Human experience of acute overdose with Атазанавир Канон 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.
Treatment of overdose with Атазанавир Канон 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 Атазанавир Канон. 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.
Атазанавир Канон is contraindicated in patients with severe hepatic insufficiency. Атазанавир Канон with ritonavir is contraindicated in patients with moderate hepatic insufficiency.
Co-administration with simvastatin or lovastatin.
Combination of rifampicin.
Combination of the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) only.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 , and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine).
Co-administration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used to treat chronic hepatitis C infection).
Co-administration with products containing St. John's wort (Hypericum perforatum).
Not applicable.
Summary of the safety profile
Атазанавир Канон has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving Атазанавир Канон 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or Атазанавир Канон 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 Атазанавир Канон 400 mg once daily and patients who received Атазанавир Канон 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with Атазанавир Канон plus ritonavir.
Among patients who received Атазанавир Канон 400 mg once daily or Атазанавир Канон 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 Атазанавир Канон and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving Атазанавир Канон 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.
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.
Tabulated list of adverse reactions
Assessment of adverse reactions for Атазанавир Канон 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 Атазанавир Канон 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.
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.
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
Rash and associated syndromes
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with Атазанавир Канон.
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 Атазанавир Канон.
Laboratory abnormalities
The most frequently reported laboratory abnormality in patients receiving regimens containing Атазанавир Канон 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 Атазанавир Канон 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 Атазанавир Канон 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.
Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in > 2% of patients receiving regimens containing Атазанавир Канон 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 Атазанавир Канон 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 Атазанавир Канон 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 Атазанавир Канон 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 Атазанавир Канон 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 Атазанавир Канон 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 Атазанавир Канон and comparator regimens.
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
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. The potential for PR prolongation should be considered in cases of overdose.
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.
Атазанавир Канон capsules, co-administered with low dose ritonavir, are indicated for the treatment of HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products.
Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (> 4 PI mutations).
The choice of Атазанавир Канон in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient's treatment history.
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 Атазанавир Канон/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 Атазанавир Канон/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 Атазанавир Канон/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 | Атазанавир Канон/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 Атазанавир Канон/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.
)
Study 136 (INDUMA)
In an open-label, randomised, comparative study following a 26- to 30-week induction phase with Атазанавир Канон 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted Атазанавир Канон 400 mg once daily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral efficacy compared with Атазанавир Канон + 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 Атазанавир Канон and two NRTIs compared with 75% on Атазанавир Канон + ritonavir and two NRTIs.
Eleven subjects (13%) in the unboosted Атазанавир Канон group and 6 (7%) in the Атазанавир Канон + ritonavir group, had virologic rebound. Four subjects in the unboosted Атазанавир Канон group and 2 in the Атазанавир Канон + 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 Атазанавир Канон and 1 subject in the Атазанавир Канон + ritonavir group.
There were fewer treatment discontinuations in the unboosted Атазанавир Канон group (1 vs. 4 subjects in the Атазанавир Канон + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboosted Атазанавир Канон group compared with the Атазанавир Канон + ritonavir group (18 and 28 subjects, respectively).
In antiretroviral experienced adult patients
Study 045 is a randomised, multicenter trial comparing Атазанавир Канон/ritonavir (300/100 mg once daily) and Атазанавир Канон/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 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 Атазанавир Канон + 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 Атазанавир Канон + 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 Атазанавир Канон + 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 Атазанавир Канон + 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 Атазанавир Канон + 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.
Атазанавир Канон + saquinavir was shown to be inferior to lopinavir + ritonavir.
Paediatric population
Assessment of the pharmacokinetics, safety, tolerability, and efficacy of Атазанавир Канон 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 Атазанавир Канон (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 Атазанавир Канон 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 Атазанавир Канон Capsules/ritonavir (300 mg/100 mg once daily) n=16 | Treatment-Experienced Атазанавир Канон 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.
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 Атазанавир Канон 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 Атазанавир Канон 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 Атазанавир Канон and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300 mg dose of Атазанавир Канон 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 Атазанавир Канон 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, Атазанавир Канон 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 Атазанавир Канон with ritonavir in patients with renal insufficiency. Атазанавир Канон (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.
Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. Атазанавир Канон (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.
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 Атазанавир Канон 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.
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 Атазанавир Канон 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. The safety and efficacy of Атазанавир Канон 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.
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, Атазанавир Канон is not recommended in patients undergoing haemodialysis.
QT prolongation: Dose related asymptomatic prolongations in PR interval with Атазанавир Канон 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), Атазанавир Канон should be used with caution and only if the benefits exceed the risk. Particular caution should be used when prescribing Атазанавир Канон 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.
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, Атазанавир Канон (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 Атазанавир Канон. Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving Атазанавир Канон should be evaluated for alternative aetiologies. Alternative antiretroviral therapy to Атазанавир Канон 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 Атазанавир Канон and indinavir have not been studied and co-administration of these medicinal products is not recommended.
Withdrawal of ritonavir only under restrictive conditions
The recommended standard treatment is Атазанавир Канон boosted with ritonavir, ensuring optimal pharmacokinetic parameters and level of virologic suppression.
The withdrawal of ritonavir from the boosted regimen of Атазанавир Канон 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:
â–ª absence of prior virologic failure
â–ª undetectable viral load during the last 6 months under current regimen
â–ª viral strains not harbouring HIV resistance associated mutations (RAMs) to current regimen.
) or in case of perceived challenging compliance.Атазанавир Канон 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 Атазанавир Канон. 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.
Nephrolithiasis
Nephrolithiasis has been reported in patients receiving Атазанавир Канон. 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 Атазанавир Канон.
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 Атазанавир Канон. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. Атазанавир Канон 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 Атазанавир Канон, Атазанавир Канон may not be restarted.
Interactions with other medicinal products
The combination of Атазанавир Канон with atorvastatin is not recommended.
Co-administration of Атазанавир Канон with nevirapine or efavirenz is not recommended.
If the co-administration of Атазанавир Канон with an NNRTI is required, an increase in the dose of both Атазанавир Канон 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 Атазанавир Канон and medicinal products that induce CYP3A4 is not recommended.
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 Атазанавир Канон. Co-administration of Атазанавир Канон 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.
Co-administration of voriconazole and Атазанавир Канон 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.
Concomitant use of Атазанавир Канон/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.
Concomitant use of salmeterol and Атазанавир Канон may result in increased cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and Атазанавир Канон is not recommended.
The absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective of cause.
Co-administration of Атазанавир Канон with proton pump inhibitors is not recommended. If the combination of Атазанавир Канон with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of Атазанавир Канон 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 Атазанавир Канон with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate or norethindrone has not been studied, and therefore should be avoided.
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. 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), Атазанавир Канон 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.
Patients should be informed that dizziness has been reported during treatment with regimens containing Атазанавир Канон.
Therapy should be initiated by a physician experienced in the management of HIV infection.
Posology
Adults
The recommended dose of Атазанавир Канон capsules is 300 mg once daily taken with ritonavir 100 mg once daily and with food.).
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. Атазанавир Канон 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 Атазанавир Канон capsules with ritonavir | ||
| Body Weight (kg) | Атазанавир Канон 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): Атазанавир Канон 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 Атазанавир Канон oral powder). Switching to Атазанавир Канон capsules from Атазанавир Канон 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 Атазанавир Канон oral powder).
Special populations
Renal impairment
No dosage adjustment is needed. Атазанавир Канон with ritonavir is not recommended in patients undergoing haemodialysis.
Hepatic impairment
Атазанавир Канон with ritonavir has not been studied in patients with hepatic impairment. Атазанавир Канон with ritonavir should be used with caution in patients with mild hepatic impairment. Атазанавир Канон with ritonavir must not be used in patients with moderate to severe hepatic impairment.
In case of withdrawal of ritonavir from the initial recommended ritonavir boosted regimen , unboosted Атазанавир Канон 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. Unboosted Атазанавир Канон must not be used in patients with severe hepatic impairment.
Pregnancy and Postpartum
During the second and third trimesters of pregnancy:
Атазанавир Канон 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).
â–ª If tenofovir disoproxil or an H2-receptor antagonist is needed, a dose increase to Атазанавир Канон 400 mg with ritonavir 100 mg with TDM may be considered.
â–ª It is not recommended to use Атазанавир Канон with ritonavir for pregnant patients who are receiving both tenofovir disoproxil and an H2-receptor antagonist.
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. Therefore, postpartum patients should be closely monitored for adverse reactions.
â–ª 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.
Paediatric patients (less than 3 months of age)
Атазанавир Канон 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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
