients, see section 6.1.

Hard capsule

REYATAZ 100 mg hard capsules

Opaque blue and white capsule printed with white and blue inks, with 'BMS 100 mg' on one half andwith '3623' on the other half.

REYATAZ 150 mg hard capsules

Opaque blue and powder blue capsule printed with white and blue inks, with 'BMS 150 mg' on onehalf and with '3624' on the other half.

REYATAZ 200 mg hard capsules

Opaque blue capsule printed with white ink, with 'BMS 200 mg' on one half and with '3631' on theother half.

REYATAZ 300 mg hard capsules

Opaque red and blue capsule printed with white ink, with 'BMS 300 mg' on one half and with '3622'on the other half.

REYATAZ capsules, co-administered with low dose ritonavir, are indicated for the treatment of

HIV-1-infected adults and paediatric patients 6 years of age and older in combination with otherantiretroviral medicinal products (see section 4.2).

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

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

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

The recommended dose of REYATAZ capsules is 300 mg once daily taken with ritonavir 100 mgonce daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics(see sections 4.5 and 5.1). (See also section 4.4 Withdrawal of ritonavir only under restrictiveconditions).

Paediatric patients (6 years to less than 18 years of age and weighing at least 15 kg)

The dose of atazanavir capsules for paediatric patients is based on body weight as shown in Table 1and should not exceed the recommended adult dose. REYATAZ capsules must be taken with ritonavirand have to be taken with food.

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

Body Weight (kg) REYATAZ once daily dose ritonavir once daily dosea15 to less than 35 200 mg 100 mgat least 35 300 mg 100 mga Ritonavir capsules, tablets or oral solution.

Paediatric patients (at least 3 months of age and weighing at least 5 kg): REYATAZ oral powder isavailable for paediatric patients at least 3 months of age and weighing at least 5 kg (see Summary of

Product Characteristics for REYATAZ oral powder). Switching to REYATAZ capsules from

REYATAZ oral powder is encouraged as soon as patients are able to consistently swallow capsules.

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

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

REYATAZ with ritonavir has not been studied in patients with hepatic impairment. REYATAZ withritonavir should be used with caution in patients with mild hepatic impairment. REYATAZ withritonavir must not be used in patients with moderate to severe hepatic impairment (see sections pct. 4.3, pct. 4.4and 5.2).

In case of withdrawal of ritonavir from the initial recommended ritonavir-boosted regimen(see section 4.4), unboosted REYATAZ could be maintained in patients with mild hepatic impairmentat a dose of 400 mg, and in patients with moderate hepatic impairment with a reduced dose of 300 mgonce daily with food (see section 5.2). Unboosted REYATAZ must not be used in patients with severehepatic impairment.

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

REYATAZ 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir,especially when the activity of atazanavir or the whole regimen may be compromised due to drugresistance. Since there are limited data available and due to inter-patient variability during pregnancy,

Therapeutic Drug Monitoring (TDM) may be considered to ensure adequate exposure.

The risk of a further decrease in atazanavir exposure is expected when atazanavir is given withmedicinal products known to reduce its exposure (e.g., tenofovir disoproxil or H2-receptorantagonists). If tenofovir disoproxil or an H2-receptor antagonist is needed, a dose increase to REYATAZ400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2). It is not recommended to use REYATAZ with ritonavir for pregnant patients who are receivingboth tenofovir disoproxil and an H2-receptor antagonist.

(See section 4.4 Withdrawal of ritonavir only under restrictive conditions).

During postpartum:

Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavirexposures might increase during the first two months after delivery (see section 5.2). Therefore,postpartum patients should be closely monitored for adverse reactions. During this time, postpartum patients should follow the same dose recommendation as for non-pregnant patients, including those for co-administration of medicinal products known to affectatazanavir exposure (see section 4.5).

Paediatric patients (less than 3 months of age)

REYATAZ should not be used in children less than 3 months because of safety concerns especiallytaking into account the potential risk of kernicterus.

For oral use. The capsules should be swallowed whole.

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

REYATAZ is contraindicated in patients with severe hepatic insufficiency (see sections 4.2, pct. 4.4and 5.2). REYATAZ with ritonavir is contraindicated in patients with moderate hepatic insufficiency(see sections 4.2, pct. 4.4, and 5.2).

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

Combination of rifampicin (see section 4.5).

Combination of the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterialhypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment oferectile dysfunction see sections 4.4 and 4.5.

Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome

P450 and have narrow therapeutic windows (e.g., quetiapine, lurasidone, alfuzosin, astemizole,terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (forcaution on parenterally administered midazolam, see section 4.5), lomitapide, and ergot alkaloids,particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5).

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

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

Co-administration with products containing St. John’s wort (Hypericum perforatum) (see section 4.5).

Co-administration with apalutamide (see section 4.5).

Co-administration of REYATAZ with ritonavir at doses greater than 100 mg once daily has not beenclinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir(cardiac effects, hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir withritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could beconsidered. In this instance, close clinical monitoring is warranted (see Interaction with other

Medicinal Products below).

Patients with coexisting conditions

Hepatic impairment: Atazanavir is primarily hepatically metabolised and increased plasmaconcentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). Thesafety and efficacy of REYATAZ has not been established in patients with significant underlying liverdisorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapyare at an increased risk for severe and potentially fatal hepatic adverse reactions. In case ofconcomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of

Product Characteristics for these medicinal products (see section 4.8).

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

Renal impairment: No dosage adjustment is needed in patients with renal impairment. However,

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

QT prolongation: Dose-related asymptomatic prolongations in PR interval with REYATAZ have beenobserved in clinical studies. Caution should be used with medicinal products known to induce PRprolongations. In patients with pre-existing conduction problems (second degree or higheratrioventricular or complex bundle-branch block), REYATAZ should be used with caution and only ifthe benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing

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

Haemophiliac patients: There have been reports of increased bleeding, including spontaneous skinhaematomas and haemarthroses, in type A and B haemophiliac patients treated with proteaseinhibitors. In some patients additional factor VIII was given. In more than half of the reported cases,treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. Acausal relationship has been suggested, although the mechanism of action has not been elucidated.

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

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

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

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT) have occurred in patients receiving REYATAZ (see section 4.8). Hepatictransaminase elevations that occur with elevated bilirubin in patients receiving REYATAZ should beevaluated for alternative aetiologies. Alternative antiretroviral therapy to REYATAZ may beconsidered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is notrecommended because it may result in a loss of therapeutic effect and development of resistance.

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

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

Withdrawal of ritonavir only under restrictive conditions

The recommended standard treatment is REYATAZ boosted with ritonavir, ensuring optimalpharmacokinetic parameters and level of virologic suppression.

The withdrawal of ritonavir from the boosted regimen of REYATAZ is not recommended, but may beconsidered in adults patients at the dose of 400 mg once daily with food only under the followingcombined restrictive conditions: absence of prior virologic failure undetectable viral load during the last 6 months under current regimen viral strains not harbouring HIV resistance associated mutations (RAMs) to current regimen.

REYATAZ given without ritonavir should not be considered in patients treated with a backboneregimen containing tenofovir disoproxil and with other concomitant medications that reduceatazanavir bioavailability (see section 4.5 In case of withdrawal of ritonavir from the recommendedatazanavir boosted regimen) or in case of perceived challenging compliance.

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

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

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

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

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

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

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash witheosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving

REYATAZ. Patients should be advised of the signs and symptoms and monitored closely for skinreactions. REYATAZ should be discontinued if severe rash develops.

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

REYATAZ, REYATAZ may not be restarted.

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

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

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

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

Atazanavir is metabolised principally by CYP3A4. Co-administration of REYATAZ and medicinalproducts that induce CYP3A4 is not recommended (see sections 4.3 and 4.5).

PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be used whenprescribing PDE5 inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment of erectiledysfunction in patients receiving REYATAZ. Co-administration of REYATAZ with these medicinalproducts is expected to substantially increase their concentrations and may result in PDE5-associatedadverse reactions such as hypotension, visual changes, and priapism (see section 4.5).

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

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

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

Concomitant use of salmeterol and REYATAZ may result in increased cardiovascular adverse eventsassociated with salmeterol. Co-administration of salmeterol and REYATAZ is not recommended(see section 4.5).

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

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

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

Safety

Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults.

Asymptomatic first- and second-degree AV block was reported in paediatric patients (see section 4.8).

Caution should be used with medicinal products known to induce PR prolongations. In paediatricpatients with pre-existing conduction problems (second degree or higher atrioventricular or complexbundle-branch block), REYATAZ should be used with caution and only if the benefits exceed the risk.

Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).

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

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, orglucose-galactose malabsorption should not take this medicinal product.

When REYATAZ and ritonavir are co-administered, the metabolic drug interaction profile forritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The

Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with

REYATAZ and ritonavir.

Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, REYATAZ iscontraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeuticindex: quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine,bepridil, triazolam, orally administered midazolam, lomitapide, and ergot alkaloids, particularlyergotamine and dihydroergotamine (see section 4.3).

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

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

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

Table 2: Interactions between REYATAZ and other medicinal products

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

ANTI-HCV AGENTS

Grazoprevir 200 mg once daily Atazanavir AUC: ↑43% (↑30% ↑57%) Co-administration of REYATAZ(atazanavir 300 mg/ritonavir Atazanavir Cmax: ↑12% (↑1% ↑24%) and elbasvir/grazoprevir is100 mg once daily) Atazanavir Cmin: ↑23% (↑13% ↑134%) contraindicated because of asignificant increase in grazoprevir

Grazoprevir AUC: ↑958% (↑678% plasma concentrations and an↑1 339%) associated potential increase in the

Grazoprevir Cmax: ↑524% (↑342% ↑781%) risk of ALT elevations

Grazoprevir Cmin: ↑1 064% (↑696% (see section 4.3).↑1 602%)

Grazoprevir concentrations were greatlyincreased when co-administered withatazanavir/ritonavir.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

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

Elbasvir AUC: ↑376% (↑307% ↑456%)

Elbasvir Cmax: ↑315% (↑246% ↑397%)

Elbasvir Cmin: ↑545% (↑451% ↑654%)

Elbasvir concentrations were increasedwhen co-administered withatazanavir/ritonavir.

Sofosbuvir 400 mg/velpatasvir Sofosbuvir AUC: ↑40% (↑25% ↑57%) Co-administration of REYATAZ100 mg/voxilaprevir 100 mg Sofosbuvir Cmax:↑29% (↑9% ↑52%) with voxilaprevir-containingsingle dose* products is expected to increase the(atazanavir 300 mg/ritonavir Velpatasvir AUC: ↑93% (↑58% ↑136%) concentration of voxilaprevir. Co-100 mg once daily) Velpatasvir Cmax: ↑29% (↑7% ↑56%) administration of REYATAZ withvoxilaprevir-containing regimens is

Voxilaprevir AUC: ↑331% (↑276% not recommended.↑393%)

Voxilaprevir Cmax: ↑342% (↑265% ↑435%)

*Lack of pharmacokinetics interactionbounds 70-143%

Effect on atazanavir and ritonavir exposurehas not been studied.

Expected:↔ Atazanavir↔ Ritonavir

The mechanism of interaction between

REYATAZ/ritonavir andsofosbuvir/velpatasvir/voxilaprevir isinhibition of OATP1B, P-gp, and CYP3A.

Glecaprevir Glecaprevir AUC: ↑553% (↑424% ↑714%) Co-administration of REYATAZ300 mg/pibrentasvir 120 mg Glecaprevir Cmax: ↑306% (↑215% ↑423%) with glecaprevir/pibrentasvir isonce daily Glecaprevir Cmin: ↑1 330% (↑885% contraindicated because of the(atazanavir 300 mg/ritonavir ↑1 970%) potential increase in the risk of100 mg once daily*) ALT elevations due to a significant

Pibrentasvir AUC: ↑64% (↑48% ↑82%) increase in glecaprevir and

Pibrentasvir Cmax: ↑29% (↑15% ↑45%) pibrentasvir plasma concentrations

Pibrentasvir Cmin: ↑129% (↑95% ↑168%) (see section 4.3)

*Effect of atazanavir and ritonavir on thefirst dose of glecaprevir and pibrentasvir isreported.

ANTIPLATELETS

Ticagrelor The mechanism of the interaction is Co-administration of REYATAZ

CYP3A4 inhibition by atazanavir and/or with ticagrelor is not recommendedritonavir. due to potential increase in theantiplatelet activity of ticagrelor.

Clopidogrel The mechanism of the interaction is Co-administration with clopidogrel

CYP3A4 inhibition by atazanavir and is not recommended due toor/ritonavir. potential reduction of theantiplatelet activity of clopidogrel.

Prasugrel The mechanism of the interaction is No dose adjustment is needed when

CYP3A4 inhibition by atazanavir and prasugrel is co-administered withor/ritonavir. REYATAZ (with or withoutritonavir).

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

ANTI-RETROVIRALS

Protease inhibitors: The co-administration of REYATAZ/ritonavir and other protease inhibitors has not been studiedbut would be expected to increase exposure to other protease inhibitors. Therefore, such co-administration is notrecommended.

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

Atazanavir Cmax: ↑120% (↑56% ↑211%)* pharmacokinetics.

Studies conducted in HIV- Atazanavir Cmin: ↑713% (↑359%infected patients. ↑1 339%)*

*In a combined analysis, atazanavir300 mg and ritonavir 100 mg (n = 33) wascompared to atazanavir 400 mg withoutritonavir (n = 28).

The mechanism of interaction betweenatazanavir and ritonavir is CYP3A4inhibition.

Indinavir Indinavir is associated with indirect Co-administration of REYATAZunconjugated hyperbilirubinaemia due to and indinavir is not recommendedinhibition of UGT. (see section 4.4).

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

Lamivudine 150 mg twice daily No significant effect on lamivudine and Based on these data and because+ zidovudine 300 mg twice daily zidovudine concentrations was observed. ritonavir is not expected to have a(atazanavir 400 mg once daily) significant impact on thepharmacokinetics of NRTIs, the co-administration of these medicinalproducts and REYATAZ is notexpected to significantly alter theexposure of the co-administeredmedicinal products.

Abacavir The co-administration of abacavir and

REYATAZ is not expected to significantlyalter the exposure of abacavir.

Didanosine (buffered tablets) Atazanavir, simultaneous administration Didanosine should be taken at the200 mg/stavudine 40 mg, both with ddI+d4T (fasted) fasted state 2 hours aftersingle dose Atazanavir AUC: ↓87% (↓92% ↓79%) REYATAZ taken with food. The(atazanavir 400 mg single dose) Atazanavir Cmax: ↓89% (↓94% ↓82%) co-administration of stavudine with

Atazanavir Cmin: ↓84% (↓90% ↓73%) REYATAZ is not expected tosignificantly alter the exposure of

Atazanavir, dosed 1 hr after ddI+d4T stavudine.(fasted)

Atazanavir AUC: ↔3% (↓36% ↑67%)

Atazanavir Cmax: ↑12% (↓33% ↑18%)

Atazanavir Cmin: ↔3% (↓39% ↑73%)

Atazanavir concentrations were greatlydecreased when co-administered withdidanosine (buffered tablets) andstavudine. The mechanism of interaction isa reduced solubility of atazanavir withincreasing pH related to the presence ofanti-acid agent in didanosine bufferedtablets.

No significant effect on didanosine andstavudine concentrations was observed.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

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

No significant effect on atazanavirconcentrations was observed whenadministered with enteric-coateddidanosine, but administration with fooddecreased didanosine concentrations.

Tenofovir disoproxil fumarate Atazanavir AUC: ↓22% (↓35% ↓6%) * When co-administered with300 mg once daily Atazanavir Cmax: ↓16% (↓30% ↔0%) * tenofovir disoproxil fumarate, it is(atazanavir 300 mg once daily Atazanavir Cmin: ↓23% (↓43% ↑2%) * recommended that REYATAZwith ritonavir 100 mg once daily) 300 mg be given with ritonavir

* In a combined analysis from several 100 mg and tenofovir disoproxil300 mg tenofovir disoproxil clinical studies, atazanavir/ritonavir fumarate 300 mg (all as a singlefumarate is equivalent to 245 mg 300/100 mg co-administered with dose with food).tenofovir disoproxil. tenofovir disoproxil fumarate 300 mg(n = 39) was compared to

Studies conducted in HIV- atazanavir/ritonavir 300/100 mg (n = 33).infected patients

The efficacy of REYATAZ/ritonavir incombination with tenofovir disoproxilfumarate in treatment-experienced patientshas been demonstrated in clinicalstudy 045 and in treatment naïve patientsin clinical study 138 (see sections 4.8and 5.1). The mechanism of interactionbetween atazanavir and tenofovirdisoproxil fumarate is unknown.

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

Tenofovir disoproxil fumarate Cmin: ↑29%300 mg tenofovir disoproxil (↑21% ↑36%)fumarate is equivalent to 245 mgtenofovir disoproxil.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz 600 mg once daily Atazanavir (pm): all administered with Co-administration of efavirenz and(atazanavir 400 mg once daily food REYATAZ is not recommendedwith ritonavir 100 mg once daily) Atazanavir AUC: ↔0%(↓9% ↑10%)* (see section 4.4).

Atazanavir Cmax: ↑17%(↑8% ↑27%)*

Atazanavir Cmin: ↓42%(↓51% ↓31%)*

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

Atazanavir Cmax: ↔9% (↓5% ↑26%)*/**

Atazanavir Cmin: ↔12% (↓16% ↑49%)*/**

*When compared to REYATAZ300 mg/ritonavir 100 mg once daily in theevening without efavirenz. This decreasein atazanavir Cmin might negatively impactthe efficacy of atazanavir. The mechanismof efavirenz/atazanavir interaction is

CYP3A4 induction.

**Based on historical comparison.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

Nevirapine 200 mg twice daily Nevirapine AUC: ↑26% (↑17% ↑36%) Co-administration of nevirapine(atazanavir 400 mg once daily Nevirapine Cmax: ↑21% (↑11% ↑32%) and REYATAZ is notwith ritonavir 100 mg once daily) Nevirapine Cmin: ↑35% (↑25% ↑47%) recommended (see section 4.4).

Study conducted in HIV-infected Atazanavir AUC: ↓19% (↓35% ↑2%)*patients. Atazanavir Cmax: ↔2% (↓15% ↑24%)*

Atazanavir Cmin: ↓59% (↓73% ↓40%)*

*When compared to REYATAZ 300 mgand ritonavir 100 mg without nevirapine.

This decrease in atazanavir Cmin mightnegatively impact the efficacy ofatazanavir. The mechanism ofnevirapine/atazanavir interaction is

CYP3A4 induction.

Integrase Inhibitors

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

Raltegravir C12hr: ↑77%

The mechanism is UGT1A1 inhibition.

ANTIBIOTICS

Clarithromycin 500 mg twice Clarithromycin AUC: ↑94% (↑75% No recommendation regarding dosedaily ↑116%) reduction can be made; therefore,(atazanavir 400 mg once daily) Clarithromycin Cmax: ↑50% (↑32% ↑71%) caution should be exercised if

Clarithromycin Cmin: ↑160% (↑135% REYATAZ is co-administered with↑188%) clarithromycin.

14-OH clarithromycin14-OH clarithromycin AUC: ↓70% (↓74%↓66%)14-OH clarithromycin Cmax: ↓72% (↓76%↓67%)14-OH clarithromycin Cmin: ↓62% (↓66%↓58%)

Atazanavir AUC: ↑28% (↑16% ↑43%)

Atazanavir Cmax: ↔6% (↓7% ↑20%)

Atazanavir Cmin: ↑91% (↑66% ↑121%)

A dose reduction of clarithromycin mayresult in subtherapeutic concentrations of14-OH clarithromycin.

The mechanism of theclarithromycin/atazanavir interaction is

CYP3A4 inhibition.

ANTIFUNGALS

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

Itraconazole Itraconazole, like ketoconazole, is a potent REYATAZ/ritonavir, high doses ofinhibitor as well as a substrate of CYP3A4. ketoconazole and itraconazole

Based on data obtained with other boosted (> 200 mg/day) are not

PIs and ketoconazole, where ketoconazole recommended.

AUC showed a 3-fold increase,

REYATAZ/ritonavir is expected toincrease ketoconazole or itraconazoleconcentrations.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

Voriconazole 200 mg twice daily Voriconazole AUC: ↓33% (↓42% ↓22%) Co-administration of voriconazole(atazanavir 300 mg/ritonavir Voriconazole Cmax: ↓10% (↓22% ↓4%) and REYATAZ with ritonavir is100 mg once daily) Voriconazole Cmin: ↓39% (↓49% ↓28%) not recommended unless anassessment of the benefit/risk to the

Subjects with at least one Atazanavir AUC: ↓12% (↓18% ↓5%) patient justifies the use offunctional CYP2C19 allele. Atazanavir Cmax: ↓13% (↓20% ↓4%) voriconazole (see section 4.4).

Atazanavir Cmin: ↓20% (↓28% ↓10%)

At the time voriconazole treatment

Ritonavir AUC: ↓12% (↓17% ↓7%) is required, a patient's CYP2C19

Ritonavir Cmax: ↓9% (↓17% ↔0%) genotype should be performed if

Ritonavir Cmin: ↓25% (↓35% ↓14%) feasible.

In the majority of patients with at least one Therefore if the combination isfunctional CYP2C19 allele, a reduction in unavoidable, the followingboth voriconazole and atazanavir recommendations are madeexposures are expected. according to the CYP2C19 status:

Voriconazole 50 mg twice daily Voriconazole AUC: ↑561% (↑451% - in patients with at least one(atazanavir 300 mg/ritonavir ↑699%) functional CYP2C19 allele,100 mg once daily) Voriconazole Cmax: ↑438% (↑355% close clinical monitoring for↑539%) a loss of both voriconazole

Subjects without a functional Voriconazole Cmin: ↑765% (↑571% (clinical signs) and

CYP2C19 allele. ↑1,020%) atazanavir (virologicresponse) efficacy is

Atazanavir AUC: ↓20% (↓35% ↓3%) recommended.

Atazanavir Cmax: ↓19% (↓34% ↔0.2%)

Atazanavir Cmin: ↓31% (↓46% ↓13%) - in patients without afunctional CYP2C19 allele,

Ritonavir AUC: ↓11% (↓20% ↓1%) close clinical and laboratory

Ritonavir Cmax: ↓11% (↓24% ↑4%) monitoring of voriconazole-

Ritonavir Cmin: ↓19% (↓35% ↑1%) associated adverse events isrecommended.

In a small number of patients without afunctional CYP2C19 allele, significantly If genotyping is not feasible, fullincreased voriconazole exposures are monitoring of safety and efficacyexpected. should be performed.

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

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

ANTIMYCOBACTERIAL

Rifabutin 150 mg twice weekly Rifabutin AUC: ↑48% (↑19% ↑84%)** When given with REYATAZ, the(atazanavir 300 mg and ritonavir Rifabutin Cmax: ↑149% (↑103% ↑206%)** recommended dose of rifabutin is100 mg once daily) Rifabutin Cmin: ↑40% (↑5% ↑87%)** 150 mg 3 times per week on setdays (for example Monday-25-O-desacetyl-rifabutin AUC: ↑990% Wednesday-Friday). Increased(↑714% ↑1 361%)** monitoring for rifabutin-associated25-O-desacetyl-rifabutin Cmax: ↑677% adverse reactions including(↑513% ↑883%)** neutropenia and uveitis is warranted25-O-desacetyl-rifabutin Cmin: ↑1 045% due to an expected increase in(↑715% ↑1 510%)** exposure to rifabutin. Furtherdosage reduction of rifabutin to

**When compared to rifabutin 150 mg 150 mg twice weekly on set days isonce daily alone. Total rifabutin and recommended for patients in whom25-O-desacetyl-rifabutin AUC: ↑119% the 150 mg dose 3 times per week(↑78% ↑169%). is not tolerated. It should be kept inmind that the twice weekly dosage

In previous studies, the pharmacokinetics of 150 mg may not provide anof atazanavir was not altered by rifabutin. optimal exposure to rifabutin thusleading to a risk of rifamycinresistance and a treatment failure.

No dose adjustment is needed for

REYATAZ.

Rifampicin Rifampicin is a strong CYP3A4 inducer The combination of rifampicin andand has been shown to cause a 72% REYATAZ is contraindicateddecrease in atazanavir AUC which can (see section 4.3).result in virological failure and resistancedevelopment. During attempts toovercome the decreased exposure byincreasing the dose of REYATAZ or otherprotease inhibitors with ritonavir, a highfrequency of liver reactions was seen.

ANTIPSYCHOTICS

Quetiapine Due to CYP3A4 inhibition by REYATAZ, Co-administration of quetiapineconcentrations of quetiapine are expected with REYATAZ is contraindicatedto increase. as REYATAZ may increasequetiapine-related toxicity.

Increased plasma concentrations ofquetiapine may lead to coma(see section 4.3).

Lurasidone REYATAZ is expected to increase plasma Co-administration of lurasidonelevels of lurasidone due to CYP3A4 with REYATAZ is contraindicatedinhibition. as this may increase lurasidone-related toxicity (see section 4.3).

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

ACID REDUCING AGENTS

H2-Receptor antagonists

Without Tenofovir

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

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

Atazanavir C : ↓20% (↓32% ↓7%) are co-administered, a dosemax

Atazanavir Cmin: ↔1% (↓16% ↑18%) equivalent to famotidine 20 mgtwice daily should not be exceeded.

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

Atazanavir C If a higher dose of an H2-receptormax: ↓23% (↓33% ↓12%)

Atazanavir C : ↓20% (↓31% ↓8%) antagonist is required (e.g.,min famotidine 40 mg twice daily or

In healthy volunteers with atazanavir/ritonavir at an increased dose equivalent) an increase of theof 400/100 mg once daily REYATAZ/ritonavir dose from

Famotidine 40 mg twice daily Atazanavir AUC: ↔3% (↓14% ↑22%) 300/100 mg to 400/100 mg can be

Atazanavir Cmax: ↔2% (↓13% ↑8%) considered.

Atazanavir Cmin: ↓14% (↓32% ↑8%)

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

In HIV-infected patients with atazanavir/ritonavir at the recommended dose For patients who are takingof 300/100 mg once daily tenofovir disoproxil fumarate, if

Famotidine 20 mg twice daily Atazanavir AUC: ↓21% (↓34% ↓4%)* REYATAZ/ritonavir with both

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

Atazanavir Cmin: ↓19% (↓37% ↑5%)* an H2-receptor antagonist are co-administered, a dose increase of

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

Atazanavir C : ↓23% (↓36% ↓8%)* REYATAZ to 400 mg with 100 mgmax

Atazanavir Cmin: ↓25% (↓47% ↑7%)* of ritonavir is recommended. Adose equivalent to famotidine

In HIV-infected patients with atazanavir/ritonavir at an increased dose 40 mg twice daily should not beof 400/100 mg once daily exceeded.

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

Atazanavir Cmax: ↑18% (↑6.7% ↑31%)*

Atazanavir Cmin: ↑24% (↑10% ↑39%)*

Famotidine 40 mg twice daily Atazanavir AUC: ↔2.3% (↓13% ↑10%)*

Atazanavir Cmax: ↔5% (↓17% ↑8.4%)*

Atazanavir Cmin: ↔1.3% (↓10% ↑15)*

*When compared to atazanavir 300 mgonce daily with ritonavir 100 mg oncedaily and tenofovir disoproxil fumarate300 mg all as a single dose with food.

When compared to atazanavir 300 mg withritonavir 100 mg without tenofovirdisoproxil fumarate, atazanavirconcentrations are expected to beadditionally decreased by about 20%.

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

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

Omeprazole 40 mg once daily Atazanavir (am): 2 hr after omeprazole Co-administration of REYATAZ(atazanavir 400 mg once daily Atazanavir AUC: ↓61% (↓65% ↓55%) with ritonavir and proton pumpwith ritonavir 100 mg once daily) Atazanavir Cmax: ↓66% (↓62% ↓49%) inhibitors is not recommended. If

Atazanavir Cmin: ↓65% (↓71% ↓59%) the combination is judged

Omeprazole 20 mg once daily Atazanavir (am): 1 hr after omeprazole unavoidable, close clinical(atazanavir 400 mg once daily Atazanavir AUC: ↓30% (↓43% ↓14%)* monitoring is recommended inwith ritonavir 100 mg once daily) Atazanavir C : ↓31% (↓42% ↓17%)* combination with an increase in themax

Atazanavir C : ↓31% (↓46% ↓12%)* dose of REYATAZ to 400 mg withmin100 mg of ritonavir; doses of proton

*When compared to atazanavir 300 mg pump inhibitors comparable toonce daily with ritonavir 100 mg once omeprazole 20 mg should not bedaily. exceeded (see section 4.4).

The decrease in AUC, Cmax, and Cmin wasnot mitigated when an increased dose of

REYATAZ/ritonavir (400/100 mg oncedaily) was temporally separated fromomeprazole by 12 hours. Although notstudied, similar results are expected withother proton pump inhibitors. Thisdecrease in atazanavir exposure mightnegatively impact the efficacy ofatazanavir. The mechanism of interactionis decreased solubility of atazanavir asintra-gastric pH increases with protonpump inhibitors.

Antacids

Antacids and medicinal Reduced plasma concentrations of REYATAZ should be administeredproducts containing buffers atazanavir may be the consequence of 2 hours before or 1 hour afterincreased gastric pH if antacids, including antacids or buffered medicinalbuffered medicinal products, are products.administered with REYATAZ.

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Potential for increased alfuzosin Co-administration of alfuzosin withconcentrations which can result in REYATAZ is contraindicatedhypotension. The mechanism of (see section 4.3)interaction is CYP3A4 inhibition by

REYATAZ and/or ritonavir.

ANTICOAGULANTS

Direct-acting oral anticoagulants (DOACs)

Apixaban Potential for increased apixaban and Co-administration of apixaban or

Rivaroxaban rivaroxaban concentrations which can rivaroxaban and REYATAZ withresult in a higher risk of bleeding. ritonavir is not recommended.

The mechanism of interaction is inhibitionof CYP3A4/and P-gp by

REYATAZ/ritonavir.

Ritonavir is a strong inhibitor of both

CYP3A4 and P-gp.

REYATAZ is an inhibitor of CYP3A4.

The potential inhibition of P-gp by

REYATAZ is unknown and cannot beexcluded.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

Dabigatran Potential for increased dabigatran Co-administration of dabigatranconcentrations which can result in a higher and REYATAZ with ritonavir isrisk of bleeding. The mechanism of not recommended.interaction is P-gp inhibition.

Ritonavir is a strong P-gp inhibitor.

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

Edoxaban Potential for increased edoxaban Exercise caution when edoxaban isconcentrations which can result in a higher used with REYATAZ.risk of bleeding. The mechanism ofinteraction is P-gp inhibition by Please refer to the edoxaban SmPC

REYATAZ/ritonavir. sections 4.2 and 4.5 for appropriateedoxaban dosage recommendations

Ritonavir is a strong P-gp inhibitor. for co-administration with P-gpinhibitors.

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

Warfarin Co-administration with REYATAZ has the It is recommended that thepotential to increase or decrease warfarin International Normalised Ratioconcentrations. (INR) be monitored carefullyduring treatment with REYATAZ,especially when commencingtherapy.

ANTIEPILEPTICS

Carbamazepine REYATAZ may increase plasma levels of Carbamazepine should be used withcarbamazepine due to CYP3A4 inhibition. caution in combination with

REYATAZ. If necessary, monitor

Due to carbamazepine inducing effect, a carbamazepine serumreduction in REYATAZ exposure cannot concentrations and adjust the dosebe ruled out. accordingly. Close monitoring ofthe patient's virologic responseshould be excercised.

Phenytoin, phenobarbital Ritonavir may decrease plasma levels of Phenobarbital and phenytoin shouldphenytoin and/or phenobarbital due to be used with caution in

CYP2C9 and CYP2C19 induction. combination with

REYATAZ/ritonavir.

Due to phenytoin/phenobarbital inducingeffect, a reduction in REYATAZ exposure When REYATAZ/ritonavir is co-cannot be ruled out. administered with either phenytoinor phenobarbital, a dose adjustmentof phenytoin or phenobarbital maybe required.

Close monitoring of patient'svirologic response should beexercised.

Lamotrigine Co-administration of lamotrigine and Lamotrigine should be used with

REYATAZ/ritonavir may decrease caution in combination withlamotrigine plasma concentrations due to REYATAZ/ritonavir.

UGT1A4 induction.

If necessary, monitor lamotrigineconcentrations and adjust the doseaccordingly.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS

Antineoplastics

Apalutamide The mechanism of interaction is CYP3A4 Co-administration with REYATAZinduction by apalutamide and CYP3A4 (with or without ritonavir) isinhibition by atazanavir/ritonavir. contraindicated due to the potentialfor decreased atazanavir andritonavir plasma concentration withsubsequent loss of virologicresponse and possible resistance tothe class of protease inhibitors (seesection 4.3). In addition, serumconcentrations of apalutamide maybe increased when coadministeredwith atazanavir/ritonavir, resultingin the potential for serious adverseevents including seizure.

Encorafenib The mechanism of interaction is CYP3A4 Avoid co-administration ofinhibition by atazanavir and/or ritonavir. encorafenib with REYATAZ (withor without ritonavir) due topotential for increase in encorafenibplasma concentration andsubsequent risk of serious adverseevents such as QT intervalprolongation. If co-administrationof encorafenib with REYATAZ(with or without ritonavir) cannotbe avoided, modify encorafenibdose as recommended forco-administration with strong andmoderate CYP3A4 inhibitors in the

Summary of Product

Characteristics of encorafenib.

Ivosidenib The mechanism of interaction is CYP3A4 Avoid co-administration ofinhibition by atazanavir and/or ritonavir. ivosidenib with REYATAZ (withor without ritonavir) due topotential for increase in ivosidenibplasma concentration andsubsequent risk of serious adverseevents such as QT intervalprolongation. If co-administrationof ivosidenib with REYATAZ(with or without ritonavir) cannotbe avoided, modify ivosidenib doseas recommended forco-administration with strong andmoderate CYP3A4 inhibitors in the

Summary of Product

Characteristics of ivosidenib.

Irinotecan Atazanavir inhibits UGT and may interfere If REYATAZ is co-administeredwith the metabolism of irinotecan, with irinotecan, patients should beresulting in increased irinotecan toxicities. closely monitored for adverseevents related to irinotecan.

Immunosuppressants

Cyclosporin Concentrations of these More frequent therapeutic

Tacrolimus immunosuppressants may be increased concentration monitoring of these

Sirolimus when co-administered with REYATAZ medicinal products is recommendeddue to CYP3A4 inhibition. until plasma levels have beenstabilised.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

CARDIOVASCULAR AGENTS

Antiarrhythmics

Amiodarone, Concentrations of these antiarrhythmics Caution is warranted and

Systemic lidocaine, may be increased when co-administered therapeutic concentration

Quinidine with REYATAZ. The mechanism of monitoring is recommended whenamiodarone or systemic available. The concomitant use oflidocaine/atazanavir interaction is CYP3A quinidine is contraindicatedinhibition. Quinidine has a narrow (see section 4.3).therapeutic window and is contraindicateddue to potential inhibition of CYP3A by

REYATAZ.

Calcium channel blockers

Bepridil REYATAZ should not be used in Co-administration with bepridil iscombination with medicinal products that contraindicated (see section 4.3)are substrates of CYP3A4 and have anarrow therapeutic index.

Diltiazem 180 mg once daily Diltiazem AUC: ↑125% (↑109% ↑141%) An initial dose reduction of(atazanavir 400 mg once daily) Diltiazem Cmax: ↑98% (↑78% ↑119%) diltiazem by 50% is recommended,

Diltiazem Cmin: ↑142% (↑114% ↑173%) with subsequent titration as neededand ECG monitoring.

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

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

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

No significant effect on atazanavirconcentrations was observed. There was anincrease in the maximum PR intervalcompared to atazanavir alone. Co-administration of diltiazem and

REYATAZ/ritonavir has not been studied.

The mechanism of diltiazem/atazanavirinteraction is CYP3A4 inhibition.

Verapamil Serum concentrations of verapamil may be Caution should be exercised whenincreased by REYATAZ due to CYP3A4 verapamil is co-administered withinhibition. REYATAZ.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

CORTICOSTEROIDS

Dexamethasone and other Co-administration with dexamethasone or Co-administration withcorticosteroids (all routes of other corticosteroids that induce CYP3A corticosteroids (all routes ofadministration) may result in loss of therapeutic effect of administration) that are metabolized

REYATAZ and development of resistance by CYP3A, particularly forto atazanavir and/or ritonavir. Alternative long-term use, may increase the riskcorticosteroids should be considered. for development of systemiccorticosteroid effects including

The mechanism of interaction is CYP3A4 Cushing’s syndrome and adrenalinduction by dexamethasone and CYP3A4 suppression. The potential benefitinhibition by atazanavir and/or ritonavir. of treatment versus the risk ofsystemic corticosteroid effectsshould be considered.

For co-administration ofcutaneously administeredcorticosteroids sensitive to CYP3Ainhibition, consult the Summary of

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

Fluticasone propionate The fluticasone propionate plasma levels Co-administration ofintranasal 50 μg 4 times daily increased significantly, whereas the REYATAZ/ritonavir and thesefor 7 days intrinsic cortisol levels decreased by glucocorticoids metabolised by(ritonavir 100 mg capsules twice approximately 86% (90% confidence CYP3A4 is not recommendeddaily) interval 82%-89%). Greater effects may be unless the potential benefit ofexpected when fluticasone propionate is treatment outweighs the risk of

And inhaled. Systemic corticosteroid effects systemic corticosteroid effectsincluding Cushing’s syndrome and adrenal (see section 4.4).

Inhaled/Nasal Corticosteroids suppression have been reported in patients A dose reduction of thereceiving ritonavir and inhaled or glucocorticoid should be consideredintranasally administered fluticasone with close monitoring of local andpropionate; this could also occur with systemic effects or a switch to aother corticosteroids metabolised via the glucocorticoid, which is not a

P450 3A pathway, e.g., budesonide. The substrate for CYP3A4 (e.g.,effects of high fluticasone systemic beclomethasone). Moreover, in caseexposure on ritonavir plasma levels are yet of withdrawal of glucocorticoids,unknown. The mechanism of interaction is progressive dose reduction may

CYP3A4 inhibition. have to be performed over a longerperiod.

Concomitant use of REYATAZ (with orwithout ritonavir) and other Inhaled/Nasal Concomitant use of Inhaled/Nasal

Corticosteroids is expected to produce the Corticosteroids and REYATAZsame effects. (with or without ritonavir) mayincrease plasma concentrations of

Inhaled/Nasal corticosteroids. Usewith caution. Consider alternativesto Inhaled/Nasal Corticosteroids,particularly for long-term use.

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

ERECTILE DYSFUNCTION

PDE5 Inhibitors

Sildenafil, tadalafil, vardenafil Sildenafil, tadalafil, and vardenafil are Patients should be warned aboutmetabolised by CYP3A4. Co- these possible side effects whenadministration with REYATAZ may result using PDE5 inhibitors for erectilein increased concentrations of the PDE5 dysfunction with REYATAZ (seeinhibitor and an increase in PDE5- section 4.4).associated adverse events, including Also see PULMONARYhypotension, visual changes, and priapism. ARTERIAL HYPERTENSION in

The mechanism of this interaction is this table for further information

CYP3A4 inhibition. regarding co-administration of

REYATAZ with sildenafil.

GONADOTROPIN-RELEASING HORMONE (GnRH) RECEPTOR ANTAGONISTS

Elagolix The mechanism of interaction is Concomitant use of elagolixanticipated increase in elagolix exposure in 200 mg twice daily withthe presence of CYP3A4 inhibition by REYATAZ (with or withoutatazanavir and/or ritonavir. ritonavir) for more than 1 month isnot recommended due to thepotential risk of adverse eventssuch as bone loss and hepatictransaminase elevations. Limitconcomitant use of elagolix 150 mgonce daily with REYATAZ (withor without ritonavir) to 6 months.

KINASE INHIBITORS

Fostamatinib The mechanism of interaction is CYP3A4 Concomitant use of fostamatinibinhibition by atazanavir and/or ritonavir. with REYATAZ (with or withoutritonavir) may increase the plasmaconcentration of R406, the activemetabolite of fostamatinib. Monitorfor toxicities of R406 exposureresulting in dose-related adverseevents such as hepatotoxicity andneutropenia. Fostamatinib dosereduction may be required.

HERBAL PRODUCTS

St. John’s wort (Hypericum Concomitant use of St. John's wort with Co-administration of REYATAZperforatum) REYATAZ may be expected to result in with products containing St. John'ssignificant reduction in plasma levels of wort is contraindicated.atazanavir. This effect may be due to aninduction of CYP3A4. There is a risk ofloss of therapeutic effect and developmentof resistance (see section 4.3).

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

HORMONAL CONTRACEPTIVES

Ethinyloestradiol 25 μg + Ethinyloestradiol AUC: ↓19% (↓25% If an oral contraceptive isnorgestimate ↓13%) administered with(atazanavir 300 mg once daily Ethinyloestradiol Cmax: ↓16% (↓26% ↓5%) REYATAZ/ritonavir, it iswith ritonavir 100 mg once daily) Ethinyloestradiol Cmin: ↓37% (↓45% recommended that the oral↓29%) contraceptive contain at least 30 μgof ethinyloestradiol and that the

Norgestimate AUC: ↑85% (↑67% ↑105%) patient be reminded of strict

Norgestimate Cmax: ↑68% (↑51% ↑88%) compliance with this contraceptive

Norgestimate Cmin: ↑102% (↑77% ↑131%) dosing regimen. Co-administrationof REYATAZ/ritonavir with other

While the concentration of hormonal contraceptives or oralethinyloestradiol was increased with contraceptives containingatazanavir given alone, due to both UGT progestogens other thanand CYP3A4 inhibition by atazanavir, the norgestimate has not been studied,net effect of atazanavir/ritonavir is a and therefore should be avoided.decrease in ethinyloestradiol levels An alternate reliable method ofbecause of the inducing effect of ritonavir. contraception is recommended.

The increase in progestin exposure maylead to related side-effects (e.g., insulinresistance, dyslipidemia, acne andspotting), thus possibly affecting thecompliance.

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

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

Norethindrone AUC: ↑110% (↑68%↑162%)

Norethindrone Cmax: ↑67% (↑42% ↑196%)

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

The increase in progestin exposure maylead to related side effects (e.g., insulinresistance, dyslipidemia, acne andspotting), thus possibly affecting thecompliance.

LIPID-MODIFYING AGENTS

HMG-CoA reductase inhibitors

Simvastatin Simvastatin and lovastatin are highly Co-administration of simvastatin or

Lovastatin dependent on CYP3A4 for their lovastatin with REYATAZ ismetabolism and co-administration with contraindicated due to an increased

REYATAZ may result in increased risk of myopathy includingconcentrations. rhabdomyolysis (see section 4.3).

Atorvastatin The risk of myopathy including Co-administration of atorvastatinrhabdomyolysis may also be increased with REYATAZ is notwith atorvastatin, which is also recommended. If the use ofmetabolised by CYP3A4. atorvastatin is considered strictlynecessary, the lowest possible doseof atorvastatin should beadministered with careful safetymonitoring (see section 4.4).

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

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

Fluvastatin for an increase in pravastatin or fluvastatinexposure when co-administered withprotease inhibitors. Pravastatin is notmetabolised by CYP3A4. Fluvastatin ispartially metabolised by CYP2C9.

Other lipid-modifying agents

Lomitapide Lomitapide is highly dependent on Co-administration of lomitapide

CYP3A4 for metabolism and co- and REYATAZ with ritonavir isadministration with REYATAZ with contraindicated due to a potentialritonavir may result in increased risk of markedly increasedconcentrations. transaminase levels andhepatotoxicity (see section 4.3).

INHALED BETA AGONISTS

Salmeterol Co-administration with REYATAZ may Co-administration of salmeterolresult in increased concentrations of with REYATAZ is notsalmeterol and an increase in salmeterol- recommended (see section 4.4).associated adverse events.

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

OPIOIDS

Buprenorphine, once daily, Buprenorphine AUC: ↑67% Co-administration with REYATAZstable maintenance dose Buprenorphine Cmax: ↑37% with ritonavir warrants clinical(atazanavir 300 mg once daily Buprenorphine Cmin: ↑69% monitoring for sedation andwith ritonavir 100 mg once daily) cognitive effects. A dose reduction

Norbuprenorphine AUC: ↑105% of buprenorphine may be

Norbuprenorphine Cmax: ↑61% considered.

Norbuprenorphine Cmin: ↑101%

The mechanism of interaction is CYP3A4and UGT1A1 inhibition.

Concentrations of atazanavir (when givenwith ritonavir) were not significantlyaffected.

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

has been shown to have no significanteffect on methadone concentrations, nointeraction is expected if methadone is co-administered with REYATAZ, based onthese data.

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil Co-administration with REYATAZ may A safe and effective dose inresult in increased concentrations of the combination with REYATAZ has

PDE5 inhibitor and an increase in PDE5- not been established for sildenafilinhibitor-associated adverse events. when used to treat pulmonaryarterial hypertension. Sildenafil,

The mechanism of interaction is CYP3A4 when used for the treatment ofinhibition by atazanavir and/or ritonavir. pulmonary arterial hypertension, iscontraindicated (see section 4.3).

Medicinal products by Interaction Recommendations concerning co-therapeutic area administration

SEDATIVES

Benzodiazepines

Midazolam Midazolam and triazolam are extensively Co-administration of REYATAZ

Triazolam metabolised by CYP3A4. Co- with triazolam or orallyadministration with REYATAZ may cause administered midazolam isa large increase in the concentration of contraindicated (see section 4.3),these benzodiazepines. No drug interaction whereas caution should be usedstudy has been performed for the co- with co-administration ofadministration of REYATAZ with REYATAZ and parenteralbenzodiazepines. Based on data for other midazolam. If REYATAZ is co-

CYP3A4 inhibitors, plasma concentrations administered with parenteralof midazolam are expected to be midazolam, it should be done in ansignificantly higher when midazolam is intensive care unit (ICU) or similargiven orally. Data from concomitant use of setting which ensures close clinicalparenteral midazolam with other protease monitoring and appropriate medicalinhibitors suggest a possible 3-4-fold management in case of respiratoryincrease in midazolam plasma levels. depression and/or prolongedsedation. Dosage adjustment formidazolam should be considered,especially if more than a singledose of midazolam is administered.

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

The same recommendations for drug interactions would apply except: that co-administration is not recommended with tenofovir, carbamazepine, phenytoin,phenobarbital, proton pump inhibitors, and buprenorphine. that co-administration with famotidine is not recommended but if required, atazanavir withoutritonavir should be administered either 2 hours after famotidine or 12 hours before. No singledose of famotidine should exceed 20 mg, and the total daily dose of famotidine should notexceed 40 mg.

 the need to consider that co-administration of apixaban, dabigatran, or rivaroxaban and REYATAZ withoutritonavir may affect apixaban, dabigatran, or rivaroxaban concentrations co-administration of voriconazole and REYATAZ without ritonavir may affect atazanavirconcentrations co-administration of fluticasone and REYATAZ without ritonavir may increasefluticasone concentrations relative to fluticasone given alone if an oral contraceptive is administered with REYATAZ without ritonavir, it isrecommended that the oral contraceptive contain no more than 30 μg of ethinyloestradiol no dose adjustment of lamotrigine is required

Interaction studies have only been performed in adults.

A moderate amount of data in pregnant women (between 300-1 000 pregnancy outcomes) indicate nomalformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity(see section 5.3). The use of REYATAZ with ritonavir may be considered during pregnancy only ifthe potential benefit justifies the potential risk.

In clinical trial AI424-182 REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination withzidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester.

Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on

REYATAZ/ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no casesof lactic acidosis observed in the clinical trial AI424-182.

The study assessed 40 infants who received antiretroviral prophylactic treatment (which did notinclude REYATAZ) and were negative for HIV-1 DNA at the time of delivery and/or during the first6 months postpartum. Three of 20 infants (15%) born to women treated with REYATAZ/ritonavir300/100 mg and four of 20 infants (20%) born to women treated with REYATAZ/ritonavir400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of40 infants in this study received phototherapy for a maximum of 4 days. There were no reported casesof kernicterus in neonates.

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

It is not known whether REYATAZ with ritonavir administered to the mother during pregnancy willexacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In theprepartum period, additional monitoring should be considered.

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

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

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

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

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

Among patients who received REYATAZ 400 mg once daily or REYATAZ 300 mg with ritonavir100 mg once daily, the only adverse reactions of any severity reported very commonly with at least apossible relationship to regimens containing REYATAZ and one or more NRTIs were nausea (20%),diarrhoea (10%), and jaundice (13%). Among patients receiving REYATAZ 300 mg with ritonavir100 mg, the frequency of jaundice was 19%. 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. A large prospective observational study has shownan association between an increased incidence of chronic kidney disease and cumulative exposure toatazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. Thisassociation was observed independently of exposure to tenofovir disoproxil. Regular monitoring of therenal function of patients should be maintained throughout the treatment duration (see section 4.4).

Assessment of adverse reactions for REYATAZ is based on safety data from clinical studies and post-marketing experience. Frequency is defined using the following convention: very common (≥ 1/10),common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), veryrare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness.

Immune system disorders: uncommon: hypersensitivity

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

Psychiatric disorders: uncommon: depression, disorientation, anxiety, insomnia, sleepdisorder, abnormal dream

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

Eye disorders: common: ocular icterus

Cardiac disorders: uncommon: torsades de pointesarare: QTc prolongationa, oedema, palpitation

Vascular disorders: uncommon: hypertension

Respiratory, thoracic and mediastinal uncommon: dyspnoeadisorders:

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

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

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

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

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

Reproductive system and breast uncommon: gynaecomastiadisorders:

General disorders and administration common: fatigue;site conditions: uncommon: chest pain, malaise, pyrexia, asthenia;rare: gait disturbancea These adverse reactions were identified through post-marketing surveillance, however, the frequencies were estimated froma statistical calculation based on the total number of patients exposed to REYATAZ in randomised controlled and otheravailable clinical trials (n = 2 321).b See description of selected adverse reactions for more details.

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) 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 combination antiretroviral therapy (CART).

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

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

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

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

REYATAZ (see section 4.4).

The most frequently reported laboratory abnormality in patients receiving regimens containing

REYATAZ 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 REYATAZ 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 REYATAZ 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 REYATAZ 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 REYATAZ experienced concurrent Grade 3-4 ALT/AST and

Grade 3-4 total bilirubin elevations.

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

In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of agehad a mean duration of treatment with REYATAZ oral powder of 80 weeks. No deaths were reported.

The safety profile in these studies was overall comparable to that seen in previous paediatric and adultstudies. The most frequently reported laboratory abnormalities in paediatric patients receiving

REYATAZ oral powder was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) andincreased amylase (Grade 3-4; 33%), generally of non-pancreatic origin. Elevation in ALT levels weremore frequently reported in paediatric patients in these studies than in adults.

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

Among 1,151 patients receiving atazanavir 400 mg once daily, 177 patients were co-infected withchronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily withritonavir 100 mg once daily, 97 patients were co-infected with chronic hepatitis B or C. Co-infectedpatients were more likely to have baseline hepatic transaminase elevations than those without chronicviral hepatitis. No differences in frequency of bilirubin elevations were observed between thesepatients and those without viral hepatitis. The frequency of treatment emergent hepatitis ortransaminase elevations in co-infected patients was comparable between REYATAZ and comparatorregimens (see section 4.4).

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

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

Treatment of overdose with REYATAZ should consist of general supportive measures, includingmonitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinicalstatus. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastriclavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug.

There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensivelymetabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significantremoval of this medicinal product.

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

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

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

Antiretroviral treatment naïve adult patients

In clinical trials of antiretroviral treatment-naïve patients treated with unboosted atazanavir, the I50Lsubstitution, sometimes in combination with an A71V change, is the signature resistance substitutionfor atazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence ofphenotypic cross resistance to other PIs. In clinical trials of antiretroviral treatment-naïve patientstreated with boosted atazanavir, the I50L substitution did not emerge in any patient without baseline PIsubstitutions. The N88S substitution has been rarely observed in patients with virologic failure onatazanavir (with or without ritonavir). While it may contribute to decreased susceptibility to atazanavirwhen it occurs with other protease substitutions, in clinical studies N88S by itself does not always leadto phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy.

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

Frequency de novo PI substitution (n = 26)a> 20% none10-20% nonea Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/mL).

The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologicfailure patients, respectively.

Antiretroviral treatment experienced adult patients

In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates frompatients designated as virological failures on therapy that included either atazanavir, atazanavir +ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Ofthe 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%)displayed the I50L phenotype previously described in naïve patients.

Table 4: De novo substitutions in treatment experienced patients failing therapy withatazanavir + ritonavir (Study 045, 48 weeks)

Frequency de novo PI substitution (n = 35)a,b> 20% M36, M46, I54, A71, V8210-20% L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/mL).b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]> 5.2). FC susceptibility in cellculture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco,

California, USA)

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

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

In antiretroviral naïve adult patients

Study 138 is an international randomised, open-label, multicenter, prospective trial of treatment-naïvepatients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir(400 mg/100 mg twice daily), each in combination with fixed-dose tenofovir disoproxilfumarate/emtricitabine (300 mg/200 mg tablets once daily). The REYATAZ/ritonavir arm showedsimilar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by theproportion of patients with HIV RNA < 50 copies/mL at Week 48 (Table 5).

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

Table 5: Efficacy Outcomes in Study 138a

REYATAZ/ritonavirb Lopinavir/ritonavirc (400 mg/100 mg(300 mg/100 mg once daily) twice daily)

Parameter n = 440 n = 443

Week 48 Week 96 Week 48 Week 96

HIV RNA < 50 copies/mL, %

All patientsd 78 74 76 68

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

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

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

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

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

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

HIV RNA Mean Change from Baseline, log10 copies/mL

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

CD4 Mean Change from Baseline, cells/mm3

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

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

HIV RNA 179 (n = 183) 243 (n = 163) 194 (n = 183) 267 (n = 152)< 100,000 copies/mL≥ 100,000 copies/mL 227 (n = 187) 291 (n = 173) 245 (n = 180) 310 (n = 165)a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was4.94 log10 copies/mL (range 2.6 to 5.88 log10 copies/mL)b REYATAZ/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed-dose 300 mg/200 mg tablets once daily).c Lopinavir/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed-dose 300 mg/200 mg tablets once daily).d Intent-to-treat analysis, with missing values considered as failures.e Per protocol analysis: Excluding non-completers and patients with major protocol deviations.f Number of patients evaluable.

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

Study 136 (INDUMA)

In an open-label, randomised, comparative study following a 26- to 30-week induction phase with

REYATAZ 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted REYATAZ 400 mgonce daily and two NRTIs administered during a 48-week maintenance phase (n = 87) had similarantiviral efficacy compared with REYATAZ + ritonavir and two NRTIs (n = 85) in HIV-infectedsubjects with fully suppressed HIV replication, as assessed by the proportion of subjects with

HIV RNA < 50 copies/mL: 78% of subjects on unboosted REYATAZ and two NRTIs compared with75% on REYATAZ + ritonavir and two NRTIs.

Eleven subjects (13%) in the unboosted REYATAZ group and 6 (7%) in the REYATAZ + ritonavirgroup, had virologic rebound. Four subjects in the unboosted REYATAZ group and 2 in the

REYATAZ + ritonavir group had HIV RNA > 500 copies/mL during the maintenance phase. Nosubject in either group showed emergence of protease inhibitor resistance. The M184V substitution inreverse transcriptase, which confers resistance to lamivudine and emtricitabine, was detected in2 subjects in the unboosted REYATAZ and 1 subject in the REYATAZ + ritonavir group.

There were fewer treatment discontinuations in the unboosted REYATAZ group (1 vs. 4 subjects inthe REYATAZ + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboosted

REYATAZ group compared with the REYATAZ + ritonavir group (18 and 28 subjects, respectively).

In antiretroviral experienced adult patients

Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily)and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed-dosecombination twice daily), each in combination with tenofovir disoproxil fumarate (see sections 4.5and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing atleast one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviralexposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34%of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients inthe REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir armhad four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty-two percent ofpatients in the study had a viral strain with fewer than two NRTI substitutions.

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

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

ATV/RTVb (300 mg/100 mg LPV/RTVc (400 mg/100 mg Time-averaged difference

Parameter once daily) twice daily) ATV/RTV-LPV/RTVn = 120 n = 123 [97.5% CId]

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

HIV RNA Mean Change from Baseline, log10 copies/mL

All patients -1.93 (n = 90e) -2.29 -1.87 -2.08 0.13 0.14(n = 64) (n = 99) (n = 65) [-0.12, 0.39] [-0.13, 0.41]

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

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

HIV RNA < 50 copies/mL by select baseline PI substitutions,f, g % (responder/evaluable)0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA≥ 4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA

CD4 Mean Change from Baseline, cells/mm3

All patients 110 (n = 83) 122 (n = 60) 121 (n = 94) 154 (n = 60) NA NAa The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV-1

RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.88 log10 copies/mL).b ATV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed-dose 300 mg/200 mg tablets once daily).c LPV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed-dose 300 mg/200 mg tablets once daily).d Confidence interval.e Number of patients evaluable.f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatmentbefore Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/mL were 53%and 43% for ATV/RTV and 54% and 46% for LPV/RTV at Weeks 48 and 96 respectively.g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73,

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

NA = not applicable.

Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ +ritonavir and lopinavir + ritonavir were similar (non-inferior). Consistent results were obtained withthe last observation carried forward method of analysis (time-averaged difference of 0.11, 97.5%confidence interval [-0.15, 0.36]). By as-treated analysis, excluding missing values, the proportions ofpatients with HIV RNA < 400 copies/mL (< 50 copies/mL) in the REYATAZ + ritonavir arm and thelopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively.

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

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

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on datafrom the open-label, multicenter clinical trial AI424-020 conducted in patients from 3 months to21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naïve and101 antiretroviral-experienced) received once daily REYATAZ (capsule or powder formulation), withor without ritonavir, in combination with two NRTIs.

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

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

REYATAZ capsules with ritonavir are presented in Table 7. For treatment-naïve paediatric patients,the mean baseline CD4 cell count was 344 cells/mm3 (range: 2 to 800 cells/mm3) and mean baselineplasma HIV-1 RNA was 4.67 log10 copies/mL (range: 3.70 to 5.00 log10 copies/mL). For treatment-experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm3 (range: 100 to1157 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.09 log10 copies/mL (range: 3.28 to5.00 log10 copies/mL).

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

Week 48 (Study AI424-020)

Treatment-Naïve Treatment-Experienced

REYATAZ REYATAZ

Parameter Capsules/ritonavir Capsules/ritonavir(300 mg/100 mg once (300 mg/100 mg oncedaily) daily)n = 16 n = 25

HIV RNA < 50 copies/mL, %a

All patients 81 (13/16) 24 (6/25)

HIV RNA < 400 copies/mL, %a

All patients 88 (14/16) 32 (8/25)

CD4 Mean Change from Baseline, cells/mm3

All patients 293 (n = 14b) 229 (n = 14b)

HIV RNA < 50 copies/mL by select baseline PI substitutions,c % (responder/evaluabled)0-2 NA 27 (4/15)3 NA -≥ 4 NA 0 (0/3)a Intent-to-treat analysis, with missing values considered as failures.b Number of patients evaluable.c PI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY,I54ALMSTV, L76V, V82AFLST, I84V,

N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V.d Includes patients with baseline resistance data.

NA = not applicable.

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

Absorption: in HIV-infected patients (n = 33, combined studies), multiple dosing of REYATAZ300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) foratazanavir, Cmax of 4466 (42%) ng/mL, with time to Cmax of approximately 2.5 hours. The geometricmean (CV%) for atazanavir Cmin and AUC was 654 (76%) ng/mL and 44185 (51%) ng*h/mL,respectively.

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

Food effect: co-administration of REYATAZ and ritonavir with food optimises the bioavailability ofatazanavir. Co-administration of a single 300-mg dose of REYATAZ and 100-mg dose of ritonavirwith a light meal resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the24 hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat mealdid not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% offasting values. The 24-hour concentration following a high-fat meal was increased by approximately33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Administration of

REYATAZ with ritonavir with either a light or a high fat meal decreased the coefficient of variation of

AUC and Cmax by approximately 25% compared to the fasting state. To enhance bioavailability andminimise variability, REYATAZ is to be taken with food.

Distribution: atazanavir was approximately 86% bound to human serum proteins over a concentrationrange of 100 to 10,000 ng/mL. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albuminto a similar extent (89% and 86%, respectively, at 1,000 ng/mL). In a multiple-dose study in HIV-infected patients dosed with 400-mg of atazanavir once daily with a light meal for 12 weeks,atazanavir was detected in the cerebrospinal fluid and semen.

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

Elimination: following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivitywas recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately20% and 7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion ofunchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adultpatients (n = 33, combined studies) the mean half-life within a dosing interval for atazanavir was12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a lightmeal.

Renal impairment: in healthy subjects, the renal elimination of unchanged atazanavir wasapproximately 7% of the administered dose. There are no pharmacokinetic data available for

REYATAZ with ritonavir in patients with renal insufficiency. REYATAZ (without ritonavir) has beenstudied in adult patients with severe renal impairment (n = 20), including those on haemodialysis, atmultiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbounddrug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameterswere decreased by 30% to 50% in patients undergoing haemodialysis compared to patients withnormal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.)

Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. REYATAZ(without ritonavir) has been studied in adult subjects with moderate-to-severe hepatic impairment(14 Child-Pugh Class B and 2 Child-Pugh Class C subjects) after a single 400-mg dose. The mean

AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. Themean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours inhealthy subjects. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a300 mg dose with ritonavir have not been studied. Concentrations of atazanavir with or withoutritonavir are expected to be increased in patients with moderately or severely impaired hepaticfunction (see sections 4.2, pct. 4.3, and 4.4).

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

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

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

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

Pregnant Women in the Fed Stateatazanavir 300 mg with ritonavir 100 mga

Pharmacokinetic Parameter 2nd Trimester 3rd Trimester postpartum(n = 9) (n = 20) (n = 36)

Cmax ng/mL 3 729.09 3 291.46 5 649.10

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

AUC ng*h/mL 34 399.1 34 251.5 60 532.7

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

C bmin ng/mL 663.78 668.48 1 420.64

Geometric mean (CV%) (36) (50) (47)a Atazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during the postpartum period(4-12 weeks) than those observed historically in HIV-infected, non-pregnant patients. Atazanavir plasma troughconcentrations were approximately 2-fold higher during the postpartum period when compared to those observed historicallyin HIV-infected non-pregnant patients.b Cmin is concentration 24 hours post-dose.

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

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

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at aconcentration (30 μM) of atazanavir corresponding to 30-fold the free drug concentration at Cmax inhumans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90)in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PRinterval, prolongation of QT interval, and prolongation of QRS complex) were observed only in aninitial 2-week oral toxicity study performed in dogs. Subsequent 9-month oral toxicity studies in dogsshowed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical datais unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4and 4.8). The potential for PR prolongation should be considered in cases of overdose(see 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 definitive embryo-development study. In the pre- and postnatal development assessment in rats, atazanavir produced atransient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure toatazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than thatobserved in humans given 400 mg once daily.

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

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

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

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

REYATAZ 100 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate, and magnesium stearate

Capsule shells: gelatin, indigocarmin (E132), and titanium dioxide (E171)

Blue ink containing: shellac, propylene glycol, ammonium hydroxide, and indigocarmin (E132)

White ink containing: shellac, titanium dioxide (E171), ammonium hydroxide, propylene glycol, andsimethicone

REYATAZ 150 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate, and magnesium stearate

Capsule shells: gelatin, indigocarmin (E132), and titanium dioxide (E171)

Blue ink containing: shellac, propylene glycol, ammonium hydroxide, and indigocarmin (E132)

White ink containing: shellac, titanium dioxide (E171), ammonium hydroxide, propylene glycol, andsimethicone

REYATAZ 200 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate, and magnesium stearate

Capsule shells: gelatin, indigocarmin (E132), and titanium dioxide (E171)

White ink containing: shellac, titanium dioxide (E171), ammonium hydroxide, propylene glycol, andsimethicone

REYATAZ 300 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate, and magnesium stearate

Capsule shells: gelatin, red iron oxide, black iron oxide, yellow iron oxide, indigocarmin (E132), andtitanium dioxide (E171)

White ink containing: shellac, titanium dioxide (E171), ammonium hydroxide, propylene glycol, andsimethicone

Not applicable.

2 years

Do not store above 25°C.

REYATAZ 100 mg hard capsules

Each carton contains one high-density polyethylene (HDPE) bottle closed with child-resistantpolypropylene closure. Each bottle contains 60 hard capsules.

Each carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/Alu perforated unitdose blisters.

REYATAZ 150 mg hard capsules

Each carton contains one high-density polyethylene (HDPE) bottle closed with child-resistantpolypropylene closure. Each bottle contains 60 hard capsules.

Each carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/Alu perforated unitdose blisters.

REYATAZ 200 mg hard capsules

Each carton contains one high-density polyethylene (HDPE) bottle or three high-density polyethylene(HDPE) bottles closed with child-resistant polypropylene closure. Each bottle contains 60 hardcapsules.

Each carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/Alu perforated unitdose blisters.

REYATAZ 300 mg hard capsules

Each carton contains one high-density polyethylene (HDPE) bottle or three high-density polyethylene(HDPE) bottles closed with child-resistant polypropylene closure. Each bottle contains 30 hardcapsules.

Each carton contains 30 x 1 capsules; 5 blister cards of 6 x 1 capsules each in Alu/Alu perforated unitdose blisters.

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/1/03/267/001-006; 008-011

Date of first authorisation: 02 March 2004

Date of latest renewal: 06 February 2009

{MM/YYYY}

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

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