REYATAZ 150 mg hard capsules

REYATAZ 200 mg hard capsules

REYATAZ 300 mg hard capsules

Each capsule contains 150 mg, 200 mg, or 300mg of atazanavir (as sulphate)

Excipient: 82.18 mg of lactose per 150 mg capsule

Excipient: 109.57 mg of lactose per 200 mg capsule

Excipient: 164.36 mg of lactose per 300mg capsule.

For a full list of excipients, see section 6.1.

Hard capsule

REYATAZ 150 mg capsules are opaque blue and powder blue. They are printed with white and blue inks, with "BMS 150 mg" on one half and with "3624" on the other half.

REYATAZ 200 mg capsules are opaque blue. They are printed with white ink, with "BMS 200 mg " on one half and with "3631" on the other half.

REYATAZ 300mg capsules are opaque red and blue. They are printed with white ink, with "BMS 300 mg" on one half and with "3622" on the other half.

REYATAZ is indicated for the treatment of HIV1 infected adults in combination with other antiretroviral medicinal products.

In antiretroviral treatment experienced patients, the demonstration of efficacy is based on a study comparing REYATAZ 300 mg once daily in combination with ritonavir 100 mg once daily with lopinavir/ritonavir, each regimen in combination with tenofovir (see sections 4.8 and 5.1). Based on available virological and clinical data, no benefit is expected in patients with strains resistant to multiple protease inhibitors ( 4 PI mutations). The choice of REYATAZ in treatment experienced patients should be based on individual viral resistance testing and the patient's treatment history (see section 5.1).

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

Adults: the recommended dose of REYATAZ 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).

If REYATAZ with ritonavir is coadministered with didanosine, it is recommended that didanosine be taken 2 hours after REYATAZ with ritonavir. REYATAZ with ritonavir must be taken with food (see section 4.5).

Infants, toddlers, children, and adolescents: the safety and efficacy of REYATAZ in paediatric patients has not been established (see section 5.2).

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

Patients with 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 should not be used in patients with moderate to severe hepatic impairment (see sections 4.3, 4.4, and 5.2).

Method of administration: for oral administration. The capsules should be swallowed whole. REYATAZ oral powder is available for patients who are unable to swallow capsules (see Summary of Product Characteristics for REYATAZ oral powder).

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

Patients with moderate to severe hepatic insufficiency (see sections 4.2 and 4.4).

Combination of rifampicin and REYATAZ with concomitant low-dose ritonavir is contraindicated (see section 4.5).

REYATAZ with ritonavir must not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., 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).

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

Patients should be advised that current antiretroviral therapy has not been proven to prevent the risk of transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

Coadministration of REYATAZ with ritonavir in doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended.

Patients with coexisting conditions

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 preexisting 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.

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

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 preexisting conduction problems (second degree or higher atrioventricular or complex bundlebranch 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 preexisting risk factors (bradycardia, long congenital QT, electrolyte imbalances (see sections 4.8 and 5.3).

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

Fat redistribution and metabolic disorders

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

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

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

Hyperglycaemia

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

Hyperbilirubinaemia

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDPglucuronosyl 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 etiologies. 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 coadministration of these medicinal products is not recommended (see section 4.5).

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving REYATAZ (see section 4.8). If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Immune reactivation syndrome

In HIVinfected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIVdisease and/or longterm 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.

Interactions with other medicinal products

Coadministration of REYATAZ with simvastatin or lovastatin is not recommended (see section 4.5).

Coadministration of REYATAZ with nevirapine or efavirenz is not recommended (see section 4.5).

If the coadministration 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. Coadministration of REYATAZ with ritonavir and medicinal products that induce CYP3A4 is not recommended (see sections 4.3 and 4.5).

Coadministration of voriconazole and REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole (see section 4.5).

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

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

Coadministration 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.

Coadministration of REYATAZ/ritonavir in combination with tenofovir and an H₂receptor antagonist should be avoided (see section 4.5).

Lactose

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

When REYATAZ and ritonavir are coadministered, 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 with ritonavir is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly ergotamine and dihydroergotamine (see section 4.3).

Other interactions

Interactions between atazanavir/ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors, and other nonantiretroviral medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “”, no change as “↔”, twice daily as “BID” and once daily as “QD”). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 1 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the approved regimen of atazanavir.

Table 1: Interactions between REYATAZ and other medicinal products

There are no adequate data from the use of atazanavir in pregnant women. Studies in animals have not shown evidence of selective developmental toxicity or effects on reproductive function and fertility (see section 5.3). REYATAZ should be used during pregnancy only if the potential benefit justifies the potential risk.

It is not known whether REYATAZ administered to the mother during pregnancy will exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In the prepartum period, additional monitoring and alternative therapy to REYATAZ should be considered.

It is not known whether atazanavir is excreted in human milk. Studies in rats have demonstrated that atazanavir is excreted in the milk. It is therefore recommended that mothers being treated with REYATAZ not breastfeed their infants. As a general rule, it is recommended that HIV infected women not breastfeed their infants in order to avoid transmission of HIV.

No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that dizziness has been reported during treatment with regimens containing REYATAZ (see section 4.8).

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).

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

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

Adult patients

The following adverse reactions of moderate intensity or greater with at least a possible relationship to regimens containing REYATAZ and one or more NRTIs have also been reported. The frequency of adverse reactions listed below 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), or very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In HIVinfected 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 (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or longterm exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (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 34 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 34 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 glutamicpyruvic transaminase (ALT/SGPT) (5%), low neutrophils (5%), elevated aspartate aminotransferase/serum glutamicoxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (3%).

Two percent of patients treated with REYATAZ experienced concurrent Grade 34 ALT/AST and Grade 34 total bilirubin elevations.

Patients coinfected with hepatitis B and/or hepatitis C virus

Among 1,151 patients receiving atazanavir 400 mg once daily, 177 patients were coinfected 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 coinfected with chronic hepatitis B or C. Coinfected 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 coinfected patients was comparable between REYATAZ and comparator regimens (see section 4.4).

Postmarketing experience

There have been postmarketing reports of unknown frequency for torsades de pointes, QTc prolongation, diabetes mellitus, hyperglycaemia, nephrolithiasis, and gallbladder disorders including cholelithiasis, cholecystitis, and cholestasis.

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.

Pharmacotherapeutic group: protease inhibitor, ATC code: J05AE08

Mechanism of action: atazanavir is an azapeptide HIV1 protease inhibitor (PI). The compound selectively inhibits the virusspecific processing of viral GagPol proteins in HIV1 infected cells, thus preventing formation of mature virions and infection of other cells.

Antiviral activity in vitro: atazanavir exhibits antiHIV1 (including all clades tested) and antiHIV2 activity in cell culture.

Resistance

Antiretroviral treatment naive 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 29fold 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.

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

Antiretroviral treatment experienced 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.

None of the de novo substitutions (see Table 3) 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 patients

Study 138 is an international randomised, openlabel, 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/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 4).

Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4).

Table 4: Efficacy Outcomes in Study 138 ^a

^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/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

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

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

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

^f Number of patients evaluable.

In antiretroviral experienced 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 (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. Thirtytwo percent of patients in the study had a viral strain with fewer than two NRTI substitutions.

The primary endpoint was the timeaveraged difference in change from baseline in HIV RNA through 48 weeks (Table 5).

Table 5: Efficacy Outcomes at Week 48^a and at Week 96 (Study 045)

^a The mean baseline CD4 cell count was 337 cells/mm³ (range: 14 to 1,543 cells/mm³) and the mean baseline plasma HIV1 RNA level was 4.4 log₁₀ copies/ml (range: 2.6 to 5.88 log₁₀ copies/ml).

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

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

^d Confidence interval.

^e Number of patients evaluable.

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

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

NA = not applicable.

Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (noninferior). Consistent results were obtained with the last observation carried forward method of analysis (timeaveraged difference of 0.11, 97.5% confidence interval [0.15, 0.36]). By astreated 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 noninferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. By astreated 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 96week analysis, 48 % of patients overall remained on study.

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

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIVinfected patients; significant differences were observed between the two groups. The pharmacokinetics of atazanavir exhibit a nonlinear disposition. In healthy subjects, the AUC of atazanavir from the capsules and oral powder were similar.

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, C_max of 4466 (42%) ng/ml, with time to C_max of approximately 2.5 hours. The geometric mean (CV%) for atazanavir C_min and AUC was 654 (76%) ng/ml and 44185 (51%) 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 C_max 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 C_max was within 11% of fasting values. The 24-hour concentration following a high fat meal was increased by approximately 33% due to delayed absorption; the median T_max increased from 2.0 to 5.0 hours. Administration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C_max by approximately 25% compared to the fasting state. To enhance bioavailability and minimise variability, 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 alpha1acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 ng/ml). In a multipledose study in HIVinfected 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 Ndealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised. Neither metabolite demonstrated in vitro antiviral activity.

Elimination: following a single 400mg dose of ¹⁴Catazanavir, 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 halflife 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

Impaired renal function: 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.)

Impaired hepatic function: atazanavir is metabolised and eliminated primarily by the liver. 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.

Infants, toddlers, children, and adolescents: the pharmacokinetics of atazanavir is being studied after multiple doses in paediatric patients, stratified by age. There are insufficient data at this time to recommend a dose (see section 4.2).

In repeatdose toxicity studies, conducted in mice, rats, and dogs, atazanavirrelated 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 singlecell 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 singlecell 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 30fold the free drug concentration at C_max in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD₉₀) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2week oral toxicity study performed in dogs. Subsequent 9month oral toxicity studies in dogs showed no drugrelated electrocardiographic changes. The clinical relevance of these nonclinical 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 section4.9).

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 embryodevelopment 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 reversemutation 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 longterm 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 singlecell 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.

Capsule contents:

Crospovidone

Lactose monohydrate

Magnesium stearate

Capsule shells:

Gelatine

Indigocarmin (E132)

Titanium dioxide (E171)

300mg capsule shells also contain:

Red iron oxide

Black iron oxide

Yellow iron oxide

White ink containing:

Shellac

Titanium dioxide (E171)

Ammonium hydroxide

Propylene glycol

Simethicone

150 mg capsule shells also contain blue ink containing:

Shellac

Propylene glycol

Ammonium hydroxide

Indigocarmin (E132)

Not applicable.

2 years

Do not store above 25°C.

Each 150mg and 200mg carton contains one highdensity polyethylene (HDPE) bottle closed with childresistant polypropylene closure. Each 150mg and 200mg bottle contains 60 hard capsules.

Each 150 mg and 200mg carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/Alu perforated unit dose blisters.

Each 300mg carton contains one highdensity polyethylene (HDPE) bottle or three highdensity polyethylene (HDPE) bottles closed with a childresistant polypropylene closure. Each bottle contains 30 hard capsules.

Each 300mg 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.

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

BRISTOLMYERS SQUIBB PHARMA EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

Date of first authorisation: 02 March 2004

Date of latest renewal: 02 March 2009

November 2009

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