Bristol-Myers Squibb Pharmaceutical Limited

The followign text has been deleted from section 5.2:

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. In healthy subjects, the AUC of atazanavir from the capsules and oral powder were similar

Section 4.3

The following text has been added:

The PDE5 inhibitor sildenafil is contraindicated when used for the treatment of pulmonary

arterial hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the

treatment of erectile dysfunction see section 4.4 and section 4.5.

Section 4.4

The following text has been added

Atazanavir is metabolised principally by CYP3A4. Co-administration of REYATAZ with

ritonavir and medicinal products that induce CYP3A4 is not recommended (see sections 4.3

and 4.5).

PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be

used when prescribing PDE5-inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment

of erectile dysfunction in patients receiving REYATAZ with concomitant low-dose ritonavir.

Co-administration of REYATAZ with these medicinal products is expected to substantially

increase their concentrations and may result in PDE5-associated adverse events such as

hypotension, visual changes and priapism (see section 4.5).

Co-administration of voriconazole and 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).

Concomitant use of salmeterol and REYATAZ/ritonavir 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.

Section 4.5

The following  text has been added:

In section 4.4 Added text:

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).

** When compared to rifabutin 150 mg QD alone. Total rifabutin and 25-O-desacetyl-rifabutin AUC: ↑2.19 (1.78, 2.69).

In previous studies, the pharmacokinetics of atazanavir was not altered by rifabutin.

4.4     Special warnings and precautions for use

The concomitant use of REYATAZ and oral contraceptives should be avoided (see section 4.5).

4.5     Interaction with other medicinal products and other forms of interaction

10.     DATE OF REVISION OF THE TEXT

November 2009

4.2     Posology and method of administration

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

4.4     Special warnings and precautions for use

Addition of:

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).

(.......)

Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H₂‑receptor antagonist should be avoided (see section 4.5).

4.5     Interaction with other medicinal products and other forms of interaction

(....)

Table 1: Interactions between REYATAZ and other medicinal products

4.8     Undesirable effects

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, 48 96°weeks median duration and 101108 weeks maximum duration).

(.....)

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 (8487% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 35% (537% (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 4896 weeks, 3948% 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) (45%), low neutrophils (45%), elevated aspartate aminotransferase/serum glutamic‑oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (23%).

OneTwo percent of patients treated with REYATAZ experienced concurrent Grade 3‑4 ALT/AST and Grade 3‑4 total bilirubin elevations.

5.1     Pharmacodynamic properties

Antiviral activity in vitro: atazanavir exhibits anti‑HIV‑1 activity (EC50 of 2 to 5 nM) in the absence of human serum against a variety of laboratory(including all clades tested) and clinical anti‑HIV isolates. Atazanavir has‑2 activity against HIV‑1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has activity against HIV‑2 isolates (EC_{50 of 1.9 to 32 nM). Combinations of atazanavir with stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, amprenavir, did not result in antagonistic anti‑HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation.}

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. An atazanavir resistance phenotype is expressed in all recombinant viral clones containing the I50L substitution in a variety of genetic backgrounds. Resistance levels to atazanavir ranged from 3.5‑ to 29‑fold. There was no without evidence of phenotypic cross‑resistance between atazanavir and amprenavir, with the presence resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L and I50Vsubstitution did not emerge in any patient without baseline PI substitutions yielding selective resistance to atazanavir and amprenavir, respectively. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir treatment(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 primary and secondarymajor and minor resistance substitutions described previously to be involved in protease inhibitor resistance. These isolates developed higher levels of resistance to the other protease inhibitors.

Cross‑resistance in vitro in viruses resistant to other protease inhibitors

Atazanavir susceptibility was evaluated in 943 clinical isolates from patients without prior atazanavir exposure and exhibited a wide array of genotypic and phenotypic patterns. In vitro, there was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained (83% of isolates displayed < 2.5 fold change in EC₅₀) among isolates resistant to no more than 2 protease inhibitors.

Eighteen percent of isolates had 4 or more of the following 6 substitutions considered critical substitutions for protease inhibitors: positions L10, M46, I54, V82, I84, and L90. These isolates expressed a median fold change in EC₅₀ relative to wildtype of 12.0 for atazanavir. Therefore, viral isolates having at least 4 of these specific mutations would be considered resistant for atazanavir.

Clinical results

In antiretroviral naive patients

Study 138 is an international randomised, open‑label, multicenter, prospective trial of 883 antiretroviral 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 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). The REYATAZ/ritonavir arm hasshowed 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: 78% of patients on REYATAZ/ritonavir compared to 76% on lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: 1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response.

In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%].

 (Table 2: 4).

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

Table 4:           Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis ^a

The following text has been added

300mg capsule shells also contains :

Red iron oxide
Black iron oxide
Yellow iron oxide

Updates to section 4.3, 4.4, 4.5 and 6,1

Section 4.3 and 4.5:  Updated to incorporate information regarding triazolam and midazolam.

Section 2. - Lactose content added.

Section 4.2 - updated to include 'experience in children is limited'.

Section 4.5 - Updated to include information regarding interaction between atazanavir and tenofovir.

Section 4.6 - Updated to include 'There are no adequare data from use of atazanavir in pregnant women'

Section 4.7 - Updated to include 'No studies on the effect on ability to drive and use machines have been performed.'

Section 4.8 - Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

                     Postmarketing experience:  diabetes mellitus and hyperglycaemia included as postmarketing adverse events.

Section 5.1 - Following paragraph added:

This medicinal product has been authorised under “Exceptional Circumstances”. This means that for scientific reasons, it has not been possible to obtain complete information on  this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.

Section 6.1:  Isopropyl alcohol added

Section 6.4 - 'Store in the original packaged' included.

Section 6.6 - 'Any unused product or waste material should be disposed of in accordance with local requirements' added.