Atazanavir 200 MG Oral Capsule [Reyataz]
Generic Name: ATAZANAVIR SULFATE
Brand Name: REYATAZ
- Substance Name(s):
- ATAZANAVIR SULFATE
DRUG INTERACTIONS
7 See also Contraindications (4) and Clinical Pharmacology (12.3) .
Coadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir.
The potential drug-drug interactions must be considered prior to and during therapy.
(4, 5.1, 7, 12.3) 7.1 Potential for REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1.
Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 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 indices (eg, paclitaxel, repaglinide).
When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected.
[See Clinical Pharmacology, Table 14 (12.3) .] The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir.
See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir.
7.2 Potential for Other Drugs to Affect Atazanavir Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect.
Atazanavir solubility decreases as pH increases.
Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with atazanavir.
7.3 Established and Other Potentially Significant Drug Interactions Table 13 provides dosing recommendations as a result of drug interactions with REYATAZ.
These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment a For magnitude of interactions see Clinical Pharmacology, Tables 17 and 18 (12.3) .
b See Contraindications (4), Table 3 for orally administered midazolam.
c In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules ↓ atazanavir ↓ didanosine Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure.
It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations.
Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure.
Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate ↓ atazanavir ↑ tenofovir Tenofovir may decrease the AUC and Cmin of atazanavir.
When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food).
REYATAZ without ritonavir should not be coadministered with tenofovir.
REYATAZ increases tenofovir concentrations.
The mechanism of this interaction is unknown.
Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders.
Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events.
For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir Efavirenz decreases atazanavir exposure.
In treatment-naive patients: 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 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced patients: Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
Non-nucleoside Reverse Transcriptase Inhibitors: nevirapine ↓ atazanavir ↑ nevirapine Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure.
Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established.
In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
Protease Inhibitors: ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food.
See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir.
Protease Inhibitors: others ↑ other protease inhibitor REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor.
Such coadministration is not recommended.
Other Agents Antacids and buffered medications ↓ atazanavir Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ.
REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied.
Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied.
It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied.
Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone ↑ trazodone Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone.
Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir.
If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: ketoconazole, itraconazole REYATAZ/ritonavir: ↑ ketoconazole ↑ itraconazole Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax).
Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
Antifungals: voriconazole Effect is unknown Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied.
Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%.
Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available.
Antigout: colchicine ↑ colchicine REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment.
Recommended dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later.
Not to be repeated before 3 days.
Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterials: rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended.
Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolamb ↑ midazolam Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam.
Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.
Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted.
A dose reduction of diltiazem by 50% should be considered.
ECG monitoring is recommended.
Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
eg, felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted.
Dose titration of the calcium channel blocker should be considered.
ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan ↓ atazanavir ↑ bosentan Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir.
Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
Coadministration of bosentan in patients on REYATAZ/ritonavir: For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Coadministration of REYATAZ/ritonavir in patients on bosentan: Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir.
At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin ↑ atorvastatin ↑ rosuvastatin Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with or without ritonavir).
The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H2-Receptor antagonists ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
In treatment-naive patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist.
An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients.
OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist.
No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg.
However, REYATAZ should not be used without ritonavir in pregnant women.
In treatment-experienced patients: Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist.
For pregnant women taking REYATAZ with ritonavir and an H2-receptor antagonist, see Dosage and Administration (2.3) .
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.
For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H2-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol ↑ norgestimatec ↑ ethinyl estradiol ↑ norethindroned Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered.
If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol.
If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
Potential safety risks include substantial increases in progesterone exposure.
The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended.
Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone REYATAZ ↑ fluticasone 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.
REYATAZ/ritonavir ↑ fluticasone Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations.
Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate.
Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin ↑ 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 Mycobacterium avium complex.
Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine ↑ buprenorphine ↑ norbuprenorphine Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine.
Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects.
A dose reduction of buprenorphine may be considered.
Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations.
Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations.
REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Use of REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ].
The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ: Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir): For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily.
Increase to 40 mg once daily based on individual tolerability.
Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®: Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir).
Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir).
At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily.
Increase to 40 mg once daily based on individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
REYATAZ/ritonavir: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
REYATAZ: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
In treatment-naive patients: The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
In treatment-experienced patients: Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.
7.4 Drugs with No Observed or Predicted Interactions with REYATAZ Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1.
Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8.
See the complete prescribing information for NORVIR® for information on other potential drug interactions with ritonavir.
Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ (atazanavir sulfate) and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin.
REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).
Additionally, no clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, or atenolol.
[See Clinical Pharmacology, Tables 17 and 18 (12.3) .]
OVERDOSAGE
10 Human experience of acute overdose with REYATAZ is limited.
Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic untoward effects.
A single self-administered overdose of 29.2 g of REYATAZ in an HIV-infected patient (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular 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 PR interval prolongation may be observed.
[See Warnings and Precautions (5.2, 5.4) and Clinical Pharmacology (12.2) .] Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status.
If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage.
Administration of activated charcoal may also be used to aid removal of unabsorbed drug.
There is no specific antidote for overdose with REYATAZ.
Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.
DESCRIPTION
11 REYATAZ® (atazanavir sulfate) is an azapeptide inhibitor of HIV-1 protease.
The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1).
Its molecular formula is C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt).
The free base molecular weight is 704.9.
Atazanavir sulfate has the following structural formula: Atazanavir sulfate is a white to pale yellow crystalline powder.
It is slightly soluble in water (4–5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3° C.
REYATAZ Capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150 mg, 200 mg, or 300 mg of atazanavir as atazanavir sulfate and the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate.
The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue #2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide.
The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue #2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.
atazanavir sulfate chemical structure
CLINICAL STUDIES
14 14.1 Adult Patients Without Prior Antiretroviral Therapy Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir-emtricitabine in HIV-1 infected treatment-naive subjects.
Study AI424-138 is a 96-week open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination with fixed-dose tenofovir with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients.
Patients had a mean age of 36 years (range: 19–72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male.
The median baseline plasma CD4+ cell count was 204 cells/mm3 (range: 2 to 810 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL).
Treatment response and outcomes through Week 96 are presented in Table 22.
Table 22: Outcomes of Treatment Through Week 96 (Study AI424-138) Outcome REYATAZ 300 mg + ritonavir 100 mg (once daily) with tenofovir/emtricitabine (once daily)a (n=441) lopinavir 400 mg + ritonavir 100 mg (twice daily) with tenofovir/emtricitabine (once daily)a (n=437) 96 Weeks 96 Weeks a As a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.
b Patients achieved HIV RNA <50 copies/mL at Week 96.
Roche Amplicor®, v1.5 ultra-sensitive assay.
c Pre-specified ITT analysis at Week 48 using as-randomized cohort: ATV/RTV 78% and LPV/RTV 76% [difference estimate: 1.7% (95% confidence interval: −3.8%, 7.1%)].
d Pre-specified ITT analysis at Week 96 using as-randomized cohort: ATV/RTV 74% and LPV/RTV 68% [difference estimate: 6.1% (95% confidence interval: 0.3%, 12.0%)].
e Includes viral rebound and failure to achieve confirmed HIV RNA <50 copies/mL through Week 96.
f Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
Responderb,c,d 75% 68% Virologic failuree 17% 19% Rebound 8% 10% Never suppressed through Week 96 9% 9% Death 1% 1% Discontinued due to adverse event 3% 5% Discontinued for other reasonsf 4% 7% Through 96 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ/ritonavir (165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms.
At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm3 for the REYATAZ/ritonavir arm and 273 cells/mm3 for the lopinavir/ritonavir arm.
Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine + zidovudine twice daily.
Study AI424-034 was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients.
Patients had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male.
The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range: 2.2 to 5.9 log10 copies/mL).
Treatment response and outcomes through Week 48 are presented in Table 23.
Table 23: Outcomes of Randomized Treatment Through Week 48 (Study AI424-034) Outcome REYATAZ 400 mg once daily + lamivudine + zidovudined efavirenz 600 mg once daily + lamivudine + zidovudined (n=405) (n=405) a Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.
Roche Amplicor® HIV-1 Monitor™ Assay, test version 1.0 or 1.5 as geographically appropriate.
b Includes viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48.
c Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
d As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Respondera 67% (32%) 62% (37%) Virologic failureb 20% 21% Rebound 17% 16% Never suppressed through Week 48 3% 5% Death – <1% Discontinued due to adverse event 5% 7% Discontinued for other reasonsc 8% 10% Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms.
The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the REYATAZ arm and 160 cells/mm3 for the efavirenz arm.
Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily.
Study AI424-008 was a 48-week, randomized, multicenter trial, blinded to dose of REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive patients.
Patients had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male.
The mean baseline CD4+ cell count was 295 cells/mm3 (range: 4 to 1003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log10 copies/mL (range: 1.8 to 5.9 log10 copies/mL).
Treatment response and outcomes through Week 48 are presented in Table 24.
Table 24: Outcomes of Randomized Treatment Through Week 48 (Study AI424-008) Outcome REYATAZ 400 mg once daily + lamivudine + stavudine (n=181) nelfinavir 1250 mg twice daily + lamivudine + stavudine (n=91) a Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.
Roche Amplicor® HIV-1 Monitor™ Assay, test version 1.0 or 1.5 as geographically appropriate.
b Includes viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48.
c Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
Respondera 67% (33%) 59% (38%) Virologic failureb 24% 27% Rebound 14% 14% Never suppressed through Week 48 10% 13% Death <1% – Discontinued due to adverse event 1% 3% Discontinued for other reasonsc 7% 10% Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the REYATAZ 400-mg arm and 211 cells/mm3 for the nelfinavir arm.
14.2 Adult Patients With Prior Antiretroviral Therapy Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir + one NRTI.
Study AI424-045 is an ongoing, randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir + ritonavir (400/100 mg twice daily), each in combination with tenofovir and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART regimens containing PIs, NRTIs, and NNRTIs.
The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 283 weeks for NRTIs, and 85 weeks for NNRTIs.
The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male.
The mean baseline CD4+ cell count was 338 cells/mm3 (range: 14 to 1543 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).
Treatment outcomes through Week 48 for the REYATAZ/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 25.
REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level.
Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection.
[See Clinical Pharmacology, Tables 20 and 21 (12.4) .] Table 25: Outcomes of Treatment Through Week 48 in Study AI424-045 (Patients with Prior Antiretroviral Experience) Outcome REYATAZ 300 mg + ritonavir 100 mg once daily + tenofovir + 1 NRTI lopinavir/ritonavir (400/100 mg) twice daily + tenofovir + 1 NRTI Differencea (REYATAZ-lopinavir/ritonavir) (n=119) (n=118) (CI) a Time-averaged difference through Week 48 for HIV RNA; Week 48 difference in HIV RNA percentages and CD4+ mean changes, REYATAZ/ritonavir vs lopinavir/ritonavir; CI = 97.5% confidence interval for change in HIV RNA; 95% confidence interval otherwise.
b Roche Amplicor® HIV-1 Monitor™ Assay, test version 1.5.
c Protocol-defined primary efficacy outcome measure.
d Based on patients with baseline and Week 48 CD4+ cell count measurements (REYATAZ/ritonavir, n=85; lopinavir/ritonavir, n=93).
e Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48.
HIV RNA Change from Baseline (log10 copies/mL)b −1.58 −1.70 +0.12c (−0.17, 0.41) CD4+ Change from Baseline (cells/mm3)d 116 123 −7 (−67, 52) Percent of Patients Respondinge HIV RNA <400 copies/mLb 55% 57% -2.2% (−14.8%, 10.5%) HIV RNA <50 copies/mLb 38% 45% −7.1% (−19.6%, 5.4%) No patients in the REYATAZ/ritonavir treatment arm and three patients in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.
In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ 400 mg with saquinavir (n=115) was −1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33.
The corresponding mean increase in CD4+ cell count was 72 cells/mm3.
Through 48 weeks of treatment, the proportion of patients in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%).
In this study, coadministration of REYATAZ and saquinavir did not provide adequate efficacy [see Drug Interactions (7) ].
Study AI424-045 also compared changes from baseline in lipid values.
[See Adverse Reactions (6.1).] Study AI424-043: Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior PI-containing regimen.
Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for patients randomized to REYATAZ (n=144) and 69% (53%) for patients randomized to lopinavir/ritonavir (n=146).
The mean change from baseline was −1.59 log10 copies/mL in the REYATAZ treatment arm and −2.02 log10 copies/mL in the lopinavir/ritonavir arm.
Based on the results of this study, REYATAZ without ritonavir is inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is not recommended for such patients.
14.3 Pediatric Patients Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial PACTG 1020A conducted in patients from 3 months to 21 years of age.
In this study, 193 patients (86 antiretroviral-naive and 107 antiretroviral-experienced) received once daily REYATAZ, with or without ritonavir, in combination with two NRTIs.
One-hundred and five patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated.
Using an ITT analysis, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively.
The overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively.
The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naive patients and 220 cells/mm3 in antiretroviral-experienced patients.
HOW SUPPLIED
16 /STORAGE AND HANDLING REYATAZ® (atazanavir sulfate) Capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.
Product Strength* Capsule Shell Color (cap/body) Markings on Capsule (ink color) Capsules per Bottle NDC Number cap body 150 mg blue/powder blue BMS 150 mg (white) 3624 (blue) 60 54868-4857-0 300 mg red/blue BMS 300 mg (white) 3622 (white) 30 54868-5838-0 * atazanavir equivalent as atazanavir sulfate.
REYATAZ (atazanavir sulfate) Capsules should be stored at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) [see USP Controlled Room Temperature].
RECENT MAJOR CHANGES
Dosage and Administration (2.2) 10/2011 Dosage and Administration (2.3) 02/2011
GERIATRIC USE
8.5 Geriatric 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.
Based on a comparison of mean single-dose pharmacokinetic values for Cmax and AUC, a dose adjustment based upon age is not recommended.
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.
DOSAGE FORMS AND STRENGTHS
3 100 mg capsule with blue cap and white body, printed with white ink “BMS 100 mg” on the cap and with blue ink “3623” on the body.
150 mg capsule with blue cap and powder blue body, printed with white ink “BMS 150 mg” on the cap and with blue ink “3624” on the body.
200 mg capsule with blue cap and blue body, printed with white ink “BMS 200 mg” on the cap and with white ink “3631” on the body.
300 mg capsule with red cap and blue body, printed with white ink “BMS 300 mg” on the cap and with white ink “3622” on the body.
Capsules: 100 mg, 150 mg, 200 mg, 300 mg.
(3, 16)
MECHANISM OF ACTION
12.1 Mechanism of Action Atazanavir is an antiviral drug [see Clinical Pharmacology (12.4) ].
INDICATIONS AND USAGE
1 REYATAZ® (atazanavir sulfate) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from controlled studies of 96 weeks duration in antiretroviral-naive and 48 weeks duration in antiretroviral-treatment-experienced adult and pediatric patients at least 6 years of age.
The following points should be considered when initiating therapy with REYATAZ: In Study AI424-045, REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level.
This study was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection [see Clinical Studies (14.2) ].
The number of baseline primary protease inhibitor mutations affects the virologic response to REYATAZ/ritonavir [see Clinical Pharmacology (12.4) ].
REYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.
(1)
PEDIATRIC USE
8.4 Pediatric Use REYATAZ should not be administered to pediatric patients below the age of 3 months due to the risk of kernicterus.
The safety, activity, and pharmacokinetic profiles of REYATAZ in pediatric patients ages 3 months to less than 6 years have not been established.
The safety, pharmacokinetic profile, and virologic response of REYATAZ were evaluated in pediatric patients in an open-label, multicenter clinical trial PACTG 1020A [see Clinical Pharmacology (12.3) and Clinical Studies (14.3) ].
The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions (6.2) ].
Please see Dosage and Administration (2.2) for dosing recommendations for pediatric patients 6 years of age and older.
PREGNANCY
8.1 Pregnancy Pregnancy Category B Antiretroviral Pregnancy Registry: 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.
Risk Summary Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum.
Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate.
However, because the studies in humans cannot rule out the possibility of harm, REYATAZ should be used during pregnancy only if clearly needed.
Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues.
Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome.
Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including pregnant women.
All infants, including neonates exposed to REYATAZ in-utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.
Clinical Considerations Dosing During Pregnancy and the Postpartum Period: REYATAZ should not be administered without ritonavir.
REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions: For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended.
There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
No dose adjustment is required for postpartum patients.
However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.
[See Dosage and Administration (2, 2.3) and Clinical Pharmacology (12.3) .] Human Data Clinical Trials: In clinical trial AI424-182, REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester.
Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery.
Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times the upper limit of normal).
There were no cases of lactic acidosis observed in clinical trial AI424-182.
Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12–19% of maternal concentrations.
Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum.
All 40 infants received antiretroviral prophylactic treatment containing zidovudine.
No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study.
However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.
Lack of ethnic diversity was a study limitation.
In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians.
In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).
Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of <40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.
Antiretroviral Pregnancy Registry Data : As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively).
Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure).
Among pregnant women in the U.S.
reference population, the background rate of birth defects is 2.7%.
There was no association between atazanavir and overall birth defects observed in the APR.
Pharmacokinetics of Atazanavir in Pregnancy [See Clinical Pharmacology (12.3) .] Animal Data In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir).
In pre- and post-natal development studies in the rat, atazanavir caused body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose.
However, maternal toxicity also occurred at this exposure level.
NUSRING MOTHERS
8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
It is not known whether atazanavir is present in human milk.
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 taking REYATAZ.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Cardiac conduction abnormalities: PR interval prolongation may occur in some patients.
Use with caution in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval.
(5.2, 6.4, 7.3, 12.2, 17.3) Rash: Discontinue if severe rash develops.
(5.3, 6.4, 17.4) Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation.
Do not dose reduce.
If a concomitant transaminase increase occurs, evaluate for alternative etiologies.
(5.4, 6.2) Hepatotoxicity: REYATAZ should be used with caution in patients with hepatic impairment (5.5).
Patients with hepatitis B or C infection are at risk of increased transaminases or hepatic decompensation.
Monitor hepatic laboratory tests prior to therapy and during treatment.
(2.5, 5.5, 6.3, 6.4, 8.8) Nephrolithiasis has been reported.
Consider temporary interruption or discontinuation.
(5.6, 6.4) Patients receiving REYATAZ may develop new onset or exacerbations of diabetes mellitus/hyperglycemia (5.7, 6.4), immune reconstitution syndrome (5.8), and redistribution/accumulation of body fat.
(5.9) Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required.
(5.10) 5.1 Drug Interactions See Table 3 for a listing of drugs that are contraindicated for use with REYATAZ due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity.
[See Contraindications (4) .] Please refer to Table 13 for established and other potentially significant drug interactions [see Drug Interactions (7.3) ].
5.2 Cardiac Conduction Abnormalities 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 generally limited to first-degree AV block.
There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.4) and Overdosage (10) ].
In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329).
In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements.
Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), atazanavir should be used with caution in these patients.
[See Clinical Pharmacology (12.2) .] Atazanavir in combination with diltiazem increased diltiazem plasma concentration by 2-fold with 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, no clinically significant additive effect of atazanavir and atenolol on the PR interval was observed.
Dose adjustment of atenolol is not required when used in combination with atazanavir.
[See Drug Interactions (7) and Clinical Pharmacology (12.2) .] Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers [other than atenolol, see Drug Interactions (7) ], 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 CYP3A (eg, verapamil).
5.3 Rash 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 7.3 weeks and the median duration of rash was 1.4 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 (6.1) ].
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 (4) .] 5.4 Hyperbilirubinemia Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT).
This hyperbilirubinemia is reversible upon discontinuation of REYATAZ.
Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies.
No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times ULN.
Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents 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 (6.1, 6.2) .] 5.5 Hepatotoxicity Caution should be exercised when administering REYATAZ to patients with hepatic impairment because atazanavir concentrations may be increased.
[See Dosage and Administration (2.5) .] Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation.
In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment.
[See Adverse Reactions (6.3) and Use in Specific Populations (8.8) .] 5.6 Nephrolithiasis Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-infected patients receiving REYATAZ 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.
[See Adverse Reactions (6.4) .] 5.7 Diabetes Mellitus/Hyperglycemia New-onset diabetes mellitus, exacerbation of preexisting 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.
[See Adverse Reactions (6.4) .] 5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ.
During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
5.9 Fat Redistribution 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.
5.10 Hemophilia 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.
5.11 Resistance/Cross-Resistance Various degrees of cross-resistance among protease inhibitors have been observed.
Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors.
[See Clinical Pharmacology (12.4) .]
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).
A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with REYATAZ.
Patients should be informed that REYATAZ is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease.
Patients should be told that there are currently no data demonstrating that therapy with REYATAZ can reduce the risk of transmitting HIV to others through sexual contact.
17.1 Dosing Instructions Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.
Patients should remain under the care of a physician while using REYATAZ.
Patients should be advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed.
REYATAZ must always be used in combination with other antiretroviral drugs.
Patients should not alter the dose or discontinue therapy without consulting with their doctor.
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.
17.2 Drug Interactions REYATAZ may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St.
John’s wort.
Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, syncope, visual disturbances, and priapism, and should promptly report any symptoms to their doctor.
Patients should be informed that REVATIO® (used to treat pulmonary arterial hypertension) is contraindicated with REYATAZ and that dose adjustments are necessary when REYATAZ is used with CIALIS®, LEVITRA® or VIAGRA® (used to treat erectile dysfunction), or ADCIRCA® (used to treat pulmonary arterial hypertension).
17.3 Cardiac Conduction Abnormalities Patients should be informed that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation).
Patients should consult their physician if they are experiencing symptoms such as dizziness or lightheadedness.
17.4 Rash Patients should be informed that mild rashes without other symptoms have been reported with REYATAZ use.
These rashes go away within two weeks with no change in treatment.
However, there have been a few reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by one or more of the following: fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must discontinue REYATAZ and seek medical evaluation immediately.
17.5 Hyperbilirubinemia Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ.
This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns.
17.6 Fat Redistribution Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
It is unknown whether long-term use of REYATAZ will result in a lower incidence of lipodystrophy than with other protease inhibitors.
DOSAGE AND ADMINISTRATION
2 General Dosing Recommendations: REYATAZ Capsules must be taken with food.
Do not open the capsules.
The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs.
When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.1) ].
When coadministered with didanosine buffered or enteric-coated formulations, REYATAZ should be given (with food) 2 hours before or 1 hour after didanosine.
REYATAZ without ritonavir is not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14) ].
Efficacy and safety of REYATAZ with ritonavir in doses greater than 100 mg once daily have not been established.
The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended.
Prescribers should consult the complete prescribing information for NORVIR® (ritonavir) when using this agent.
Treatment-naive patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food.
When coadministered with tenofovir, the recommended dose is REYATAZ 300 mg with ritonavir 100 mg.
(2.1) Treatment-experienced patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food.
(2.1) Pediatric patients (6 to less than 18 years of age): Dosage is based on body weight not to exceed the adult dose.
(2.2) Pregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications.
(2.3) Concomitant therapy: Dosing modifications may be required.
(2.1, 7) Renal impairment: Dosing modifications may be required.
(2.4) Hepatic impairment: Dosing modifications may be required.
(2.5) 2.1 Recommended Adult Dosage Table 1 summarizes the recommended REYATAZ dosing regimen in adults.
All REYATAZ dosing regimens are to be administered as a single dose with food.
Table 1: REYATAZ Dosing Regimens Treatment-Naive Patients REYATAZ 300 mg with ritonavir 100 mg once daily If unable to tolerate ritonavir REYATAZ 400 mg once daily When combined with any of the following: Tenofovir H2-receptor antagonist Proton-pump inhibitor REYATAZ 300 mg with ritonavir 100 mg once daily • The H2-receptor antagonist dose should not exceed a dose comparable to famotidine 40 mg twice daily.
Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the H2-receptor antagonist.
• If unable to tolerate ritonavir, administer REYATAZ 400 mg once daily at least 2 hours before and at least 10 hours after the H2-receptor antagonist.
No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg and the total daily dose should not exceed a dose comparable to famotidine 40 mg.
• The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg daily and must be taken approximately 12 hours prior to REYATAZ and ritonavir.
When combined with efavirenz REYATAZ 400 mg with ritonavir 100 mg once daily • Efavirenz should be administered on an empty stomach, preferably at bedtime.
Treatment-Experienced Patients REYATAZ 300 mg with ritonavir 100 mg once daily Do not coadminister with proton-pump inhibitors or efavirenz in treatment-experienced patients.
When given with an H2-receptor antagonist REYATAZ 300 mg with ritonavir 100 mg once daily • The H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily.
Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the H2-receptor antagonist.
When given with both tenofovirand an H2-receptor antagonist REYATAZ 400 mg with ritonavir 100 mg once daily • The H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily.
Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the H2-receptor antagonist.
[For these drugs and other antiretroviral agents for which dosing modification may be appropriate, see Drug Interactions (7) .] 2.2 Recommended Pediatric Dosage The recommended daily 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 any pediatric patient less than 13 years of age, and (3) patients less than 40 kg receiving concomitant tenofovir, H2-receptor antagonists, or proton-pump inhibitors.
The recommended dosage of REYATAZ with ritonavir in pediatric patients at least 6 years of age is shown in Table 2.
Table 2: Dosage for Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavira Body Weight REYATAZ dose ritonavir dose a The REYATAZ and ritonavir dose should be taken once daily with food.
15 kg to less than 20 kg 150 mg 100 mg 20 kg to less than 40 kg 200 mg 100 mg at least 40 kg 300 mg 100 mg For treatment-naive patients at least 13 years of age and at least 40 kg, who are unable to tolerate ritonavir, the recommended dose is REYATAZ 400 mg (without ritonavir) once daily with food.
For patients at least 13 years of age and at least 40 kg receiving concomitant tenofovir, H2-receptor antagonists, or proton-pump inhibitors, REYATAZ should not be administered without ritonavir.
2.3 Pregnancy Dosing During Pregnancy and the Postpartum Period: REYATAZ should not be administered without ritonavir.
REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions: For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended.
There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
No dose adjustment is required for postpartum patients.
However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.
[See Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) .] 2.4 Renal Impairment 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 should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis.
[See Use in Specific Populations (8.7) .] 2.5 Hepatic Impairment 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 (5.5) and Use in Specific Populations (8.8).]