This information is intended for use by health professionals

1. Name of the medicinal product

REYATAZ 100 mg hard capsules

REYATAZ 150 mg hard capsules

REYATAZ 200 mg hard capsules

REYATAZ 300 mg hard capsules

2. Qualitative and quantitative composition

REYATAZ 100 mg hard capsules

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

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

REYATAZ 150 mg hard capsules

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

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

REYATAZ 200 mg hard capsules

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

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

REYATAZ 300 mg hard capsules

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

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

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Hard capsule

REYATAZ 100 mg hard capsules

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

REYATAZ 150 mg hard capsules

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

REYATAZ 200 mg hard capsules

Opaque blue capsule printed with white ink, with "BMS 200 mg" on one half and with "3631" on the other half.

REYATAZ 300 mg hard capsules

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

4. Clinical particulars
4.1 Therapeutic indications

REYATAZ capsules, co-administered with low dose ritonavir, are indicated for the treatment of HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products (see section 4.2).

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).

The choice of REYATAZ 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

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

Posology

Adults

The recommended dose of REYATAZ capsules 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 patients (6 years to less than 18 years of age and weighing at least 15 kg)

The dose of atazanavir capsules for paediatric patients is based on body weight as shown in Table 1 and should not exceed the recommended adult dose. REYATAZ capsules 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 and weighing at least 15 kg) for REYATAZ capsules with ritonavir

Body Weight (kg)

REYATAZ once daily dose

ritonavir once daily dosea

15 to less than 35

200 mg

100 mg

at least 35

300 mg

100 mg

a Ritonavir capsules, tablets or oral solution.

Paediatric patients (at least 3 months of age and weighing at least 5 kg): REYATAZ oral powder is available for paediatric patients at least 3 months of age and weighing at least 5 kg (see Summary of Product Characteristics for REYATAZ oral powder). Switching to REYATAZ capsules from REYATAZ oral powder is encouraged as soon as patients are able to consistently swallow capsules.

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

Special populations

Renal impairment

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

Hepatic impairment

REYATAZ with ritonavir has not been studied in patients with hepatic impairment. REYATAZ with ritonavir should be used with caution in patients with mild hepatic impairment. REYATAZ with ritonavir 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 REYATAZ 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 REYATAZ must not be used in patients with severe hepatic impairment.

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

REYATAZ 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, especially when the activity of atazanavir or the whole regimen may be compromised due to 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 disoproxil or H2-receptor antagonists).

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

▪ It is not recommended to use REYATAZ with ritonavir for pregnant patients who are receiving both tenofovir disoproxil and an H2-receptor antagonist.

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

During postpartum:

Following a possible decrease in atazanavir exposure during the second and third trimester, 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.

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

Paediatric patients (less than 3 months of age)

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

Method of administration:

For oral use. 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.

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

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

Combination of rifampicin (see section 4.5).

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

Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5).

Co-administration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used to treat chronic hepatitis C infection) (see section 4.5).

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

QT prolongation: Dose related asymptomatic prolongations in PR interval with REYATAZ have 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), REYATAZ should be used with caution and only if the benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing REYATAZ in association with medicinal products which have the potential to increase the 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.

Weight and metabolic parameters

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

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

Hyperbilirubinaemia

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving REYATAZ (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving REYATAZ should be evaluated for alternative aetiologies. Alternative antiretroviral therapy to REYATAZ 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 REYATAZ 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 REYATAZ boosted with ritonavir, ensuring optimal pharmacokinetic parameters and level of virologic suppression.

The withdrawal of ritonavir from the boosted regimen of REYATAZ 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.

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

REYATAZ 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 REYATAZ (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.

Chronic kidney disease

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

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving REYATAZ (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 jirovecii 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 occurs many months after initiation of treatment.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported 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 REYATAZ.

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 REYATAZ. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. REYATAZ 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 REYATAZ, REYATAZ may not be restarted.

Interactions with other medicinal products

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

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

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

Atazanavir is metabolised principally by CYP3A4. Co-administration of REYATAZ 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 REYATAZ. Co-administration of REYATAZ with these medicinal products is expected to substantially increase their concentrations and may result in PDE5-associated adverse reactions such as hypotension, visual changes and priapism (see section 4.5).

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

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

Concomitant use of REYATAZ/ritonavir and fluticasone or other glucocorticoids that are metabolised 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 REYATAZ may result in increased cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and REYATAZ is not recommended (see section 4.5).

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

Co-administration of REYATAZ with proton pump inhibitors is not recommended (see section 4.5). If the combination of REYATAZ with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ 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 REYATAZ 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).

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), REYATAZ should be used with caution and only if the benefits exceed the risk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).

Efficacy

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

Excipients

Lactose

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

4.5 Interaction with other medicinal products and other forms of interaction

When REYATAZ 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 REYATAZ and ritonavir.

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

Co-administration of REYATAZ with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used to treat chronic hepatitis C infection) is contraindicated because of the increase in grazoprevir and elbasvir plasma concentrations and potential for the increase in risk of ALT elevations associated with increased grazoprevir concentrations (see section 4.3).

Other interactions

Interactions between atazanavir and other medicinal products are listed in the table 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 recommended regimen of atazanavir (see section 4.4).

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 REYATAZ and other medicinal products

Medicinal products by therapeutic area

Interaction

Recommendations concerning co-administration

ANTI-HCV AGENTS

Grazoprevir 200 mg once daily

(atazanavir 300 mg / ritonavir 100 mg once daily)

Atazanavir AUC ↑43% (↑30% ↑57%)

Atazanavir Cmax ↑12% (↑1% ↑24%)

Atazanavir Cmin ↑23% (↑13% ↑134%)

Grazoprevir AUC: ↑958% (↑678% ↑1339%)

Grazoprevir Cmax: ↑524% (↑342% ↑781%)

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

Grazoprevir concentrations were greatly increased when co-administered with atazanavir/ritonavir.

Co-administration of REYATAZ and elbasvir/grazoprevir is contraindicated because of a significant increase in grazoprevir plasma concentrations and an associated potential increase in the risk of ALT elevations (see section 4.3).

Elbasvir 50 mg once daily

(atazanavir 300 mg / ritonavir 100 mg once daily)

Atazanavir AUC ↑7% (↓2% ↑17%)

Atazanavir Cmax ↑2% (↓4% ↑8%)

Atazanavir Cmin ↑15% (↑2% ↑29%)

Elbasvir AUC: ↑376% (↑307% ↑456%)

Elbasvir Cmax: ↑315% (↑246% ↑397%)

Elbasvir Cmin: ↑545% (↑451% ↑654%)

Elbasvir concentrations were increased when co-administered with atazanavir/ritonavir.

ANTI-RETROVIRALS

Protease inhibitors: The co-administration of REYATAZ/ritonavir and other protease inhibitors has not been studied but would be expected to increase exposure to other protease inhibitors. Therefore, such co-administration 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 REYATAZ 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 these medicinal products and REYATAZ is not expected to significantly alter the exposure of the co-administered medicinal products.

Abacavir

The co-administration of abacavir and REYATAZ 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 REYATAZ taken with food. The co-administration of stavudine with REYATAZ 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)

300 mg tenofovir disoproxil fumarate is equivalent to 245 mg tenofovir disoproxil.

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 REYATAZ/ritonavir in combination with tenofovir disoproxil fumarate in treatment-experienced patients has been demonstrated in clinical study 045 and in treatment naive patients in clinical study 138 (see sections 4.8 and 5.1). The mechanism of interaction between atazanavir and tenofovir disoproxil fumarate is unknown.

When co-administered with tenofovir disoproxil fumarate, it is recommended that REYATAZ 300 mg 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)

300 mg tenofovir disoproxil fumarate is equivalent to 245 mg tenofovir disoproxil.

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 disoproxil fumarate-associated adverse reactions, 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 and REYATAZ 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 REYATAZ 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 REYATAZ 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 and REYATAZ 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 REYATAZ 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 REYATAZ/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, REYATAZ/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 REYATAZ 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 REYATAZ/ritonavir was co-administered with fluconazole.

No dosage adjustments are needed for fluconazole and REYATAZ.

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 REYATAZ, 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 REYATAZ.

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 REYATAZ or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.

The combination of rifampicin and REYATAZ is contraindicated (see section 4.3).

ANTIPSYCHOTICS

Quetiapine

Due to CYP3A4 inhibition by REYATAZ, concentrations of quetiapine are expected to increase.

Co-administration of quetiapine with REYATAZ is contraindicated as REYATAZ may increase quetiapine-related toxicity. Increased plasma concentrations of quetiapine may lead to coma (see section 4.3).

Lurasidone

REYATAZ is expected to increase plasma levels of lurasidone due to CYP3A4 inhibition.

Co-administration of lurasidone with REYATAZ is contra-indicated as this may increase lurasidone-related toxicity (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 REYATAZ 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 (e.g., famotidine 40 mg twice daily or equivalent) an increase of the REYATAZ/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 disoproxil fumarate 300 mg once daily (equivalent to 245 mg tenofovir disoproxil)

In HIV-infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg once daily

For patients who are taking tenofovir disoproxil fumarate, if REYATAZ/ritonavir with both tenofovir disoproxil fumarate and an H2-receptor antagonist are co-administered, a dose increase of REYATAZ 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 disoproxil fumarate, 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 REYATAZ with ritonavir and proton pump inhibitors is not recommended. If the combination is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ 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 REYATAZ/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 REYATAZ.

REYATAZ 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 REYATAZ and/or ritonavir.

Co-administration of alfuzosin with REYATAZ is contraindicated (see section 4.3)

ANTICOAGULANTS

Warfarin

Co-administration with REYATAZ has the potential to increase or decrease warfarin concentrations.

It is recommended that the International Normalised Ratio (INR) be monitored carefully during treatment with REYATAZ, especially when commencing therapy.

ANTIEPILEPTICS

Carbamazepine

REYATAZ may increase plasma levels of carbamazepine due to CYP3A4 inhibition.

Due to carbamazepine inducing effect, a reduction in REYATAZ exposure cannot be ruled out.

Carbamazepine should be used with caution in combination with REYATAZ. If necessary, monitor carbamazepine serum concentrations and adjust the dose accordingly. Close monitoring of the patient's virologic response should be excercised.

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 REYATAZ exposure cannot be ruled out.

Phenobarbital and phenytoin should be used with caution in combination with REYATAZ/ritonavir.

When REYATAZ/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 REYATAZ/ritonavir may decrease lamotrigine plasma concentrations due to UGT1A4 induction.

Lamotrigine should be used with caution in combination with REYATAZ/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 REYATAZ is co-administered 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 REYATAZ 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 REYATAZ. 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 REYATAZ.

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

REYATAZ 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 REYATAZ/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 REYATAZ due to CYP3A4 inhibition.

Caution should be exercised when verapamil is co-administered with REYATAZ.

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 metabolised 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 REYATAZ/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 REYATAZ 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 REYATAZ (see section 4.4).

Also see PULMONARY ARTERIAL HYPERTENSION in this table for further information regarding co-administration of REYATAZ with sildenafil.

HERBAL PRODUCTS

St. John's wort (Hypericum perforatum)

Concomitant use of St. John's wort with REYATAZ 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 REYATAZ 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 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.

If an oral contraceptive is administered with REYATAZ/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 REYATAZ/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.

Ethinyloestradiol 35 µg + norethindrone

(atazanavir 400 mg once daily)

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.

LIPID LOWERING AGENTS

HMG-CoA reductase inhibitors

Simvastatin

Lovastatin

Simvastatin and lovastatin are highly dependent on CYP3A4 for their metabolism and co-administration with REYATAZ may result in increased concentrations.

Co-administration of simvastatin or lovastatin with REYATAZ 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 REYATAZ 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 co-administered 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 REYATAZ 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 REYATAZ 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 with REYATAZ 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 co-administered with REYATAZ, based on these data.

No dosage adjustment is necessary if methadone is co-administered with REYATAZ.

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil

Co-administration with REYATAZ 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 REYATAZ 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 metabolised by CYP3A4. Co-administration with REYATAZ may cause a large increase in the concentration of these benzodiazepines. No drug interaction study has been performed for the co-administration of REYATAZ 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 REYATAZ with triazolam or orally administered midazolam is contraindicated (see section 4.3), whereas caution should be used with co-administration of REYATAZ and parenteral midazolam. If REYATAZ 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 REYATAZ without ritonavir may affect atazanavir concentrations

▪ co-administration of fluticasone and REYATAZ without ritonavir may increase fluticasone concentrations relative to fluticasone given alone

▪ if an oral contraceptive is administered with REYATAZ 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 REYATAZ with ritonavir may be considered during pregnancy only if the potential benefit justifies the potential risk.

In clinical trial AI424-182 REYATAZ/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 REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no 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 REYATAZ) 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 REYATAZ/ritonavir 300/100 mg and four of 20 infants (20%) born to women treated with REYATAZ/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 REYATAZ with ritonavir 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

Atazanavir has been detected in human 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

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

4.8 Undesirable effects

Summary of the safety profile

REYATAZ has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving REYATAZ 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or REYATAZ 300 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 REYATAZ 400 mg once daily and patients who received REYATAZ 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with REYATAZ plus ritonavir.

Among patients who received REYATAZ 400 mg once daily or REYATAZ 300 mg with ritonavir 100 mg once daily, the only adverse reactions of any severity reported very commonly with at least a possible relationship to regimens containing REYATAZ and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving REYATAZ 300 mg with 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).

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.4).

Tabulated list of adverse reactions

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

Immune system disorders:

uncommon: hypersensitivity

Metabolism and nutrition disorders:

uncommon: weight decreased, weight gain, anorexia, 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 pointesa

rare: QTc prolongationa, oedema, palpitation

Vascular disorders:

uncommon: hypertension

Respiratory, thoracic and mediastinal disorders:

uncommon: dyspnoea

Gastrointestinal disorders:

common: vomiting, diarrhoea, abdominal pain, nausea, dyspepsia;

uncommon: pancreatitis, gastritis, abdominal distension, stomatitis aphthous, flatulence, dry mouth

Hepatobiliary disorders:

common: jaundice;

uncommon: hepatitis, cholelithiasisa, cholestasisa;

rare: hepatosplenomegaly, cholecystitisa

Skin and subcutaneous tissue disorders:

common: rash;

uncommon: erythemia multiformea,b, toxic skin eruptionsa,b, drug rash with eosinophilia and systemic symptoms (DRESS) syndromea,b, angioedemaa, urticaria, alopecia, pruritus;

rare: Stevens-Johnson syndromea,b, vesiculobullous rash, eczema, vasodilatation

Musculoskeletal and connective tissue disorders:

uncommon: muscle atrophy, arthralgia, myalgia;

rare: myopathy

Renal and urinary disorders:

uncommon: nephrolithiasisa, haematuria, proteinuria, pollakiuria, interstitial nephritis, chronic kidney diseasea;

rare: kidney pain

Reproductive system and breast disorders:

uncommon: gynaecomastia

General disorders and administration site conditions:

common: fatigue;

uncommon: chest pain, malaise, pyrexia, asthenia;

rare: gait disturbance

a These adverse reactions were identified through post-marketing surveillance, however, the frequencies were estimated from a statistical calculation based on the total number of patients exposed to REYATAZ in randomised controlled and other available clinical trials (n = 2321).

b See description of selected adverse reactions for more details.

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).

Metabolic parameters

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

Rash and associated syndromes

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

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 REYATAZ (see section 4.4).

Laboratory abnormalities

The most frequently reported laboratory abnormality in patients receiving regimens containing REYATAZ 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 REYATAZ 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 REYATAZ 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 REYATAZ 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 REYATAZ experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations.

Paediatric population

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

In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of age had a mean duration of treatment with REYATAZ oral powder of 80 weeks. No deaths were reported. The safety profile in these studies was overall comparable to that seen in previous paediatric and adult studies. The most frequently reported laboratory abnormalities in paediatric patients receiving REYATAZ oral powder was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) and increased amylase (Grade 3-4; 33%), generally of non-pancreatic origin. Elevation in ALT levels were more frequently reported in paediatric patients in these studies than in adults.

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 REYATAZ and comparator regimens (see section 4.4).

Reporting of suspected adverse reactions

Reporting 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

Human experience of acute overdose with REYATAZ 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 REYATAZ 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 REYATAZ. 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: antivirals for systemic use, protease inhibitors, 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 REYATAZ/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 PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA)

None of the de novo substitutions (see Table 4) are specific to atazanavir and may reflect re-emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-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 REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir disoproxil fumarate/emtricitabine (300 mg/200 mg tablets once daily). The REYATAZ/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

REYATAZ/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 REYATAZ/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

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

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

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

f Number of patients evaluable.

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

Study 136 (INDUMA)

In an open-label, randomised, comparative study following a 26- to 30-week induction phase with REYATAZ 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted REYATAZ 400 mg once daily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral efficacy compared with REYATAZ + 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 REYATAZ and two NRTIs compared with 75% on REYATAZ + ritonavir and two NRTIs.

Eleven subjects (13%) in the unboosted REYATAZ group and 6 (7%) in the REYATAZ + ritonavir group, had virologic rebound. Four subjects in the unboosted REYATAZ group and 2 in the REYATAZ + ritonavir group had HIV RNA > 500 copies/ml during the maintenance phase. 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 REYATAZ and 1 subject in the REYATAZ + ritonavir group.

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

In antiretroviral experienced adult patients

Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir disoproxil fumarate (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 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 REYATAZ + 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 48a 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 disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

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

d Confidence interval.

e Number of patients evaluable.

f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed 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 REYATAZ + 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 REYATAZ + 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 REYATAZ + 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 REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96-week analysis, 48 % of patients overall remained on study.

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

Paediatric population

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial AI424-020 conducted in patients from 3 months to 21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naive and 101 antiretroviral-experienced) received once daily REYATAZ (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 REYATAZ 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 AI424-020)

Parameter

Treatment-Naive REYATAZ Capsules/ritonavir (300 mg/100 mg once daily) n=16

Treatment-Experienced REYATAZ 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.

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 REYATAZ 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, Cmax of 4466 (42%) ng/ml, with time to Cmax of approximately 2.5 hours. The geometric mean (CV%) for atazanavir Cmin and AUC was 654 (76%) ng/ml and 44185 (51%) ng•h/ml, respectively.

In HIV-infected patients (n=13), multiple dosing of REYATAZ 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 REYATAZ and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300 mg dose of REYATAZ 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 Cmax and 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 Cmax 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 Tmax increased from 2.0 to 5.0 hours. Administration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. To enhance bioavailability and minimise variability, REYATAZ 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 REYATAZ with ritonavir in patients with renal insufficiency. REYATAZ (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. REYATAZ (without ritonavir) has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh Class B and 2 Child-Pugh Class C subjects) after a single 400 mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. 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 REYATAZ 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 Cmin is concentration 24 hours post-dose.

Paediatric population

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

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 Cmax in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2 week 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

REYATAZ 100 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate and magnesium stearate

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

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

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

REYATAZ 150 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate and magnesium stearate

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

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

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

REYATAZ 200 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate and magnesium stearate

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

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

REYATAZ 300 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate and magnesium stearate

Capsule shells: gelatine, red iron oxide, black iron oxide, yellow iron oxide, indigocarmin (E132) and titanium dioxide (E171)

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

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

REYATAZ 100 mg hard capsules

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

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

REYATAZ 150 mg hard capsules

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

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

REYATAZ 200 mg hard capsules

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

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

REYATAZ 300 mg hard capsules

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

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

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

BRISTOL-MYERS SQUIBB PHARMA EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

8. Marketing authorisation number(s)

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

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 02 March 2004

Date of latest renewal: 02 March 2009

10. Date of revision of the text

February 2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu