Document: Atazanavir Teva capsule, hard Marknadsförs ej för närvarande, ENG SmPC change

• Atazanavir Teva capsule, hard, Marknadsförs ej för närvarande SmPC
• Atazanavir Teva capsule, hard Marknadsförs ej för närvarande, ENG SmPC

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1. NAME OF THE MEDICINAL PRODUCT

Atazanavir Teva 150 mg Capsules, hard

Atazanavir Teva 200 mg Capsules, hard

Atazanavir Teva 300 mg Capsules, hard

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains atazanavir sulfate corresponding to 150 mg, 200 mg and 300 mg of atazanavir.

Excipient with known effect:

Each 150 mg capsule contains 67.2 mg of lactose monohydrate.

Each 200 mg capsule contains 89.6 mg of lactose monohydrate.

Each 300 mg capsule contains 134.4 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Capsule, hard

Atazanavir Teva 150 mg hard capsules are non transparent size 1 capsules with overall closed length 19.4 ± 0.3 mm, with dark blue cap, and black mark 150 on light blue body. The content of the capsule is light yellow powder.

Atazanavir Teva 200 mg hard capsules are non transparent size 0 capsules with overall closed length 21.7 ± 0.3 mm with blue cap, and black mark 200 on blue body. The content of the capsule is light yellow powder.

Atazanavir Teva 300 mg hard capsules are non transparent size 00 capsules with overall closed length 23.3 ± 0.3 mm with red cap, and black mark 300 on blue body. The content of the capsule is light yellow powder.

4. Clinical particulars

4.1 Therapeutic indications

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

HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other

antiretroviral medicinal products.

Based on available virological and clinical data from adult patients, no benefit is expected in patients

with strains resistant to multiple protease inhibitors (≥ 4 PI mutations). There are very limited data

available from children aged 6 to less than 18 years (see sections 4.4 and 5.1).

The choice of Atazanavir Teva in treatment experienced adult and paediatric patients should be based on

individual viral resistance testing and the patient’s treatment history (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Posology

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

Adults: the recommended dose of Atazanavir Teva is 300 mg once daily taken with ritonavir

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

(see sections 4.5 and 5.1). (See also section 4.4 Withdrawal of ritonavir only under restrictive conditions).

Paediatric population

Paediatric patients (6 years to less than 18 years of age): The dose of Atazanavir Teva for

paediatric patients is based on body weight as shown in Table 1 and should not exceed the

recommended adult dose. Atazanavir Teva must be taken with ritonavir and have to be taken with

food.

Table 1: Dose for Paediatric Patients (6 years to less than 18 years of age) for Atazanavir Teva

with ritonavir

Body Weight(kg)	Atazanavir Teva once daily dose	Ritonavir once daily dosea
15 to less than 20	150 mg	100 mgb
20 to less than 40	200 mg	100 mg
at least 40	300 mg	100 mg

^a Ritonavir capsules, tablets or oral solution.

^b Ritonavir oral solution no lower than 80 mg and not more than 100 mg may be used for paediatric

patients from 15 kg to less than 20 kg who cannot swallow ritonavir capsules/tablets.

The available data do not support the use of atazanavir in combination with low dose ritonavir in

paediatric patients weighing less than 15 kg.

Paediatric patients (less than 6 years of age): The safety and efficacy of atazanavir in children aged 3 months to 6 years has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. Atazanavir Teva should not be used in children less than 3 months because of safety concerns especially taking into account the potential risk of kernicterus.

Special populations

Patients with renal impairment: no dosage adjustment is needed. Atazanavir Teva with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.4 and 5.2).

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

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

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

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

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

• If tenofovir or an H₂-receptor antagonist is needed, a dose increase to Atazanavir Teva 400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2).

• It is not recommended to use Atazanavir Teva with ritonavir for pregnant patients who are receiving both tenofovir and an H₂-receptor antagonist.

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

During postpartum:

Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavir exposures might increase during the first two months after delivery (see section 5.2). Therefore, postpartum patients should be closely monitored for adverse reactions.

Method of administration: for oral administration. The capsules should be swallowed whole.

4.3 Contraindications

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

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

Co-administration of atazanavir with simvastatin or lovastatin is contraindicated (see section 4.5).

Combination of rifampicin and atazanavir is contraindicated (see section 4.5).

The PDE5 inhibitor sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment of erectile dysfunction see section 4.4 and section 4.5.

Atazanavir must not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g. quetiapine, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5).

Atazanavir must not be used in combination with products containing St. John’s wort (Hypericum perforatum) (see section 4.5)

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines

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

Patients with coexisting conditions

Hepatic impairment: Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). The safety and efficacy of atazanavir has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products (see section 4.8).

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

Renal impairment: No dosage adjustment is needed in patients with renal impairment. However, atazanavir with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).

QT prolongation: Dose related asymptomatic prolongations in PR interval with atazanavir have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), atazanavir should be used with caution and only if the benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing atazanavir in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances (see sections 4.8 and 5.3).

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

Fat redistribution and metabolic disorders

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution.

Combination antiretroviral therapy (CART), including atazanavir (with or without ritonavir)-based CART, is associated with dyslipidaemia. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

In clinical studies, atazanavir (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators. The clinical impact of such findings has not been demonstrated in the absence of specific studies on cardiovascular risk. The selection of antiretroviral therapy must be guided principally by antiviral efficacy. Consultation with standard guidelines for management of dyslipidaemia is recommended.

Hyperglycaemia

New onset diabetes mellitus, hyperglycaemia, and exacerbation of existing diabetes mellitus have been reported in patients receiving protease inhibitors. In some of these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with medicinal products that have been associated with development of diabetes or hyperglycaemia.

Hyperbilirubinaemia

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving atazanavir (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving atazanavir should be evaluated for alternative etiologies. Alternative antiretroviral therapy to atazanavir may be considered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not recommended because it may result in a loss of therapeutic effect and development of resistance.

Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. Combinations of atazanavir and indinavir have not been studied and co-administration of these medicinal products is not recommended (see section 4.5).

Withdrawal of ritonavir only under restrictive conditions

The recommended standard treatment is atazanavirboosted with ritonavir, ensuring optimal pharmacokinetic parameters and level of virologic suppression.

The withdrawal of ritonavir from the boosted regimen of atazanavir is not recommended, but may be considered in adults patients at the dose of 400 mg once daily with food only under the following combined restrictive conditions:

• absence of prior virologic failure

• undetectable viral load during the last 6 months under current regimen

• viral strains not harbouring HIV resistance associated mutations (RAMs) to current regimen.

Atazanavir given without ritonavir should not be considered in patients treated with a backbone regimen containing tenofovir disoproxil fumarate and with other concomitant medications that reduce atazanavir bioavailability (see section 4.5 In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen) or in case of perceived challenging compliance.

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

Cholelithiasis

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

Nephrolithiasis

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

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

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

Rash and associated syndromes

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

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

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

Interactions with other medicinal products

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

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

If the co-administration of atazanavir with an NNRTI is required, an increase in the dose of both atazanavir and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.

Atazanavir is metabolised principally by CYP3A4. Co-administration of atazanavir with ritonavir and medicinal products that induce CYP3A4 is not recommended (see sections 4.3 and 4.5).

PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be used when prescribing PDE5-inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment of erectile dysfunction in patients receiving atazanavir. Co-administration of atazanavir with these medicinal products is expected to substantially increase their concentrations and may result in PDE5-associated adverse events such as hypotension, visual changes and priapism (see section 4.5).

Co-administration of voriconazole and atazanavir with ritonavir is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole (see section 4.5).

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

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

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

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

cause.

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded.

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

Excipients

Atazanavir Teva contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Paediatric population

Safety

Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults. Asymptomatic first- and second-degree AV block was reported in paediatric patients (see section 4.8). Caution should be used with medicinal products known to induce PR prolongations. In paediatric patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), atazanavir should be used with caution and only if the benefits exceed the risk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).

Efficacy

Atazanavir/ritonavir is not effective in viral strains harbouring multiple mutations of resistance. While in adults no benefit can be expected in patients with ≥4 PI mutations, in treatment experienced children even lower numbers of PI mutations may be predictive of a lack of benefit (see section 5.1).

4.5 Interaction with other medicinal products and other forms of interaction

When atazanavir and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with atazanavir and ritonavir.

Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, atazanavir with ritonavir is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly ergotamine and dihydroergotamine (see section 4.3).

Other interactions

Interactions between atazanavir and other medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the approved regimen of atazanavir.

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

Table 2: Interactions between atazanavir and other medicinal products.

Medicinal products by therapeutic area	Interactions	Recommendations concerning co-administration
ANTI-RETROVIRALS
Protease inhibitors: The co-administration of atazanavir/ritonavir and other protease inhibitors has not been studied but would be expected to increase exposure to other protease inhibitors. Therefore, such coadministration is not recommended.
Ritonavir 100 mg once daily (atazanavir 300 mg once daily) Studies conducted in HIV-infected patients.	Atazanavir AUC: ↑250% (↑144% ↑403%)* Atazanavir Cmax: ↑120% (↑56% ↑211%)* Atazanavir Cmin: ↑713% (↑359% ↑1339%)* * In a combined analysis, atazanavir 300 mg and ritonavir 100 mg (n=33) was compared to atazanavir 400 mg without ritonavir (n=28). The mechanism of interaction between atazanavir and ritonavir is CYP3A4 inhibition.	Ritonavir 100 mg once daily is used as a booster of atazanavir pharmacokinetics.
Indinavir	Indinavir is associated with indirect unconjugated hyperbilirubinaemia due to inhibition of UGT.	Co-administration of atazanavir and indinavir is not recommended (see section 4.4).
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
Lamivudine 150 mg twice daily + zidovudine 300 mg twice daily (atazanavir 400 mg once daily)	No significant effect on lamivudine and zidovudine concentrations was observed.	Based on these data and because ritonavir is not expected to have a significant impact on the pharmacokinetics of NRTIs, the co-administration of atazanavir with these medicinal products is not expected to significantly alter the exposure of the coadministered drugs.
Abacavir	The co-administration of atazanavir with abacavir is not expected to significantly alter the exposure of abacavir.
Didanosine (buffered tablets) 200 mg/stavudine 40 mg, both single dose (atazanavir 400 mg single dose)	Atazanavir, simultaneous administration with ddI+d4T (fasted) Atazanavir AUC ↓87% (↓92% ↓79%) Atazanavir Cmax ↓89% (↓94% ↓82%) Atazanavir Cmin ↓84% (↓90% ↓73%) Atazanavir, dosed 1 hr after ddI+d4T (fasted) Atazanavir AUC ↔3% (↓36% ↑67%) Atazanavir Cmax ↑12% (↓33% ↑18%) Atazanavir Cmin ↔3% (↓39% ↑73%) Atazanavir concentrations were greatly decreased when co-administered with didanosine (buffered tablets) and stavudine. The mechanism of interaction is a reduced solubility of atazanavir with increasing pH related to the presence of anti-acid agent in didanosine buffered tablets. No significant effect on didanosine and stavudine concentrations was observed.	Didanosine should be taken at the fasted state 2 hours after atazanavir taken with food. The co-administration of atazanavir with stavudine is not expected to significantly alter the exposure of stavudine.
Didanosine (enteric coated capsules) 400 mg single dose (atazanavir 300 mg once daily with ritonavir 100 mg once daily)	Didanosine (with food) Didanosine AUC ↓34% (↓41% ↓27%) Didanosine Cmax ↓38% (↓48% ↓26%) Didanosine Cmin ↑25% (↓8% ↑69%) No significant effect on atazanavir concentrations was observed when administered with enteric-coated didanosine, but administration with food decreased didanosine concentrations.
Tenofovir disoproxil fumarate 300 mg once daily (atazanavir 300 mg once daily with ritonavir 100 mg once daily) Studies conducted in HIV infected patients	Atazanavir AUC ↓22% (↓35% ↓6%) * Atazanavir Cmax ↓16% (↓30% ↔0%) * Atazanavir Cmin ↓23% (↓43% ↑2%) * * In a combined analysis from several clinical studies, atazanavir/ritonavir 300/100 mg co-administered with tenofovir disoproxil fumarate 300 mg (n=39) was compared to atazanavir/ritonavir 300/100 mg (n=33). The efficacy of atazanavir/ritonavir in combination with tenofovir in treatment-experienced patients has been demonstrated in clinical study 045 and in treatment naïve patients in clinical study 138 (see sections 4.8 and 5.1). The mechanism of interaction between atazanavir and tenofovir is unknown.	When co-administered with tenofovir disoproxil fumarate, it is recommended that atazanavir 300mg be given with ritonavir 100 mg and tenofovir disoproxil fumarate 300 mg (all as a single dose with food).
Tenofovir disoproxil fumarate 300 mg once daily (atazanavir 300 mg once daily with ritonavir 100 mg once daily)	Tenofovir disoproxil fumarate AUC↑37% (↑30% ↑45%) Tenofovir disoproxil fumarate Cmax ↑34% (↑20% ↑51%) Tenofovir disoproxil fumarate Cmin↑29% (↑21% ↑36%)	Patients should be closely monitored for tenofovir-associated adverse events, including renal disorders.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily)	Atazanavir (pm): all administered with food Atazanavir AUC ↔0%(↓9% ↑10%)* Atazanavir Cmax ↑17%(↑8% ↑27%)* Atazanavir Cmin ↓42%(↓51% ↓31%)*	Co-administration of efavirenz with atazanavir is not recommended (see section 4.4)
Efavirenz 600 mg once daily (atazanavir 400 mg once daily with ritonavir 200 mg once daily)	Atazanavir (pm): all administered with food Atazanavir AUC ↔6% (↓10% ↑26%)*/** Atazanavir Cmax ↔9% (↓5% ↑26%)*/** Atazanavir Cmin ↔12% (↓16% ↑49%)*/** * When compared to atazanavir 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir Cmin, might negatively impact the efficacy of atazanavir. The mechanism of efavirenz/atazanavir interaction is CYP3A4 induction. ** Based on historical comparison.
Nevirapine 200 mg twice daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily) Study conducted in HIV infected patients	Nevirapine AUC ↑26% (↑17% ↑36%) Nevirapine Cmax ↑21% (↑11% ↑32%) Nevirapine Cmin ↑35% (↑25% ↑47%) Atazanavir AUC ↓19% (↓35% ↑2%) * Atazanavir Cmax ↔2% (↓15% ↑24%) * Atazanavir Cmin ↓59% (↓73% ↓40%) * * When compared to atazanavir 300 mg and ritonavir 100 mg without nevirapine. This decrease in atazanavir Cmin, might negatively impact the efficacy of atazanavir. The mechanism of nevirapine/atazanavir interaction is CYP3A4 induction.	Co-administration of nevirapine with atazanavir is not recommended (see section 4.4)
Integrase Inhibitors
Raltegravir 400 mg twice daily (atazanavir/ritonavir)	Raltegravir AUC↑ 41% Raltegravir Cmax↑ 24% Raltegravir C12hr↑ 77% The mechanism is UGT1A1 inhibition.	No dose adjustment required for raltegravir.
HCV Protease Inhibitors
Boceprevir 800 mg three times daily (atazanavir 300 mg/ritonavir 100 mg once daily)	boceprevir AUC ↔5% boceprevir Cmax ↔7% boceprevir Cmin ↔18% atazanavir AUC ↓ 35% atazanavir Cmax ↓ 25% atazanavir Cmin ↓ 49% ritonavir AUC ↓ 36% ritonavir Cmax ↓ 27% ritonavir Cmin ↓ 45%	Co-administration of atazanavir/ritonavir with boceprevir resulted in lower exposure of atazanavir which may be associated with lower efficacy and loss of HIV control. This co-administration might be considered on a case by case basis if deemed necessary, in patients with suppressed HIV viral loads and with HIV viral strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring for HIV suppression is warranted.
ANTIBIOTICS
Clarithromycin 500 mg twice daily (atazanavir 400 mg once daily)	Clarithromycin AUC ↑94% (↑75% ↑116%) Clarithromycin Cmax ↑50% (↑32% ↑71%) Clarithromycin Cmin ↑160% (↑135% ↑188%) 14-OH clarithromycin 14-OH clarithromycin AUC ↓70% (↓74% ↓66%) 14-OH clarithromycin Cmax ↓72% (↓76% ↓67%) 14-OH clarithromycin Cmin ↓62% (↓66% ↓58%) Atazanavir AUC ↑28% (↑16% ↑43%) Atazanavir Cmax ↔6% (↓7% ↑20%) Atazanavir Cmin ↑91% (↑66% ↑121%) A dose reduction of clarithromycin may result in subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of the clarithromycin/atazanavir interaction is CYP3A4 inhibition.	No recommendation regarding dose reduction can be made; therefore, caution should be exercised if atazanavir is co-administered with clarithromycin.
ANTIFUNGALS
Ketoconazole 200 mg once daily (atazanavir 400 mg once daily)	No significant effect on atazanavir concentrations was observed.	Ketoconazole and itraconazole should be used cautiously with atazanavir/ritonavir. High doses of ketoconazole and itraconazole (>200 mg/day) are not recommended.
Itraconazole	Itraconazole, like ketoconazole, is a potent inhibitor as well as a substrate of CYP3A4.
	Based on data obtained with other boosted PIs and ketoconazole, where ketoconazole AUC showed a 3-fold increase, atazanavir/ritonavir is expected to increase ketoconazole or itraconazole concentrations.
Voriconazole 200 mg twice daily (atazanavir 300 mg/ritonavir 100 mg once daily) Subjects with at least one functional CYP2C19 allele.	Voriconazole AUC ↓33% (↓42% ↓22%) Voriconazole Cmax ↓10% (↓22% ↓4%) Voriconazole Cmin ↓39% (↓49% ↓28%) Atazanavir AUC ↓12% (↓18% ↓5%) Atazanavir Cmax ↓13% (↓20% ↓4%) Atazanavir Cmin ↓ 20 % (↓28 % ↓10%) Ritonavir AUC ↓12% (↓17% ↓7%) Ritonavir Cmax ↓9% (↓17% ↔0%) Ritonavir Cmin ↓25% (↓35% ↓14%) In the majority of patients with at least one functional CYP2C19 allele, a reduction in both voriconazole and atazanavir exposures are expected.	Co-administration of voriconazole and atazanavir with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see section 4.4). At the time voriconazole treatment is required, a patient's CYP2C19 genotype should be performed if feasible. Therefore if the combination is unavoidable, the following recommendations are made according to the CYP2C19 status: - in patients with at least one functional CYP2C19 allele, close clinical monitoring for a loss of both voriconazole (clinical signs) and atazanavir (virologic response) efficacy is recommended. - in patients without a functional CYP2C19 allele, close clinical and laboratory monitoring of voriconazole-associated adverse events is recommended If genotyping is not feasible, full monitoring of safety and efficacy should be performed.
Voriconazole 50 mg twice daily (atazanavir 300 mg/ritonavir 100 mg once daily) Subjects without a functional CYP2C19 allele.	Voriconazole AUC ↑561% (↑451% ↑699%) Voriconazole Cmax ↑438% (↑355% ↑539%) Voriconazole Cmin ↑765% (↑571% ↑1,020%) Atazanavir AUC ↓20% (↓35% ↓3%) Atazanavir Cmax ↓19% (↓34% ↔0.2%) Atazanavir Cmin ↓ 31 % (↓46 % ↓13%) Ritonavir AUC ↓11% (↓20% ↓1%) Ritonavir Cmax ↓11% (↓24% ↑4%) Ritonavir Cmin ↓19% (↓35% ↑1%) In a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole exposures are expected.
Fluconazole 200 mg once daily (atazanavir 300 mg and ritonavir 100 mg once daily)	Atazanavir and fluconazole concentrations were not significantly modified when atazanavir/ritonavir was co-administered with fluconazole.	No dosage adjustments are needed for fluconazole and atazanavir.
ANTIMYCOBACTERIAL
Rifabutin 150 mg twice weekly (atazanavir 300 mg and ritonavir 100 mg once daily)	Rifabutin AUC ↑48% (↑19% ↑84%)** Rifabutin Cmax ↑149% (↑103% ↑206%)** Rifabutin Cmin ↑40% (↑5% ↑87%) ** 25-O-desacetyl-rifabutin AUC ↑990% (↑714% ↑1361%) ** 25-O-desacetyl-rifabutin Cmax ↑677% (↑513% ↑883%) ** 25-O-desacetyl-rifabutin Cmin ↑1045% (↑715% ↑1510%) ** ** When compared to rifabutin 150 mg once daily alone. Total rifabutin and 25-O-desacetyl-rifabutin AUC ↑119% (↑78% ↑169%). In previous studies, the pharmacokinetics of atazanavir was not altered by rifabutin.	When given with atazanavir, the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday- Wednesday-Friday). Increased monitoring for rifabutin associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin to 150 mg twice weekly on set days is recommended for patients in whom the 150 mg dose 3 times per week is not tolerated. It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. No dose adjustment is needed for atazanavir.
Rifampicin	Rifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of atazanavir or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.	The combination of rifampicin and atazanavir is contraindicated (see section 4.3).
ANTIPSYCOTICS
Quetiapine	Due to CYP3A4 inhibition by atazanavir, concentrations of quetiapine are expected to increase.	Co-administration of quetiapine with atazanavir is contraindicated as atazanavir may increase quetiapine-related toxicity. Increased plasma concentrations of quetiapine may lead to coma (see section 4.3).
ACID REDUCING AGENTS
H2-Receptor antagonists
Without Tenofovir
In HIV-infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg once daily		For patients not taking tenofovir, if atazanavir 300 mg/ritonavir 100 mg and H2-receptor antagonists are co-administered, a dose equivalent to famotidine 20 mg twice daily should not be exceeded. If a higher dose of an H2-receptor antagonist is required (eg, famotidine 40 mg twice daily or equivalent) an increase of the atazanavir/ritonavir dose from 300/100 mg to 400/100 mg can be considered.
Famotidine 20 mg twice daily	Atazanavir AUC ↓18% (↓25% ↑1%) Atazanavir Cmax ↓20% (↓32% ↓7%) Atazanavir Cmin ↔1% (↓16% ↑18%)
Famotidine 40 mg twice daily	Atazanavir AUC ↓23% (↓32% ↓14%) Atazanavir Cmax ↓23% (↓33% ↓12%) Atazanavir Cmin ↓20% (↓31% ↓8%)
In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg once daily
Famotidine 40 mg twice daily	Atazanavir AUC ↔3% (↓14% ↑22%) Atazanavir Cmax ↔2% (↓13% ↑8%) Atazanavir Cmin ↓14% (↓32% ↑8%)
With Tenofovir 300 mg once daily
In HIV-infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg once daily		For patients who are taking tenofovir, if atazanavir/ritonavir with both tenofovir and an H2-receptor antagonist are coadministered, a dose increase of atazanavir to 400 mg with 100 mg of ritonavir is recommended. A dose equivalent to famotidine 40 mg twice daily should not be exceeded.
Famotidine 20 mg twice daily	Atazanavir AUC ↓21% (↓34% ↓4%) * Atazanavir Cmax ↓21% (↓36% ↓4%) * Atazanavir Cmin ↓19% (↓37% ↑5%) *
Famotidine 40 mg twice daily	Atazanavir AUC ↓24% (↓36% ↓11%)* Atazanavir Cmax ↓23% (↓36% ↓8%) * Atazanavir Cmin ↓25% (↓47% ↑7%) *
In HIV-infected patients with atazanavir/ritonavir at an increased dose of 400/100 mg once daily
Famotidine 20 mg twice daily	Atazanavir AUC ↑18% (↑6.5% ↑30%)* Atazanavir Cmax ↑18% (↑6.7% ↑31%)* Atazanavir Cmin ↑24 % (↑10% ↑39%)*
Famotidine 40 mg twice daily	Atazanavir AUC ↔2.3% (↓13% ↑10%)* Atazanavir Cmax ↔5% (↓17% ↑8.4%)* Atazanavir Cmin ↔1.3% (↓10% ↑15)* * When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily and tenofovir disoproxil fumarate 300 mg all as a single dose with food. When compared to atazanavir 300 mg with ritonavir 100 mg without tenofovir, atazanavir concentrations are expected to be additionally decreased by about 20%. The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with H2 blockers.
Proton pump inhibitors
Omeprazole 40 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily)	Atazanavir (am): 2 hr after omeprazole Atazanavir AUC ↓61% (↓65% ↓55%) Atazanavir Cmax ↓66% (↓62% ↓49%) Atazanavir Cmin ↓65% (↓71% ↓59%)	Co-administration of atazanavir with ritonavir with proton pump inhibitors is not recommended. If the combination of atazanavir/ritonavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded (see section 4.4).
Omeprazole 20 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily)	Atazanavir (am): 1 hr after omeprazole Atazanavir AUC ↓30% (↓43% ↓14%) * Atazanavir Cmax ↓31% (↓42% ↓17%) * Atazanavir Cmin ↓31% (↓46% ↓12%) * * When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily. The decrease in AUC, Cmax, and Cmin was not mitigated when an increased dose of atazanavir/ritonavir (400/100 mg once daily) was temporally separated from omeprazole by 12 hours. Although not studied, similar results are expected with other proton pump inhibitors. This decrease in atazanavir exposure might negatively impact the efficacy of atazanavir. The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with proton pump inhibitors.
Antacids
Antacids and medicinal products containing buffers	Reduced plasma concentrations of atazanavir may be the consequence of increased gastric pH if antacids, including buffered medicinal products, are administered with atazanavir.	Atazanavir should be administered 2 hours before or 1 hour after antacids or buffered medicinal products.
ALPHA 1-ADRENORECEPTOR ANTAGONIST
Alfuzosin	Potential for increased alfuzosin concentrations which can result in hypotension. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.	Co-administration of alfuzosin with atazanavir is contraindicated (see section 4.3)
ANTICOAGULANTS
Warfarin	Co-administration with atazanavir has the potential to increase or decrease warfarin concentrations.	It is recommended that the International Normalised Ratio (INR) be monitored carefully during treatment with atazanavir, especially when commencing therapy.
ANTIEPILEPTICS
Carbamazepine	Atazanavir may increase plasma levels of carbamazepine due to CYP3A4 inhibition. Due to carbamazepine inducing effect, a reduction in atazanavir exposure cannot be ruled out.	Carbamazepine should be used with caution in combination with atazanavir. If necessary, monitor carbamazepine serum concentrations and adjust the dose accordingly. Close monitoring of the patient's virologic response should be exercised.
Phenytoin, phenobarbital	Ritonavir may decrease plasma levels of phenytoin and/or phenobarbital due to CYP2C9 and CYP2C19 induction. Due to phenytoin/phenobarbital inducing effect, a reduction in atazanavir exposure cannot be ruled out.	Phenobarbital and phenytoin should be used with caution in combination with atazanavir/ritonavir. When atazanavir/ritonavir is co-administered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required. Close monitoring of patient's virologic response should be exercised.
Lamotrigine	Co-administration of lamotrigine and atazanavir/ritonavir may decrease lamotrigine plasma concentrations due to UGT1A4 induction.	Lamotrigine should be used with caution in combination with atazanavir/ritonavir. If necessary, monitor lamotrigine concentrations and adjust the dose accordingly.
ANTINEOPLASTICS AND IMMUNOSUPRESSANTS
Antineoplastics
Irinotecan	Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.	If atazanavir is coadministered with irinotecan, patients should be closely monitored for adverse events related to irinotecan.
Immunosuppressants
Cyclosporin Tacrolimus Sirolimus	Concentrations of these immunosuppressants may be increased when co-administered with atazanavir due to CYP3A4 inhibition.	More frequent therapeutic concentration monitoring of these medicinal products is recommended until plasma levels have been stabilised.
CARDIOVASCULAR AGENTS
Antiarrhythmics
Amiodarone, Systemic lidocaine, Quinidine	Concentrations of these antiarrhythmics may be increased when co-administered with atazanavir. The mechanism of amiodarone or systemic lidocaine/atazanavir interaction is CYP3A inhibition. Quinidine has a narrow therapeutic window and is contraindicated due to potential inhibition of CYP3A by atazanavir.	Caution is warranted and therapeutic concentration monitoring is recommended when available. The concomitant use of quinidine is contraindicated (see section 4.3).
Calcium channel blockers
Bepridil	Atazanavir should not be used in combination with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index.	Co-administration with bepridil is contraindicated (see section 4.3)
Diltiazem 180 mg once daily (atazanavir 400 mg once daily)	Diltiazem AUC ↑125% (↑109% ↑141%) Diltiazem Cmax ↑98% (↑78% ↑119%) Diltiazem Cmin ↑142% (↑114% ↑173%) Desacetyl-diltiazem AUC ↑165% (↑145% ↑187%) Desacetyl-diltiazem Cmax ↑172% (↑144% ↑203%) Desacetyl-diltiazem Cmin ↑121% (↑102% ↑142%) No significant effect on atazanavir concentrations was observed. There was an increase in the maximum PR interval compared to atazanavir alone. Co-administration of diltiazem and atazanavir/ritonavir has not been studied. The mechanism of diltiazem/atazanavir interaction is CYP3A4 inhibition.	An initial dose reduction of diltiazem by 50% is recommended, with subsequent titration as needed and ECG monitoring.
Verapamil	Serum concentrations of verapamil may be increased by atazanavir due to CYP3A4 inhibition.	Caution should be exercised when verapamil is co-administered with atazanavir.
CORTICOSTEROIDS
Fluticasone propionate intranasal 50 μg 4 times daily for 7 days (ritonavir 100 mg capsules twice daily)	The fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82%-89%) Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolized via the P450 3A pathway, e.g., budesonide. The effects of high fluticasone systemic exposure on ritonavir plasma levels are yet unknown. The mechanism of interaction is CYP3A4 inhibition.	Co-administration of atazanavir/ritonavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g., beclomethasone). Moreover, in case of withdrawal of glucocorticoids, progressive dose reduction may have to be performed over a longer period.
ERECTILE DYSFUNCTION
PDE5 Inhibitors
Sildenafil, tadalafil, vardenafil	Sildenafil, tadalafil, and vardenafil are metabolised by CYP3A4. Co-administration with atazanavir may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-associated adverse events, including hypotension, visual changes, and priapism. The mechanism of this interaction is CYP3A4 inhibition.	Patients should be warned about these possible side effects when using PDE5 inhibitors for erectile dysfunction with atazanavir (see section 4.4). Also see PULMONARY ATERIAL HYPERTENSION in this table for further information regarding co-administration of atazanavir with sildenafil.
HERBAL PRODUCTS
St. John’s wort (Hypericum perforatum)	Concomitant use of St. John's wort with atazanavir may be expected to result in significant reduction in plasma levels of atazanavir. This effect may be due to an induction of CYP3A4. There is a risk of loss of therapeutic effect and development of resistance (see section 4.3).	Co-administration of atazanavir with products containing St. John's wort is contraindicated.
HORMONAL CONTRACEPTIVES
Ethinyloestradiol 25 μg + norgestimate (atazanavir 300 mg once daily with ritonavir 100 mg once daily) Ethinyloestradiol 35 μg + norethindrone (atazanavir 400 mg once daily)	Ethinyloestradiol AUC ↓19% (↓25% ↓13%) Ethinyloestradiol Cmax ↓16% (↓26% ↓5%) Ethinyloestradiol Cmin ↓37% (↓45% ↓29%) Norgestimate AUC ↑85% (↑67% ↑105%) Norgestimate Cmax ↑68% (↑51% ↑88%) Norgestimate Cmin ↑102% (↑77% ↑131%) While the concentration of ethinyloestradiol was increased with atazanavir given alone, due to both UGT and CYP3A4 inhibition by atazanavir, the net effect of atazanavir/ritonavir is a decrease in ethinyloestradiol levels because of the inducing effect of ritonavir. The increase in progestin exposure may lead to related side-effects (e.g. insulin resistance, dyslipidemia, acne and spotting), thus possibly affecting the compliance. Ethinyloestradiol AUC ↑48% (↑31% ↑68%) 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 may lead to related side-effects (e.g. insulin resistance, dyslipidemia, acne and spotting), thus possibly affecting the compliance.	If an oral contraceptive is administered with atazanavir/ritonavir, it is recommended that the oral contraceptive contain at least 30 μg of ethinyloestradiol and that the patient be reminded of strict compliance with this contraceptive dosing regimen. Co-administration of atazanavir/ritonavir with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate has not been studied, and therefore should be avoided. An alternate reliable method of contraception is recommended.
LIPID LOWERING AGENTS
HMG-CoA reductase inhibitors
Simvastatin Lovastatin	Simvastatin and lovastatin are highly dependent on CYP3A4 for their metabolism and co-administration with atazanavir may result in increased concentrations.	Co-administration of simvastatin or lovastatin with atazanavir is contraindicated due to an increased risk of myopathy including rhabdomyolysis. (see section 4.3).
Atorvastatin	The risk of myopathy including rhabdomyolysis may also be increased with atorvastatin, which is also metabolised by CYP3A4.	Co-administration of atorvastatin with atazanavir is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring (see section 4.4).
Pravastatin Fluvastatin	Although not studied, there is a potential for an increase in pravastatin or fluvastatin exposure when coadministered with protease inhibitors. Pravastatin is not metabolised by CYP3A4. Fluvastatin is partially metabolised by CYP2C9.	Caution should be exercised.
INHALED BETA AGONISTS
Salmeterol	Co-administration with atazanavir may result in increased concentrations of salmeterol and an increase in salmeterol-associated adverse events. The mechanism of interaction is CYP3A4 inhibition by Atazanavir and/or ritonavir.	Co-administration of salmeterol with atazanavir is not recommended (see section 4.4).
OPIOIDS
Buprenorphine, once daily, stable maintenance dose (atazanavir 300 mg once daily with ritonavir 100 mg once daily)	Buprenorphine AUC ↑67% Buprenorphine Cmax ↑37% Buprenorphine Cmin ↑69% Norbuprenorphine AUC ↑105% Norbuprenorphine Cmax ↑61% Norbuprenorphine Cmin ↑101% The mechanism of interaction is CYP3A4 and UGT1A1 inhibition. Concentrations of atazanavir (when given with ritonavir) were not significantly affected.	Co-administration atazanavir with ritonavir warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered
Methadone, stable maintenance dose (atazanavir 400 mg once daily)	No significant effect on methadone concentrations was observed. Given that low dose ritonavir (100 mg twice daily) has been shown to have no significant effect on methadone concentrations, no interaction is expected if methadone is coadministered with atazanavir and ritonavir, based on these data.	No dosage adjustment is necessary if methadone is co-administered with atazanavir.
PULMONARY ARTERIAL HYPERTENSION
PDE5 Inhibitors
Sildenafil	Co-administration with atazanavir may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5- inhibitor-associated adverse events. The mechanism of interaction is CYP3A4 inhibition by Atazanavir and/or ritonavir.	A safe and effective dose in combination with atazanavir has not been established for sildenafil when used to treat pulmonary arterial hypertension. Sildenafil, when used for the treatment of pulmonary arterial hypertension, is contraindicated (see section 4.3).
SEDATIVES
Benzodiazepines
Midazolam Triazolam	Midazolam and triazolam are extensively metabolized by CYP3A4. Co-administration with atazanavir may cause a large increase in the concentration of these benzodiazepines. No drug interaction study has been performed for the co-administration of atazanavir with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.	Co-administration of atazanavir with triazolam or orally administered midazolam is contraindicated (see section 4.3), whereas caution should be used with co-administration of atazanavir and parental midazolam. If atazanavir is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.

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

The same recommendations for drug drug interactions would apply except:

• that co-administration is not recommended with tenofovir, boceprevir, carbamazepine, phenytoin, phenobarbital, proton pump inhibitors, and buprenorphine.

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

• the need to consider that

• co-administration of voriconazole and atazanavir without ritonavir may affect atazanavir concentrations

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

concentrations relative to fluticasone given alone

• if an oral contraceptive is administered with atazanavir without ritonavir, it is recommended that the

oral contraceptive contain no more than 30 μg of ethinyloestradiol

• no dose adjustment of lamotrigine is required

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data in pregnant women (between 300-1000 pregnancy outcomes) indicate no

malformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity (see

section 5.3). The use of atazanavir may be considered during pregnancy only if the potential benefit

justifies the potential risk.

In clinical trial AI424-182 atazanavir/ritonavir (300/100 mg or 400/100 mg) in combination with

zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester.

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

atazanavir/ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no cases

of lactic acidosis observed in the clinical trial AI424-182.

The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not

include atazanavir) and were negative for HIV-1 DNA at the time of delivery and/or during the first

6 months postpartum. Three of 20 infants (15%) born to women treated with atazanavir/ritonavir

300/100 mg and four of 20 infants (20%) born to women treated with atazanavir/ritonavir

400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases

of kernicterus in neonates.

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

It is not known whether atazanavir administered to the mother during pregnancy will exacerbate

physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In the prepartum

period, additional monitoring should be considered.

Breast-feeding

It is unknown whether atazanavir or atazanavir metabolites are excreted in human milk. Studies in rats

have demonstrated that atazanavir is excreted in the milk. As a general rule, it is recommended that

HIV infected women not breast-feed their infants in order to avoid transmission of HIV.

Fertility

In a nonclinical fertility and early embryonic development study in rats, atazanavir altered oestrus

cycling with no effects on mating or fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on effects of atazanavir on the ability to drive and use machines have been performed.

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

a. Summary of the safety profile

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

Adverse reactions were consistent between patients who received atazanavir 400 mg once daily and

patients who received atazanavir 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with atazanavir plus ritonavir.

Among patients who received atazanavir 400 mg once daily or atazanavir 300 mg with ritonavir

100 mg once daily, the only adverse reactions of any severity reported very commonly with at least a possible relationship to regimens containing atazanavir and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving atazanavir 300 mg with ritonavir

100 mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported within a few days to a few months after the initiation of treatment (see section 4.4).

b. Tabulated list of adverse reactions

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

Immune system disorders: uncommon: hypersensitivity

Metabolism and nutrition uncommon: diabetes^a, hyperglycaemia^a,b, weight

disorders: decreased, weight gain, anorexia, appetite increased

Psychiatric disorders: uncommon: depression, disorientation, anxiety, insomnia,

sleep disorder, abnormal dream

Nervous system disorders: common: headache;

uncommon: peripheral neuropathy, syncope, amnesia,

dizziness, somnolence, dysgeusia

Eye disorders: common: ocular icterus

Cardiac disorders: uncommon: torsades de pointes^a

rare: QTc prolongation^a, oedema, palpitation

Vascular disorders: uncommon: hypertension

Respiratory, thoracic and uncommon: dyspnoea

mediastinal disorders:

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, cholelithiasis^a, cholestasis^a;

rare: hepatosplenomegaly, cholecystitis^a

Skin and subcutaneous tissue common: rash;

disorders: uncommon: erythemia multiforme^a,b, toxic skin

eruptions^a,b, drug rash with eosinophilia and systemic

symptoms (DRESS) syndrome^a,b, angioedema^a urticaria,

alopecia, pruritus;

rare: Stevens-Johnson syndrome^a,b, vesiculobullous rash,

eczema, vasodilatation

Musculoskeletal and connective uncommon: muscle atrophy, arthralgia, myalgia;

tissue disorders: rare: myopathy

Renal and urinary disorders: uncommon: nephrolithiasis^a, hematuria, proteinuria,

pollakiuria; interstitial nephritis;

rare: kidney pain

Reproductive system and breast uncommon: gynaecomastia

disorders:

General disorders and common: lipodystrophy syndrome^b, fatigue;

administration site conditions: uncommon: chest pain, malaise, pyrexia, asthenia;

rare: gait disturbance

^a These adverse reactions were identified through post-marketing surveillance but not observed in clinical trials with atazanavir. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to atazanavir in randomised controlled and other available clinical trials (n = 2321).

^b See section c. Description of selected adverse reactions for more details.

c. Description of selected adverse reactions

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

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

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

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy, and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia (see sections 4.4 and 5.1).

Rash and associated syndromes

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

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

Laboratory abnormalities

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

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

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

d. Paediatric population

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

e. Other special populations

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

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

Reporting of suspected adverse reactions

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

4.9 Overdose

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

Treatment of overdose with atazanavir should consist of general supportive measures, including monitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with atazanavir. Since atazanavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicinal product.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: protease inhibitor, ATC code: J05AE08

Mechanism of action: atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.

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

Resistance

Antiretroviral treatment naive adult patients

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

Table 3 De novo substitutions in treatment naive patients failing therapy with atazanavir +

ritonavir (Study 138, 96 weeks)

Frequency	de novo PI substitution (n=26)a
20%	none
10-20%	none

^a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

The M184I/V substitution emerged in 5/26 atazanavir/ritonavir and 7/26 lopinavir/ritonavir virologic

failure patients, respectively.

Antiretroviral treatment experienced adult patients

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

Table 4. De novo substitutions in treatment experienced patients failing therapy with atazanavir

+ ritonavir (Study 045, 48 weeks)

Frequency	de novo PI substitution (n=35)a,b
20%	M36, M46, I54, A71, V82
10-20%	L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90

^a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

^b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSense^TM (Monogram Biosciences, South San Francisco, California, USA).

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

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

Clinical results

In antiretroviral naive adult patients

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

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

Table 5 Efficacy Outcomes in Study 138 ^a

Parameter	atazanavir/ritonavirb (300 mg/100 mg once daily) n=440		Lopinavir/ritonavirc (400 mg/100 mg twice daily) n=443
	Week 48	Week 96	Week 48	Week 96
HIV RNA <50 copies/ml, %
All patientsd	78	74	76	68
Difference estimate [95% CI]d	Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%]
Per protocol analysise	86 (n=392f)	91 (n=352)	89 (n=372)	89 (n=331)
Difference estimatee [95% CI]	Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%]
HIV RNA <50 copies/ml, % by Baseline Characteristicd
HIV RNA <100,000 copies/ml	82 (n=217)	75 (n=217)	81 (n=218)	70 (n=218)
≥100,000 copies/ml	74 (n=223)	74 (n=223)	72 (n=225)	66 (n=225)
CD4 count <50 cells/mm3	78 (n=58)	78 (n=58)	63 (n=48)	58 (n=48)
50 to <100 cells/mm3	76 (n=45)	71 (n=45)	69 (n=29)	69 (n=29)
100 to <200 cells/mm3	75 (n=106)	71 (n=106)	78 (n=134)	70 (n=134)
≥ 200 cells/mm3	80 (n=222)	76 (n=222)	80 (n=228)	69 (n=228)
HIV RNA Mean Change from Baseline, log10 copies/ml
All patients	-3.09 (n=397)	-3.21 (n=360)	-3.13 (n=379)	-3.19 (n=340)
CD4 Mean Change from Baseline, cells/mm3
All patients	203 (n=370)	268 (n=336)	219 (n=363)	290 (n=317)
CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic
HIV RNA <100,000 copies/ml	179 (n=183)	243 (n=163)	194 (n=183)	267 (n=152)
≥100,000 copies/ml	227 (n=187)	291 (n=173)	245 (n=180)	310 (n=165)

^a Mean baseline CD4 cell count was 214 cells/mm³ (range 2 to 810 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.94 log₁₀ copies/ml (range 2.6 to 5.88 log₁₀ copies/ml)

^b atazanavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

^c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

^d Intent-to-treat analysis, with missing values considered as failures.

^e Per protocol analysis: Excluding non-completers and patients with major protocol deviations.

^f Number of patients evaluable.

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

Study 136 (INDUMA)

In an open-label, randomised, comparative study following a 26- to 30-week induction phase with atazanavir 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted atazanavir 400 mg once daily and two NRTIs administered

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

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

There were fewer treatment discontinuations in the unboosted atazanavir group (1 vs. 4 subjects in the atazanavir + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboosted atazanavir group compared with the atazanavir + ritonavir group (18 and 28 subjects, respectively).

In antiretroviral experienced adult patients

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

The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through

48 weeks (Table 6).

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

Parameter	ATV/RTVb (300 mg/ 100 mg once daily) n=120		LPV/RTVc (400 mg/ 100 mg twice daily) n=123		Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId]
	Week 48	Week 96	Week 48	Week 96	Week 48	Week 96
HIV RNA Mean Change from Baseline, log10 copies/ml
All patients	-1.93 (n=90 e)	-2.29 (n=64)	-1.87 (n=99)	-2.08 (n=65)	0.13 [-0.12, 0.39]	0.14 [-0.13, 0.41]
HIV RNA <50 copies/ml, %f (responder/evaluable)
All patients	36 (43/120)	32 (38/120)	42 (52/123	35 (41/118)	NA	NA
HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable)
0-2	44 (28/63)	41 (26/63)	56 (32/57)	48 (26/54)	NA	NA
3	18 (2/11)	9 (1/11)	38 (6/16)	33 (5/15)	NA	NA
≥ 4	27 (12/45)	24 (11/45)	28 (14/50)	20 (10/49)	NA	NA
CD4 Mean Change from Baseline, cells/mm3
All patients	110 (n=83)	122 (n=60)	121 (n=94)	154 (n=60)	NA	NA

^a The mean baseline CD4 cell count was 337 cells/mm³ (range: 14 to 1,543 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.4 log₁₀ copies/ml (range: 2.6 to 5.88 log₁₀ copies/ml).

^b ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

^c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

^d Confidence interval.

^e Number of patients evaluable.

^f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively.

^g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline.

NA = not applicable.

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

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

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

Paediatric population

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of atazanavir is based on data from the open-label, multicenter clinical trial PACTG 1020A conducted in patients from 3 months to 21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naive and 101 antiretroviral-experienced) received once daily atazanavir (capsule or powder formulation), with or without ritonavir, in combination with two NRTIs.

The clinical data derived from this study are inadequate to support the use of atazanavir (with or without ritonavir) in children below 6 years of age.

Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received atazanavir capsules with ritonavir are presented in Table 7. For treatment-naive paediatric patients, the mean baseline CD4 cell count was 344 cells/mm³ (range: 2 to 800 cells/ mm³) and mean baseline plasma HIV 1 RNA was 4.67 log₁₀ copies/ml (range: 3.70 to 5.00 log₁₀ copies/ml). For treatment experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm³ (range: 100 to 1157 cells/ mm³) and mean baseline plasma HIV 1 RNA was 4.09 log₁₀ copies/ml (range: 3.28 to 5.00 log₁₀ copies/ml).

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

48 (Study PACTG 1020A)

Parameter	Treatment-Naive atazanavir Capsules/ritonavir (300 mg/100 mg once daily) n=16	Treatment- Experienced atazanavir Capsules/ritonavir (300 mg/100 mg once daily) n=25
HIV RNA <50 copies/ml, % a
All patients	81 (13/16)	24 (6/25)
HIV RNA <400 copies/ml, % a
All patients	88 (14/16)	32 (8/25)
CD4 Mean Change from Baseline, cells/mm3
All patients	293 (n=14b)	229 (n=14b)
HIV RNA <50 copies/ml by select baseline PI substitutions,c % (responder/evaluabled)
0-2	NA	27 (4/15)
3	NA	-
≥ 4	NA	0 (0/3)

^a Intent-to-treat analysis, with missing values considered as failures.

^b Number of patients evaluable.

^c PI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY,I54ALMSTV, L76V, V82AFLST, I84V, N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V.

^d Includes patients with baseline resistance data.

NA = not applicable.

Data in the paediatric population are very limited. Available data do suggest that atazanavir in combination with ritonavir may not be effective in treatment experienced children even with very few (<3) PI mutations.

The European Medicines Agency has waived the obligation to submit the results of studies with atazanavir hard capsules in all subsets of the paediatric population in treatment of immunodeficiency virus (HIV-1) infection (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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

Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of atazanavir 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, C_maxof 4466 (42%) ng/ml, with time to C_maxof approximately 2.5 hours. The geometric mean (CV%) for atazanavir C_minand AUC was 654 (76%) ng/ml and 44185 (51%) ng•h/ml, respectively.

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

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

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

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

Elimination: following a single 400 mg dose of ¹⁴C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion of unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult patients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was 12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light meal.

Special populations

Renal impairment: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available for atazanavir with ritonavir in patients with renal insufficiency. Atazanavir (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.)

Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. Atazanavir (without ritonavir) has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh Class B and 2 Child-Pugh Class C subjects) after a single 400 mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects.The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavir are expected to be increased in patients with moderately or severely impaired hepatic function (see sections 4.2, 4.3, and 4.4).

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

Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race on the pharmacokinetics of atazanavir.

Pregnancy:

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

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

Pregnant Women in the Fed State

	atazanavir 300 mg with ritonavir 100 mg
Pharmacokinetic Parameter	2nd Trimester (n=9)	3rd Trimester (n=20)	postpartuma (n=36)
Cmax ng/mL Geometric mean (CV%)	3729.09 (39)	3291.46 (48)	5649.10 (31)
AUC ng•h/mL Geometric mean (CV%)	34399.1 (37)	34251.5 (43)	60532.7 (33)
Cmin ng/mLb Geometric mean (CV%)	663.78 (36)	668.48 (50)	1420.64 (47)

^a Atazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during the postpartum period (4-12 weeks) than those observed historically in HIV infected, non-pregnant patients. Atazanavir plasma trough concentrations were approximately 2-fold higher during the postpartum period when compared to those observed historically in HIV infected non-pregnant patients.

^b C_min is concentration 24 hours post-dose.

Paediatric population

The pharmacokinetics of atazanavir in paediatric patients exhibit an increased absorption rate compared to adults. There is a slight trend toward a higher clearance in younger children when normalised for body weight. As a result, greater peak to trough ratios are observed. The geometric mean AUC values in paediatric patients at recommended doses are expected to be similar to those observed in adults, with higher geometric mean C_max (13-17%) and lower geometric mean C_min (up to 30%) values compared to those in adults. The variability of pharmacokinetic parameters in younger children is higher.

5.3 Preclinical safety data

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

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a concentration (30 μM) of atazanavir corresponding to 30 fold the free drug concentration at C_max in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD₉₀) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2 week oral toxicity study performed in dogs. Subsequent 9 month oral toxicity studies in dogs showed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical data is unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 and 4.8). The potential for PR prolongation should be considered in cases of overdose (see section 4.9).

In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxic doses. In pregnant rabbits, gross lesions of the stomach and intestines were observed in dead or moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive embryo-development study. In the pre- and postnatal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given 400 mg once daily.

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

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

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents:

Crospovidone

Lactose monohydrate

Magnesium stearate

(150 mg & 200 mg) Capsule shell:

Gelatine

Indigotine (E132)

Titanium dioxide (E171)

(300 mg) Capsule shell:

Gelatine

Indigotine (E132)

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (172)

Printing ink:

Shellac

Iron oxide black (E172)

Propylene glycol (E1520)

Ammonia solution, concentrated 28%

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 30°C.

OPA/Al/PVC – Aluminium blisters.

(150 and 200 mg) Pack size of 60 and 60 x 1 capsules.

(300 mg) Pack sizes of 30, 30 x 1, 60 and 90 capsules.

White HDPE bottles with polypropylene child resistant closures.

(150 mg and 200 mg) Pack size of 60 capsules.

(300 mg) Pack size of 30 and 3 x 30 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal <and other handling>

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

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

2016-04-08