Drug Interactions
REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor
REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist.
| HMG-CoA Reductase Inhibitors: | ↑ atorvastatin
↑ rosuvastatin | The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including REYATAZ, are used in combination with these drugs. Caution should be exercised. Use the lowest possible dose with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with and without ritonavir). |
| Immunosuppressants: | ↑cyclosporin, sirolimus, tacrolimus | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ. |
| Inhaled/nasal corticosteroids (interaction with ritonavir): | ↑ fluticasone propionate | In healthy volunteers, ritonavir significantly increased plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of REYATAZ/ritonavir with fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported when ritonavir was coadministered with inhaled or intranasally administered fluticasone propionate. These effects could also occur with other corticosteroids metabolized via the cytochrome P450 3A pathway, eg, budesonide. Therefore, concomitant use of REYATAZ/ritonavir and fluticasone propionate or other glucocorticoids that are metabolized by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with Caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
| Macrolide Antibiotics: | ↑ clarithromycin
↓ 14-OH clarithromycin
↑ atazanavir | Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to M. avium complex. Caution is advised during coadministration as a high incidence of rash (20%) was observed in the pharmacokinetic trial in healthy volunteers. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied. |
| Oral Contraceptives: ethinyl estradiol and norgestimate or norethindrone | ↑ ethinyl estradiol
↑ norethindronec
↓ ethinyl estradiol
↑ norgestimateb | Mean concentrations of ethinyl estradiol and norethindrone, when coadministered with REYATAZ, are increased.
Administration of REYATAZ/ritonavir with ethinyl estradiol and norgestimate decreases the mean concentration of ethinyl estradiol, and increases the mean concentration of 17- deacetyl norgestimate, the active metabolite of norgestimate. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 30 µg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more that 30 µg of ethinyl estradiol.
Use with caution as the effect of increases in concentration of the progestational agent are unknown and could increase the risk of acne, dyslipidemia, and insulin resistance.
Coadministration of REYATAZ or REYATAZ /ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestagens other than norethindrone or norgestimate, or less than 25 µg of ethinyl estradiol have not been studied; therefore alternative methods of contraception are recommended. |
a. See Table 13 for orally administered midazolam.
b. In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
c. In combination with atazanavir 400 mg once daily.
Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin or erythromycin. Coadministration of methadone and REYATAZ in subjects chronically treated with methadone did not result in clinically relevant interactions. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Additionally, no clinically significant drug interaction was observed when REYATAZ was coadministered with fluconazole or acetaminophen.
Refer to Norvir Product Monograph for drug interaction of ritonavir with these drugs before prescribing REYATAZ 300 mg with ritonavir 100 mg.
Information for the Patient
Reyataz
Dosage and Administration
Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
There are limited safety data from controlled trials for REYATAZ plus ritonavir regimens without tenofovir. (See Warnings and Precautions and Drug Interactions.)
| Body Weight | REYATAZ Dosea , b | Ritonavir Doseb |
| (kg) | (lbs) | (mg) | (mg) |
| 25 to less than 32 | 55 to less than 70 | 200 | 100c |
| 32 to less than 39 | 70 to less than 86 | 250 | 100c |
| at least 39 | at least 86 | 300 | 100c |
a. The recommended dosage of REYATAZ can be achieved using a combination of commercially available capsule strengths.
b. The dosage was calculated as REYATAZ 7 mg/kg with ritonavir 4 mg/kg once daily with food not to exceed REYATAZ 300 mg and ritonavir 100 mg.
c. Ritonavir capsule or liquid.
If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200 mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz should be administered on an empty stomach, preferably at bedtime.
| Body Weight | REYATAZ Dosea , b | Ritonavir Doseb |
| (kg) | (lbs) | (mg) | (mg) |
| 15 to less than 25 | 33 to less than 55 | 150 | 80c |
| 25 to less than 32 | 55 to less than 70 | 200 | 100d |
| 32 to less than 39 | 70 to less than 86 | 250 | 100d |
| at least 39 | at least 86 | 300 | 100d |
a. The recommended dosage of REYATAZ can be achieved using a combination of commercially available capsule strengths.
b. The dosage of REYATAZ and ritonavir was calculated as follows:• 15 kg to less than 20 kg: REYATAZ 8.5 mg/kg with ritonavir 4 mg/kg once daily with food.• at least 20 kg: REYATAZ 7 mg/kg with ritonavir 4 mg/kg once daily with food not to exceed REYATAZ 300 mg and ritonavir 100 mg.
c. Ritonavir liquid.
d. Ritonavir capsule or liquid.
For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ, with or without ritonavir, should not be used in antiretroviral-treatment experienced patients with end stage renal disease managed with hemodialysis. REYATAZ without ritonavir should not be administered to patients managed with hemodialysis (see Warnings and Precautions and Action and Clinical Pharmacology, Special Populations and Conditions).
If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.
REYATAZ should be used with caution in patients with mild-to-moderate hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure, a dose reduction to 300 mg once daily should be considered. REYATAZ should not be used in patients with severe hepatic impairment (Child-Pugh Class C). REYATAZ/ritonavir has not been studied in subjects with hepatic impairment and is not recommended. (See Warnings and Precautions, Hepatic/Biliary/Pancreatic.)
If coadministered with tenofovir DF, it is recommended that 300 mg of REYATAZ and ritonavir 100 mg be given with tenofovir 300 mg (together as single daily doses with food). There are limited safety data from controlled trials for REYATAZ plus ritonavir regimens without tenofovir. REYATAZ without ritonavir should not be coadministered with tenofovir. (See Drug Interactions.)
REYATAZ 300 mg once daily taken with ritonavir 100 mg once daily taken with food.
Capsules should not be opened, they should be swallowed whole with water.
When coadministered with didanosine buffered formulations, REYATAZ should be given (with food) two hours before or one hour after didanosine.
The recommended dosage of REYATAZ for pediatric patients (6 to less than 18 years of age) is based on body weight and should not exceed the recommended adult dosage. REYATAZ Capsules must be taken with food. The data are insufficient to recommend dosing of REYATAZ for any of the following: (1) patients less than 6 years of age, (2) without ritonavir in patients less than 13 years of age, and (3) treatment-experienced pediatric patients with body weight less than 25 kg.
REYATAZ 300 mg once daily taken with ritonavir 100 mg once daily taken with food.
or
REYATAZ 400 mg (two 200-mg capsules) once daily (without ritonavir) taken with food, for patients who are unable to tolerate ritonavir.
(See Warnings and Precautions and Drug Interactions.)
Adverse Reactions
abdominal distension, aphthous stomatitis, dysgeusia, flatulence, gastritis, hepatitis, hepatosplenomegaly, pancreatitis, dry mouth.
The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric patients at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. Use of REYATAZ in pediatric patients less than 6 years of age is under investigation.
The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) was comparable to that observed in clinical studies of REYATAZ in adults. The most common Grade 2-4 adverse events (≥5%, regardless of causality) reported in pediatric patients were cough (21%), fever (19%), rash (14%), jaundice/scleral icterus (13%), diarrhea (8%), vomiting (8%), headache (7%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in 2% of patients. The most common Grade 3-4 laboratory abnormality was elevation of total bilirubin (≥3.2 mg/dL) which occurred in 49% of pediatric patients. All other Grade 3-4 laboratory abnormalities occurred with a frequency of less than 3%. Both the frequency and severity of cardiac conduction abnormalities were greater in pediatric patients in this study than observed in clinical studies in adults.
pruritus, alopecia, maculopapular rash.
REYATAZ has been evaluated for safety and tolerability in combination therapy with other antiretroviral medications in controlled clinical trials in 1806 adult patients receiving REYATAZ 400 mg once daily (1151 patients, 52 weeks median duration and 152 weeks maximum duration), or REYATAZ 300 mg once daily plus ritonavir 100 mg once daily (655 patients, 48 weeks median duration and 101 weeks maximum duration).
The more frequent adverse events of any severity with at least a possible relationship to regimens containing REYATAZ and one or more NRTIs were nausea (20%), diarrhea (10%) and jaundice (12%).
Jaundice was reported within a few days to a few months after the initiation of treatment and resulted in discontinuation of treatment in <1% of patients. Discontinuation of treatment due to adverse reactions was 5% in treatment-naive patients and 5% in treatment-experienced patients.
Lipodystrophy, of moderate intensity or greater, was reported in regimens containing REYATAZ and one or more NRTIs as shown in Table 3 and Table 4 (see Warnings and Precautions).
| | Phase III
Study AI424-034 | Phase II
Studies AI424-007, -008 |
64 Weeksc REYATAZ 400 mg Once Daily + Lamivudine + Zidovudinee
N=404 | 64 Weeksc
Efavirenz 600 mg
Once Daily +
Lamivudine +
Zidovudinee
N=401 | 120 Weeksc , d
REYATAZ 400 mg
Once Daily +
Stavudine/
Lamivudine or +
Stavudine/
DidanosineN=279 | 73 Weeksc , d Nelfinavir 750 mg TID or 1250 mg BID + Stavudine + Lamivudine or + Stavudine + Didanosine
N=191 |
| Body as a Whole |
| Headache | 6% | 6% | 1% | 2% |
| Digestive System |
| Diarrhea | 1% | 2% | 3% | 16% |
| Dyspepsia | 2% | 2% | <1% | <1% |
| Scleral icterus | 2% | * | 2% | * |
| Jaundice | 5% | * | 5% | * |
| Nausea | 14% | 12% | 6% | 4% |
| Abdominal pain | 4% | 4% | 4% | 2% |
| Vomiting | 4% | 7% | 3% | 3% |
| Metabolic and Nutritional System |
| Lipodystrophy | 1% | 1% | 7% | 3% |
| Nervous System |
| Insomnia | 3% | 3% | <1% | * |
| Dizziness | 2% | 7% | <1% | * |
| Peripheral neurologic symptoms | <1% | 1% | 4% | 3% |
| Skin and Appendages |
| Rash | 7% | 10% | 5% | 1% |
a. Includes adverse events of possible, probable, certain, or unknown relationship to treatment regimen. Assessments of relationship refer to regimens containing REYATAZ or comparator.
b. Based on regimen(s) containing REYATAZ.
c. Median time on therapy. In study AI424-034 efficacy analyses are based on 48 week data. Safety data are derived from a 64 week safety update report.
d. Includes long-term follow-up.
e. As a fixed dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
* Not reported in this treatment arm.
hypertension, palpitation, syncope, edema.
| | Phase III
Study AI424-043 | Phase III
Study AI424-045** |
48 Weeksc REYATAZ 400 mg Once Daily + 2 NRTIs
N=144 | 48 Weeksc Lopinavir + Ritonavir (400/100 mg) b.i.d.d +
2 NRTIs
N=146 | 48 Weeksc REYATAZ 300 mg Once Daily + Ritonavir 100 mg Once Daily + Tenofovir + NRTI
N=119 | 48 Weeksc Lopinavir + Ritonavir (400/100 mg) b.i.d.d + Tenofovir + NRTI
N=118 |
| Body as a Whole |
| Headache | 4% | 3% | <1% | <1% |
| Fever | — | — | 2% | * |
| Digestive System |
| Diarrhea | 2% | 4% | 3% | 11% |
| Scleral icterus | * | * | 3% | * |
| Jaundice | 3% | * | 6% | * |
| Nausea | 3% | 4% | 3% | 2% |
| Vomiting | 2% | 2% | * | <1% |
| Pain abdomen | 3% | 2% | 2% | 2% |
| Metabolic and Nutritional System |
| Lipodystrophy | 6% | 1% | 5% | 4% |
| Weight decreased | 2% | <1% | * | 2% |
| Musculoskeletal System |
| Myalgia | * | * | 4% | * |
| Nervous System |
| Peripheral neurologic symptom | 2% | 5% | <1% | 3% |
| Depression | — | — | 2* | * |
| Skin and Appendages |
| Rash | 2% | * | * | <1% |
a. Includes adverse events of possible, probable, certain, or unknown relationship to treatment regimen. Assessments of relationship refer to regimens containing REYATAZ or comparator.
b. Based on regimen(s) containing REYATAZ.
c. Median time on therapy.
d. As a fixed dose combination.
e. Soft gelatin capsules.
* Not reported in this treatment arm.
** Note: There are limited safety data from controlled trials for REYATAZ plus ritonavir regimens without tenofovir (see Drug Interactions).
| | REYATAZa | Efavirenzb |
| Baseline | Week 48 | Baseline | Week 48 |
mmol/Lc
(n=383e) | mmol/Lc
(n=283e) | % Changec , f
(n=272e) | mmol/Lc
(n=378e) | mmol/Lc
(n=264e) | % Changec , f
(n=253e) |
| Total Cholesterol | 4.24 | 4.34 | +2% | 4.19 | 5.04 | +21% |
| HDL-Cholesterol | 1.01 | 1.11 | +13% | 0.98 | 1.19 | +24% |
| LDL-Cholesterolg | 2.53 | 2.53 | +1% | 2.53 | 2.95 | +18% |
| Triglyceridesg | 1.56 | 1.4 | −9% | 1.46 | 1.9 | +23% |
| Total-to-HDL Cholesterol Ratio <3 | 13% | 17% | — | 9% | 14% | — |
| Insulind , g | 81.1 | 88.3 | +9.3 | 71 | 82.5 | +10.1 |
| Glucosed , g | 5 | 5.2 | +0.17 | 5 | 5.2 | +0.33 |
a. REYATAZ 400 mg once daily with the fixed dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
b. Efavirenz 600 mg once daily with the fixed dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
c. Units are pmol/mL for insulin levels.
d. Absolute changes are reported for insulin and glucose levels.
e. Number of patients with LDL cholesterol measured.
f. The change from baseline is the mean of within patient changes from baseline for patients with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values.
g. Fasting.
* No multivariate analyses were performed on these data.
second-degree AV block, third-degree AV block, QTc prolongation, Torsades de Pointes, left bundle branch block.
hepatic function abnormalities.
| | Baseline
Study AI424-008 | Entry
Study AI424-044 | Week 12
Study AI424-044 |
mmol/La
(n=54b) | mmol/La
(n=33b) | mmol/La
(n=41b) | % Changec
(n=29b) |
| Total Cholesterol | 4.34 | 5.53 | 4.53 | −16% |
| HDL-Cholesterol | 1.09 | 1.19 | 1.24 | +5% |
| LDL-Cholesterold | 2.53 | 3.57 | 2.69 | −21% |
| Triglyceridesd | 1.19 | 1.77 | 1.22 | −28% |
| Insulind | — | 70.3 | 66.7 | — |
| Glucosed | — | 4.77 | 4.88 | — |
a. Units are pmol/mL for insulin levels.
b. Number of patients with LDL cholesterol measured.
c. The change from entry is the mean of within patient changes from entry for patients with both entry and Week 12 values and is not a simple difference of the entry and Week 12 mean values.
d. Fasting.
* No multivariate analyses were performed on these data.
The following events have been identified during post approval use of REYATAZ. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, or causal connection to REYATAZ, or a combination of these factors.
hyperglycemia, diabetes mellitus.
weight gain, anorexia, appetite increased, weight decreased.
cholelithiasis, cholecystitis, cholestasis.
abnormal dream, abnormal gait, amnesia, anxiety, confusion, sleep disorder, somnolence.
Treatment-emergent adverse events of at least moderate intensity occurring in less than 2% of adult patients receiving REYATAZ in all phase II/III clinical trials with at least a possible relationship to treatment with REYATAZ-containing regimens, and not listed in Table 2, Table 3 or Table 4 are listed below by body system.
gynecomastia, hematuria, kidney pain, proteinuria, pollakiuria, nephrolithiasis.
| Variable | Limitc | Treatment-Experienced Patients |
| Phase III Study AI424-043 | Phase III Studies AI424-045** |
| 48 Weeksb | 48 Weeksb | 48 Weeksb |
REYATAZ 400 mg Once Daily + 2NRTIs
N=144 | Lopinavir + Ritonavir (400/100 mg) BIDd + 2NRTIs
N=146 | REYATAZ 300 mg Once Daily + Ritonavir 100 mg Once Daily + Tenofovir + NRTI
N=119 | Lopinavir + Ritonavir (400/100 mg) BIDd + Tenofovir + NRTI
N=118 |
| Chemistry | High | | | | |
| AST | ≥5.1×ULN | 3% | 3% | 3% | 3% |
| ALT | ≥5.1×ULN | 7% | 3% | 4% | 3% |
| Total Bilirubin | ≥2.6×ULN | 25% | <1% | 49% | <1% |
| Lipase | ≥2.1×ULN | 4% | 3% | 5% | 6% |
| Creatine Kinase | ≥5.1×ULN | 8% | 6% | 8% | 8% |
| Hematology | Low | | | | |
| Platelets | <50 000/mm3 | * | * | 2% | 3% |
| Neutrophils | <750 cells/mm3 | 6% | 5% | 7% | 8% |
a. Based on regimen(s) containing REYATAZ.
b. Median time on therapy. In Study AI424-034 efficacy analyses are based on 48 week data. Safety data are derived from a 64 week safety update report.
c. ULN=upper limit of normal.
d. As a fixed dose combination.
* Not reported in this treatment arm.
** Note: There are limited safety data from controlled trials for REYATAZ plus ritonavir regimens without tenofovir. (See Drug Interactions.)
Liver function tests should be monitored in patients with a history of hepatitis B or C.
In study AI424-138, 60 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose tenofovir-emtricitabine were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 8% (5/60) of the REYATAZ/ritonavir-treated patients, and 6% (3/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 8% (5/60) of the REYATAZ/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.
In study AI424-045, 20 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily and 18 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (2/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).
In studies AI424-008 and AI424-034, 74 patients treated with 400 mg of REYATAZ once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. AST levels >5 times the upper limit of normal (ULN) developed in 9% of the REYATAZ-treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. ALT levels >5 times ULN developed in 15% of the REYATAZ-treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients.
Indications and Clinical Use
Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Dosage is based on body weight not to exceed the adult dose (see Dosage and Administration). There are no dosing recommendations for pediatric patients less than 6 years of age.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
Administration of activated charcoal may be used to aid in removal of unabsorbed drug. Treatment of overdosage with atazanavir should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient's clinical status. There is no specific antidote for overdose with atazanavir. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.
Human experience of acute overdose with atazanavir is limited. Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 58.4 g of atazanavir in an HIV-infected patient (146 times the 400 mg recommended dose) was associated with asymptomatic bilateral bundle branch block and PR interval prolongation. These events resolved spontaneously. At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or cardiac conduction abnormalities, including PR and/or QT interval prolongations, may be observed. (See Warnings and Precautions, Cardiovascular.)
Dosage Forms, Composition and Packaging
Each red opaque cap and blue opaque body, hard gelatin capsule, printed in white with “BMS”, “300 mg”, and “3622”, contains: atazanavir sulfate equivalent to 300 mg of atazanavir. Nonmedicinal ingredients: crospovidone, lactose monohydrate and magnesium stearate; capsule shell: black iron oxide, FD&C Blue #2, gelatin, red iron oxide, titanium dioxide and yellow iron oxide. HDPE bottles of 30.
Each blue opaque cap and body, hard gelatin capsule, printed in white with “BMS”, “200 mg”, and “3631”, contains: atazanavir sulfate equivalent to 200 mg of atazanavir. Nonmedicinal ingredients: crospovidone, lactose monohydrate and magnesium stearate; capsule shell: FD&C Blue #2, gelatin and titanium dioxide. HDPE bottles of 60.
Each blue opaque cap and powder-blue opaque body, hard gelatin capsule, printed in white with “BMS”, “150 mg”, and in blue “3624”, contains: atazanavir sulfate equivalent to 150 mg of atazanavir. Nonmedicinal ingredients: crospovidone, lactose monohydrate and magnesium stearate; capsule shell: FD&C Blue #2, gelatin and titanium dioxide. HDPE bottles of 60.
Warnings and Precautions
In healthy subjects, approximately 7% of the dose of atazanavir is eliminated unchanged in the urine. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The impact of renal impairment on atazanavir elimination for patients without hemodialysis is anticipated to be low. Moderate increases in atazanvir clearance and decreased exposure levels were seen in patients managed with hemodialysis. REYATAZ should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. (See Dosage and Administration and Action and Clinical Pharmacology.)
Cases of nephrolithiasis were reported during post-marketing surveillance in HIV-infected patients receiving atazanavir therapy. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.
Atazanavir 400 mg once daily has been shown to be inferior to lopinavir/ritonavir in antiretroviral experienced patients. There are limited safety data from controlled trials for REYATAZ plus ritonavir regimens without tenofovir. (See Drug Interactions and Dosage and Administration.)
Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and limited to first degree AV block with some exceptions (see Overdosage). There have been post-marketing reports of second-degree AV block, third-degree AV block, QTc prolongation, Torsades de Pointes and other conduction abnormalities in patients treated with REYATAZ (see Adverse Reactions, Post-Market Adverse Drug Reactions). In clinical trials, asymptomatic first degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 3.0% of efavirenz treated patients (n=329), 5.2% of lopinavir/ritonavir treated patients (n=252) and 10.4% of nelfinavir treated patients (n=48). In study AI424-045 asymptomatic first degree AV block was observed in 5% (6/118) of REYATAZ/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience, atazanavir should be used with caution in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second or third-degree AV block).
Dose related asymptomatic prolongations in PR interval with REYATAZ have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), REYATAZ should be used with caution and only if the benefits exceed the risk. Particular caution should be used when prescribing REYATAZ in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances). (See Action and Clinical Pharmacology.)
In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A substrate, there was a 2-fold increase in the diltiazem plasma concentration and an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one half should be considered and ECG monitoring is recommended. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, there was no substantial additive effect of atazanavir and atenolol on the PR interval. When used in combination with atazanavir, there is no need to adjust the dose of atenolol. (See Drug Interactions.)
Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers (other than atenolol), verapamil and digoxin have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are metabolized by CYP3A4 (e.g., verapamil). (See Drug Interactions.)
The incidence of benign hepatocellular adenomas was increased in high-dose female mice at systemic exposures approximately 7-fold higher than those in humans at the recommended 400 mg clinical dose. There was no increase in the incidence of tumors in male mice or in male or female rats at any dose tested. The clinical significance of the carcinogenic findings in female mice is unknown as the benign hepatic tumors occurred only at doses that induced liver toxicity.
Most patients taking atazanavir experience elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is generally reversible upon discontinuation of REYATAZ. If hepatic transaminase elevations occur with hyperbilirubinemia while a patient is receiving atazanavir, consideration should be given to also evaluating alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5×ULN. Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations present cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established (see Adverse Reactions).
There have been post-marketing reports of cholelithiasis, cholecystitis, and cholestasis in patients treated with atazanavir with ritonavir as part of their ART regimen (see Adverse Reactions, Post-Market Adverse Drug Reactions).
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B 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. A causal relationship between protease inhibitor therapy and these events has not been established.
To monitor maternal-fetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
There are no adequate and well-controlled studies in pregnant women. Cases of lactic acidosis, sometimes fatal, and symptomatic hyperlactatemia have been reported in patients (including pregnant women) receiving REYATAZ in combination with nucleoside analogues, which are known to be associated with increased risk of lactic acidosis. Female gender and obesity are also known risk factors for lactic acidosis syndrome. The contribution of REYATAZ to the risk of development of lactic acidosis syndrome has not been established.
Hyperbilirubinemia occurred frequently during treatment with REYATAZ. It is not known whether REYATAZ administered to the mother during pregnancy will exacerbate physiologic hyperbilirubinemia and lead to kernicterus in neonates and young infants. In the prepartum period, additional monitoring and alternative therapy should be considered. REYATAZ has been shown to cross the placenta.
No teratogenic effects were observed at maternally toxic doses in rats or rabbits. Systemic drug exposure levels were equal to (in rabbits) or two times (in rats) those at the human clinical dose (400 mg once daily). In the pre-and post-natal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at maternally toxic drug exposure levels two times those at the human clinical dose.
REYATAZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Warnings and Precautions, Endocrine and Metabolism).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicinal product.
In vitro HIV-1 isolates with a decreased susceptibility to ATV have been selected in vitro and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates that were 93- to 183-fold resistant to ATV from three different viral strains were selected in vitro by 5 months. The mutations in these HIV-1 viruses that contributed to ATV resistance included I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L mutation were growth impaired and displayed increased in vitro susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.
Both genotypic and phenotypic resistances have developed during clinical studies.
Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, appropriate caution should be exercised in the administration and monitoring of REYATAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of treatment, a patient whose immune system responds to therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP and TB), which may necessitate further evaluation and treatment.
Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced subjects showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with mutations that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N mutation in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L mutation in addition to other PI resistance-associated mutations were also cross-resistant to other PIs.
Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy.
Overall, both the number and type of baseline PI mutations affected response rates in treatment-experienced patients.
Alert: Find out about medicines that should NOT be taken with REYATAZ. (See Contraindications and Drug Interactions.)
Atazanavir should always be used in combination with other antiretroviral agents. Atazanavir should not be added as a single agent when antiretrovirals are changed due to loss of virologic response.
In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with REYATAZ. The median time to onset of rash in clinical studies was 7.1 weeks and the median duration of rash was 1.3 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies (see Adverse Reactions). Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. REYATAZ should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme and toxic skin eruptions have been reported in patients receiving REYATAZ. (See Contraindications.)
REYATAZ is principally metabolized by the liver; caution should be exercised when administering this drug to patients with hepatic impairment because atazanavir concentrations may be increased (see Dosage and Administration). Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, test for liver enzymes before initiating therapy with REYATAZ and monitor liver enzymes during treatment. REYATAZ should not be administered to patients with severe hepatic impairment. REYATAZ/ritonavir is not recommended for use in patients with hepatic impairment.
Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A [eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and phosphodiesterase (PDE5) inhibitors], or UGT1A1 (eg, irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.
Atazanavir is a weak inhibitor of CYP2C8. Caution should be used when REYATAZ without ritonavir is coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indicies (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected. See the complete prescribing information for NORVIR for information on other potential drug interactions with ritonavir. Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1 (see Drug Interactions).
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
REYATAZ should not be administered in pediatric patients below the age of 3 months due to the risk of kernicterus. The safety, pharmacokinetic profile, and virologic response of REYATAZ were evaluated in pediatric patients in an open-label, multicenter clinical trial PACTG 1020A. The safety profile in pediatric patients was comparable to that observed in adults (see Adverse Reactions). The safety, activity, and pharmacokinetic profiles of REYATAZ in pediatric patients ages 3 months to less than 6 years have not been established.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
In a fertility and early embryonic development study in rats, atazanavir altered estrus cycling with no effects on mating, fertility or early embryonic development. Systemic drug exposure levels were equal (in male rats) or two times (in female rats) those at the human clinical dose (400 mg/day).
It is not known whether atazanavir is secreted in human milk. A study in lactating rats demonstrated that atazanavir is secreted in milk. It is recommended that HIV infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving REYATAZ.
Storage and Stability
REYATAZ capsules should be stored at 25°C excursions permitted to 15-30°C. Protect from moisture.
Action and Clinical Pharmacology
Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with atazanavir 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.
Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200-800 mg once daily. Steady-state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold.
Figure 1 displays the mean plasma concentrations of atazanavir on Day 29 (steady state) following atazanavir 400 mg once daily (as two 200-mg capsules) with a light meal and after atazanavir 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.
| Parameter | 400 mg Once Daily | 300 mg with Ritonavir
100 mg Once Daily |
Healthy Subjects
(n=14) | HIV-Infected Patients
(n=13) | Healthy Subject
(n=28) | HIV-Infected Patients
(n=10) |
| Cmax (ng/mL) |
| Geometric mean (CV%) | 5199 (26) | 2298 (71) | 6129 (31) | 4422 (58) |
| Mean (SD) | 5358 (1371) | 3152 (2231) | 6450 (2031) | 5233 (3033) |
| Tmax (h) | | |
| Median | 2.5 | 2.0 | 2.7 | 3.0 |
| AUC (ng·h/mL) |
| Geometric mean (CV%) | 28132 (28) | 14874 (91) | 57039 (37) | 46073 (66) |
| Mean (SD) | 29303 (8263) | 22262 (20159) | 61435 (22911) | 53761 (35294) |
| T-half (h) |
| Mean (SD) | 7.9 (2.9) | 6.5 (2.6) | 18.1 (6.2)a | 8.6 (2.3) |
| Cmin (ng/mL) |
| Geometric mean (CV%) | 159 (88) | 120 (109) | 1227 (53) | 636 (97) |
| Mean (SD) | 218 (191) | 273 (298)b | 1441 (757) | 862 (838) |
a. n=26.
b. n=12.
A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 years) and elderly (n=30; ≥65 years) healthy subjects. There were no clinically important pharmacokinetic differences observed due to age or gender. There are insufficient data to determine whether there are any effects of race on the pharmacokinetics of atazanavir.
Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.
Studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolized by CYP3A4 isozyme to oxygenated metabolites, which are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation, hydrolysis and oxygenation with dehydrogenation.
Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity.
Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one half compared to the fasting state. Thus, REYATAZ is taken with food in order to enhance its bioavailability and reduce the pharmacokinetic variability.
Coadministration of REYATAZ and ritonavir with food optimizes the bioavailability of atazanavir. Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 total kcal, 5.1 g fat, 9.3 g protein and 63.3 g carbohydrates) 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. Coadministration with a high-fat meal (951 total kcal, 54.7 g fat, 35.9 g protein and 77.9 g carbohydrates) 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. Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.
Atazanavir is metabolized and eliminated primarily by the liver. Atazanavir has been studied in adult patients with moderate to severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in patients with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired patients was 12.1 hours compared to 6.4 hours in healthy volunteers. Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function. The pharmacokinetics of REYATAZ in combination with ritonavir have not been studied in subjects with hepatic impairment. REYATAZ should not be administered to patients with severe hepatic impairment. REYATAZ/ritonavir is not recommended for use in patients with hepatic impairment (see Warnings and Precautions and Dosage and Administration).
REYATAZ (atazanavir) is an azapeptide HIV-1 protease inhibitor. The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.
Concentration-and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (+/−SD) maximum change in PR interval from the pre-dose value was 24 (+ /−15 msec) following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (+11 msec) following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram (see Warnings and Precautions).
Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg and 800 mg were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient had a QTc interval >500 msec.
In healthy subjects, approximately 7% of the dose of atazanavir is eliminated unchanged in the urine. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age, weight, and gender matched subjects with normal renal function. Atazanavir was not appreciably cleared during hemodialysis. In a 4-hour dialysis session, 2.1% of the administered dose was removed. Subjects on hemodialysis appeared to display lower exposures as compared to healthy subjects and renally impaired subjects without hemodialysis. The geometric means for ATV AUC, Cmax and Cmin, for REYATAZ administered immediately following dialysis in subjects on hemodialysis (n=10) were 42%, 37% and 54% lower, respectively, relative to subjects with normal renal function. When REYATAZ was administered 2 hours before a 4 hour hemodialysis session, the geometric means for ATV AUC, Cmax and Cmin in hemodialysis subjects were 28%, 25% and 43% lower, respectively, than subjects with normal renal function. The mechanism of this decrease is unknown. (See Dosage and Administration.)
Mean (SD) Steady-state Plasma Concentrations of Atazanavir 400-mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-infected Adult Patients
Steady-State Pharmacokinetics of Atazanavir with Ritonavir in HIV Infected Pediatric Patients (6 to 18 years of age) in the Fed State
| | 205 mg/m2 Atazanavir with 100 mg/m2 Ritonavir Once Daily |
| Age Range (years) |
At least 6 to 13
(n=17) | At least 13 to 18
(n=10) |
| Dose mg | | |
Median
[min-max] | 200
[150–400] | 400
[250–500] |
| Cmax ng/mL | | |
| Geometric Mean (CV%) | 4451 (33) | 3711 (46) |
| AUC ng·h/mL | | |
| Geometric Mean (CV%) | 42 503 (36) | 44 970 (34) |
| Cmin ng/mL | | |
| Geometric Mean (CV%) | 535 (62) | 1090 (60) |
Contraindications
Patients with previously demonstrated clinically significant hypersensitivity (eg. Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any component of the product or container, including atazanavir. For a complete listing (see Dosage Forms, Composition and Packaging).
Coadministration of REYATAZ is contraindicated with drugs that are highly dependent on CYP3A4 and/or UGT1A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 1.
