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Labeling Changes for Atazanavir (Reyataz)

January 26, 2006

Updates to the REYATAZ (atazanavir sulfate) package insert were approved on January 25, 2006, to reflect new in vitro inhibition data and clinical drug-drug interaction information regarding coadministration of atazanavir and/or atazanavir/ritonavir with proton pump inhibitors, H2 receptor antagonists, methadone, rifampin, enteric-coated didanosine and tenofovir.


Summary of Label Changes

Clinical Pharmacology: Drug-Drug Interaction Section

The following text was added to this section.

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min-1 and Ki value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki = 1.9 µM) and CYP2C8 (Ki = 2.1 µM). REYATAZ should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A, UGT1A1, or CYP2C8 (see CONTRAINDICATIONS).

Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1.

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The following information was added to Table 4: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs


Coadministered DrugCoadministered Drug Dose/ScheduleREYATAZ Dose/ScheduleNRatio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00
    CmaxAUCCmin
ddI (enteric-coated [EC] capsules)c400 mg QD
d 8 (fed)
400 mg QD
d 2-8
341.03 (0.93, 1.14)0.99 (0.91, 1.08)0.98 (0.89, 1.08)
400 mg QD
d 19 (fed)
300 mg/ritonavir
100 mg QD d 9-19
311.04 (1.01, 1.07)1.00 (0.96, 1.03)0.87 (0.82, 0.92)
famotidine40 mg BID
d 7-12
400 mg QD
d 1-12 (simultaneous administration)
150.53 (0.34, 0.82)0.59 (0.40, 0.87)0.58 (0.37, 0.89)
omeprazole40 mg QD
d 7-12e
400 mg QD
d 1-12
160.04 (0.04, 0.05)0.06 (0.05, 0.07)0.05 (0.03, 0.07)
rifampin600 mg QD
d 17-26
300 mg QD/ritonavir 100 mg QD
d 7-26
160.47 (0.41, 0.53)0.28 (0.25, 0.32)0.02 (0.02, 0.03)

c. 400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19.

e. omeprazole was administered on an empty stomach 2 hours before REYATAZ.


The following information was added to Table 5: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZ


Coadministered DrugCoadministered Drug Dose/ScheduleREYATAZ Dose/ScheduleNRatio (90% Confidence Interval) of Coadministered Pharmacokinetic Parameters with/without Reyataz; No Effect = 1.00
    CmaxAUCCmin
ddI (enteric- coated [EC] capsules)c400 mg QD
d 1 (fasted), 8 (fed)
400 mg QD
d 2-8
340.64 (0.55, 0.74)0.66 (0.60, 0.74)1.13 (0.91, 1.41)
methadonestable maintenance dose
d 1-15
400 mg QD
d 2-15
16(R)-metha-doned 0.91 (0.84, 1.0)
total: 0.85 (0.78, 0.93)
(R)-metha-doned 1.03 (0.95, 1.10)
total: 0.94 (0.87, 1.02)
(R)-metha-doned 1.11 (1.02, 1.20)
total: 1.02 (0.93, 1.12)
omeprazolee40 mg single dose
d 7 and d 20
400 mg QD
d 1-12
161.24 (1.04, 1.47)1.45 (1.20, 1.76)NA
Tenofovir300 mg QD
d 1-7 (pm)
d 25-34 (pm)i
300 mg QD/ritonavir 100 mg qd
D 25-34 (am)i
121.34 (1.20, 1.51)1.37 (1.30, 1.45)1.29 (1.21, 1.36)

c. 400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19.

d. (R)-methadone is the active isomer of methadone.

e. omeprazole was used as a metabolic probe for CY2C19. Omperazole was given 2 hours after REYATAZ on Day 7; and was given alone 2 hours after a light meal on Day 20.

i. administration of tenofovir and REYATAZ was temporally separated by 12 hours.


Precautions: Drug Interactions

Information regarding atazanavir is an inhibitor of CYP2C8 was added. In addition the following text was added.

Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors (see Table 10), antacids, buffered medications, or H2-receptor antagonists (see Table 11) are administered with atazanavir. The following text was added or revised in Table 10 and 11:


Table 10: Drugs That Should Not Be Administered with Reyataz
Antimycobacterials: rifampinRifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.
Proton-Pump InhibitorsOmeprazole substantially decreases plasma concentrations of atazanavir. Concomitant use of proton-pump inhibitors and REYATAZ may result in loss of therapeutic effect and development of resistance.


Table 11: 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):
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules↓ atazanavir
↓ didanosine
Coadministration of REYATAZ with didanosine buffered tablets results in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 hr 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.
Antifungals: voriconazoleEffect is unknownCoadministration 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.
H2-Receptor antagonists↓ atazanavirPlasma 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 taking an H2-receptor antagonist, either of the following regimens may be used: REYATAZ 400 mg once daily with food at least 2 hours before and at least 10 hours after the H2-receptor antagonist OR REYATAZ 300 mg with ritonavir 100 mg once daily with food, without the need for separation from the H2-receptor antagonist.

In treatment-experienced patients, the following regimen should be used: REYATAZ 300 mg with ritonavir 100 mg once daily with food at least 2 hours before and at least 10 hours after the H2-receptor antagonist.


Additionally, the following text was added to the drug interaction section:

No clinically significant drug interaction was observed when REYATAZ was coadministered with methadone.


Dosage and Administration

The following text was included in this section:

Didanosine. When coadministered with didanosine buffered or enteric-coated formulations, REYATAZ should be given (with food) 2 hours before or 1 hour after didanosine.

H2-receptor antagonists.

Treatment-naive patients: REYATAZ 400 mg once daily with food at least 2 hours before and at least 10 hours after the H2-receptor antagonist OR REYATAZ 300 mg with ritonavir 100 mg once daily with food, without the need for separation from the H2-receptor antagonist.

Treatment-experienced patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food at least 2 hours before and at least 10 hours after the H2-receptor antagonist.



  
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