Reyataz (Atazanavir)

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Dosage & administration

Reyataz prescribing information

in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder

[see Warnings and Precautions (5.2)]

when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).

when coadministered with drugs that are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance.

Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6:

•
Contraindications 4 CONTRAINDICATIONS REYATAZ is contraindicated:

Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
^aSee Drug Interactions, Table 16 (7) for parenterally administered midazolam. ^bSee Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA^®for erectile dysfunction.
Drug Class	Drugs within class that are contraindicated with REYATAZ
Alpha 1-adrenoreceptor antagonist	Alfuzosin
Anticonvulsants	Carbamazepine, phenobarbital, phenytoin
Antiarrhythmics	Amiodarone (with ritonavir), quinidine (with ritonavir)
Antimycobacterials	Rifampin
Antineoplastics	Apalutamide, encorafenib, irinotecan, ivosidenib
Antipsychotics	Lurasidone (with ritonavir), pimozide
Benzodiazepines	Orally administered midazolam^a, triazolam
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI Motility Agent	Cisapride
Hepatitis C Direct-Acting Antivirals	Elbasvir/grazoprevir; glecaprevir/pibrentasvir
Herbal Products	St. John’s wort ( Hypericum perforatum )
Lipid-Modifying Agents:	Lomitapide, lovastatin, simvastatin
Phosphodiesterase-5 (PDE-5) Inhibitor	Sildenafil^bwhen dosed as REVATIO^®for the treatment of pulmonary arterial hypertension
Protease Inhibitors	Indinavir
Non-nucleoside Reverse Transcriptase Inhibitors	Nevirapine

•In patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ. (4)
•Coadministration with drugs that are strong inducers of CYP3A, due to the potential for loss of therapeutic effect and development of resistance.
•Coadministration with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events.

12/2024

REYATAZ^® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg.

Limitations of Use:

•REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus
[see
8.4 Pediatric Use
REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1, 3 months of age and older weighing at least 5 kg. REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus
[see Indications and Usage (1)]
. All REYATAZ contraindications, warnings, and precautions apply to pediatric patients
[see Contraindications (4)and Warnings and Precautions (5)]
.
The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 5 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397
[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 (6.1)]
. See
Dosage and Administration (2.4
,
2.5)
for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients.
]
.

•Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions

[see

12.4 Microbiology

Mechanism of Action

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). 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.

Antiviral Activity in Cell Culture

Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC₅₀) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC₅₀values above the EC₅₀values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

Resistance

In Cell Culture:

HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies of Treatment-Naive Participants: Comparison of Ritonavir-Boosted REYATAZ vs Unboosted REYATAZ:

Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs REYATAZ 400 mg once daily when administered with lamivudine and extended-release stavudine in treatment-naive participants with HIV-1. A summary of the number of virologic failures and virologic failure isolates with atazanavir resistance in each arm is shown in Table 23.

Table 23: Summary of Virologic Failures^aat Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs Unboosted REYATAZ: Randomized Participants
^aVirologic failure includes participants who were never suppressed through Week 96 and on study at Week 96, had virologic rebound or discontinued due to insufficient viral load response. ^bPercentage of Virologic Failure Isolates with genotypic and phenotypic data. ^cMixture of I50I/L emerged in 2 other atazanavir 400 mg-treated participants. Neither isolate was phenotypically resistant to atazanavir.
	REYATAZ 300 mg with ritonavir 100 mg (n=95)	REYATAZ 400 mg (n=105)
Virologic Failure (≥50 copies/mL) at Week 96	15 (16%)	34 (32%)
Virologic Failure with Genotypes and Phenotypes Data	5	17
Virologic Failure Isolates with atazanavir-resistance at Week 96	0/5 (0%)^b	4/17 (24%)^b
Virologic Failure Isolates with I50L Emergence at Week 96^c	0/5 (0%)^b	2/17 (12%)^b
Virologic Failure Isolates with Lamivudine Resistance at Week 96	2/5 (40%)^b	11/17 (65%)^b

Clinical Studies of Treatment-Naive Participants Receiving REYATAZ 300 mg with Ritonavir 100 mg:

In Phase 3 Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from participants who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on atazanavir with ritonavir (n=39; 9%) and lopinavir/ritonavir (n=39; 9%) through 96 weeks of treatment. In the atazanavir with ritonavir arm, one of the virologic failure isolates had a 56-fold decrease in atazanavir susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two atazanavir with ritonavir-virologic failure isolates had baseline phenotypic atazanavir resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in atazanavir susceptibility from baseline and the other failure isolate with baseline atazanavir resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on atazanavir treatment associated with a 3-fold decrease in atazanavir susceptibility from baseline. Five of the treatment failure isolates in the atazanavir with ritonavir arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the lopinavir/ritonavir arm, one of the virologic failure participant isolates had a 69-fold decrease in lopinavir susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six lopinavir/ritonavir virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naive Participants Receiving REYATAZ 400 mg without Ritonavir:

atazanavir-resistant clinical isolates from treatment-naive participants who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of atazanavir therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive participants, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to atazanavir but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs.

Clinical Studies of Treatment-Experienced Participants:

In studies of treatment-experienced participants treated with atazanavir or atazanavir with ritonavir, most atazanavir-resistant isolates from participants who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of participants who failed treatment with atazanavir 300 mg once daily and ritonavir 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on atazanavir with ritonavir treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of participant isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the participant at baseline, atazanavir resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced participants experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on atazanavir treatment, but their presence did not correlate with the level of atazanavir resistance.

Clinical Studies of Pediatric Participants in AI424-397 (PRINCE I) and AI424-451 (PRINCE II):

Treatment-emergent atazanavir with ritonavir resistance-associated amino acid substitution M36I in the protease was detected in the virus of one participant among treatment failures in AI424-397. In addition, three known resistance-associated substitutions for other PIs arose in the viruses from one participant each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to atazanavir, ritonavir, or atazanavir with ritonavir was not seen with these viruses. In AI424-451, atazanavir with ritonavir resistance-associated substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two participants. The virus population harboring the M46M/V, V82V/I, I84I/V, and L90L/M substitutions acquired phenotypic resistance to ritonavir (ritonavir phenotypic fold-change of 3.5, with a ritonavir cutoff of 2.5-fold change). However, these substitutions did not result in phenotypic resistance to atazanavir (atazanavir phenotypic fold-change of <1.8, with an atazanavir cutoff of 2.2-fold change). Secondary PI resistance-associated amino acid substitutions also arose in the viruses of one participant each, including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged in the viruses of two participants who failed treatment with atazanavir with ritonavir. Viruses from nine participants in the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V (n=7), and T215I (n=1).

Cross-Resistance

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of PI-experienced participants showed that isolates cross-resistant to multiple PIs were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir 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 participants, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs.

Baseline Genotype/Phenotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir with ritonavir therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced participants receiving atazanavir with ritonavir once daily or lopinavir / ritonavir (fixed-dose product) twice daily in Study AI424-045 is shown in Table 24.

Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced participants. In the atazanavir with ritonavir group, participants had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to participants with 1–2 PI substitutions, including one of these substitutions.

Table 24: HIV RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Participants in Study AI424-045, As-Treated Analysis
^aPrimary substitutions include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90. ^bResults should be interpreted with caution because the subgroups were small. ^cAdministered as a fixed-dose product. ^dThere were insufficient data (n<3) for PI substitutions V32I, I47V, G48V, I50V, and F53L.
	Virologic Response = HIV-1 RNA <400 copies/mL^b
Number and Type of Baseline PI Substitutions^a	atazanavir with ritonavir (n=110)	lopinavir/ritonavir^c (n=113)
3 or more primary PI substitutions including^d:
D30N	75% (6/8)	50% (3/6)
M36I/V	19% (3/16)	33% (6/18)
M46I/L/T	24% (4/17)	23% (5/22)
I54V/L/T/M/A	31% (5/16)	31% (5/16)
A71V/T/I/G	34% (10/29)	39% (12/31)
G73S/A/C/T	14% (1/7)	38% (3/8)
V77I	47% (7/15)	44% (7/16)
V82A/F/T/S/I	29% (6/21)	27% (7/26)
I84V/A	11% (1/9)	33% (2/6)
N88D	63% (5/8)	67% (4/6)
L90M	10% (2/21)	44% (11/25)
Number of baseline primary PI substitutions^a
All patients, as-treated	58% (64/110)	59% (67/113)
0–2 PI substitutions	75% (50/67)	75% (50/67)
3–4 PI substitutions	41% (14/34)	43% (12/28)
5 or more PI substitutions	0% (0/9)	28% (5/18)

The response rates of antiretroviral-experienced participants in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select population with 62% of participants receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.

Table 25: Baseline Phenotype by Outcome, Antiretroviral-Experienced Participants in Study AI424-045, As-Treated Analysis
	Virologic Response = HIV-1 RNA <400 copies/mL^b
Baseline Phenotype^a	atazanavir with ritonavir (n=111)	lopinavir/ritonavir^c (n=111)
^aFold change susceptibility in cell culture relative to the wild-type reference. ^bResults should be interpreted with caution because the subgroups were small. ^cAdministered as a fixed-dose product.
0–2	71% (55/78)	70% (56/80)
>2–5	53% (8/15)	44% (4/9)
>5–10	13% (1/8)	33% (3/9)
>10	10% (1/10)	23% (3/13)

]

REYATAZ is contraindicated:

•in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder
[see
5.2 Severe Skin Reactions
In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of participants with HIV-1 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%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving REYATAZ
[see Contraindications (4)and Adverse Reactions (6.1)]
. REYATAZ should be discontinued if severe rash develops.
]
.
•when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).
•when coadministered with drugs that are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance.

Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6:

^a See

7 DRUG INTERACTIONS

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, 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. Use of REYATAZ without ritonavir is not recommended when 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 22 (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 ritonavir for information on drug interactions with ritonavir.

7.2 Potential for Other Drugs to Affect REYATAZ

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect (

see Table 16

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 REYATAZ

[see Dosage and Administration ( 2.3, 2.4, 2.5and

2.6)

]

7.3 Established and Other Potentially Significant Drug Interactions

Table 16 provides dosing recommendations in adults 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.

For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.

For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA.

REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA.

REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA.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 with ritonavir:

Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.

REYATAZ

: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions.

Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^aor 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
^aFor magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . ^bSee Contraindications (4), Table 6 for orally administered midazolam. ^cIn combination with atazanavir 300 mg with ritonavir 100 mg once daily. ^dIn combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules	↓ atazanavir ↓ didanosine	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 (DF)	↓ atazanavir ↑ tenofovir	When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.6) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz	↓ atazanavir	In HIV-treatment-naive adult patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended.
nevirapine	↓ atazanavir ↑ nevirapine	Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4)] .
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 DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2)] .
indinavir		Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4)] .
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 in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.
Others	↑ other protease inhibitor	Coadministration with other protease inhibitors is not recommended.
Hepatitis C Antiviral Agents
elbasvir/grazoprevir	↑ grazoprevir	Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4)] .
glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4)] .
voxilaprevir/sofosbuvir/velpatasvir	↑ voxilaprevir	Coadministration with REYATAZ is not recommended.
Other Agents
Alpha 1-Adrenoreceptor Antagonist: alfuzosin	↑ alfuzosin	Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4)] .
Antacids and buffered medications:	↓ atazanavir	REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications.
Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine	↑ amiodarone, bepridil, lidocaine (systemic), quinidine	Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] . Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir.
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 International Normalized Ratio (INR) be monitored.
Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban	↑ betrixaban ↑ dabigatran ↑ edoxaban	Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors.
rivaroxaban	REYATAZ with ritonavir ↑ rivaroxaban	Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding.
	REYATAZ ↑ rivaroxaban	Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban.
apixaban	REYATAZ with ritonavir ↑ apixaban	Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information.
	REYATAZ ↑ apixaban	Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ.
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	Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with 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.
Antiepileptics: carbamazepine	↓ atazanavir ↑ carbamazepine	Coadministration of REYATAZ (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)].
phenytoin, phenobarbital	↓ atazanavir ↓ phenytoin ↓ phenobarbital	Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)].
lamotrigine	↓ lamotrigine	Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals: ketoconazole, itraconazole	REYATAZ with ritonavir: ↑ ketoconazole ↑ itraconazole	Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C_max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir.
voriconazole	REYATAZ with ritonavir in participants with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ with ritonavir in participants without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir	The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.
Antigout: colchicine	↑ colchicine	The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult 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: rifampin	↓ atazanavir	Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)] .
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.
Antineoplastics: irinotecan	↑ irinotecan	Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4)] .
apalutamide	↓ atazanavir	Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4)] .
ivosidenib	↓ atazanavir ↑ ivosidenib	Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation.
encorafenib	↓ atazanavir ↑ encorafenib	Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation.
Antiplatelets:
ticagrelor	↑ ticagrelor	Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor.
clopidogrel	↓ clopidogrel active metabolite	Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel.
Antipsychotics: pimozide	↑ pimozide	Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
lurasidone	REYATAZ with ritonavir ↑ lurasidone	REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4)].
	REYATAZ ↑ lurasidone	REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.
quetiapine	↑ quetiapine	Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Benzodiazepines: midazolam (oral) triazolam	↑ midazolam ↑ triazolam	Coadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4)].
parenterally administered midazolam^b	↑ midazolam	Coadministration with parenteral midazolam 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.
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 diltiazem and REYATAZ with ritonavir has not been studied.
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.
Corticosteroids: dexamethasone and other corticosteroids (all routes of administration)	↓ atazanavir ↑ corticosteroids	Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information.
Endothelin receptor antagonists: bosentan	REYATAZ ↓ atazanavir REYATAZ with ritonavir ↑ bosentan	Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine	↑ ergot derivatives	Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)].
GI Motility Agents: cisapride	↑ cisapride	Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix	↓ atazanavir ↑ elagolix	Coadministration of elagolix and REYATAZ with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response.
Herbal Products: St. John’s wort (Hypericum perforatum)	↓ atazanavir	Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4)].
Kinase inhibitors: fostamatinib	↑ R406 (active metabolite of fostamatinib)	When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.
Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin	↑ lovastatin ↑ simvastatin	Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)].
atorvastatin, rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
Other Lipid Modifying Agents: lomitapide	↑ lomitapide	Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4)].
H₂ - Receptor antagonists	↓ atazanavir	Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult 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 (H2RA). An H2RA 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 H2RA. No single dose of the H2RA 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 use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA.
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone	↓ ethinyl estradiol ↑ norgestimate^c ↑ ethinyl estradiol ↑ norethindrone^d	Use caution if considering coadministration of oral contraceptives with REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, 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 with ritonavir and 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: cyclosporine, sirolimus, tacrolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ.
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 reactions 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 should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
	REYATAZ with ritonavir ↑ fluticasone	With concomitant use of fluticasone propionate and REYATAZ with ritonavir 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 with 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 with ritonavir and clarithromycin has not been studied.
Opioids: buprenorphine	REYATAZ or REYATAZ with ritonavir ↑ buprenorphine ↑ norbuprenorphine	Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.
	REYATAZ ↓ atazanavir	The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended.
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 reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO^®(sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4)] .
Proton-pump inhibitors: omeprazole	↓ atazanavir	Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) 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 HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended.

7.4 Drugs with No Observed Interactions with REYATAZ

No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine

[see Clinical Pharmacology, Tables 21 and 22 (12.3)]

for parenterally administered midazolam.

^b See

7 DRUG INTERACTIONS

7.1 Potential for REYATAZ to Affect Other Drugs

[see Clinical Pharmacology, Table 22 (12.3)]

7.2 Potential for Other Drugs to Affect REYATAZ

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect (

see Table 16

[see Dosage and Administration ( 2.3, 2.4, 2.5and

2.6)

]

7.3 Established and Other Potentially Significant Drug Interactions

For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.

REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA.

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^®:

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 with ritonavir:

Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.

REYATAZ

: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions.

Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^aor 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
^aFor magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . ^bSee Contraindications (4), Table 6 for orally administered midazolam. ^cIn combination with atazanavir 300 mg with ritonavir 100 mg once daily. ^dIn combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules	↓ atazanavir ↓ didanosine	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 (DF)	↓ atazanavir ↑ tenofovir	When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.6) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz	↓ atazanavir	In HIV-treatment-naive adult patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended.
nevirapine	↓ atazanavir ↑ nevirapine	Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4)] .
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 DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2)] .
indinavir		Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4)] .
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 in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.
Others	↑ other protease inhibitor	Coadministration with other protease inhibitors is not recommended.
Hepatitis C Antiviral Agents
elbasvir/grazoprevir	↑ grazoprevir	Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4)] .
glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4)] .
voxilaprevir/sofosbuvir/velpatasvir	↑ voxilaprevir	Coadministration with REYATAZ is not recommended.
Other Agents
Alpha 1-Adrenoreceptor Antagonist: alfuzosin	↑ alfuzosin	Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4)] .
Antacids and buffered medications:	↓ atazanavir	REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications.
Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine	↑ amiodarone, bepridil, lidocaine (systemic), quinidine	Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] . Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir.
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 International Normalized Ratio (INR) be monitored.
Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban	↑ betrixaban ↑ dabigatran ↑ edoxaban	Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors.
rivaroxaban	REYATAZ with ritonavir ↑ rivaroxaban	Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding.
	REYATAZ ↑ rivaroxaban	Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban.
apixaban	REYATAZ with ritonavir ↑ apixaban	Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information.
	REYATAZ ↑ apixaban	Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ.
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	Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with 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.
Antiepileptics: carbamazepine	↓ atazanavir ↑ carbamazepine	Coadministration of REYATAZ (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)].
phenytoin, phenobarbital	↓ atazanavir ↓ phenytoin ↓ phenobarbital	Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)].
lamotrigine	↓ lamotrigine	Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals: ketoconazole, itraconazole	REYATAZ with ritonavir: ↑ ketoconazole ↑ itraconazole	Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C_max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir.
voriconazole	REYATAZ with ritonavir in participants with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ with ritonavir in participants without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir	The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.
Antigout: colchicine	↑ colchicine	The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult 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: rifampin	↓ atazanavir	Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)] .
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.
Antineoplastics: irinotecan	↑ irinotecan	Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4)] .
apalutamide	↓ atazanavir	Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4)] .
ivosidenib	↓ atazanavir ↑ ivosidenib	Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation.
encorafenib	↓ atazanavir ↑ encorafenib	Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation.
Antiplatelets:
ticagrelor	↑ ticagrelor	Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor.
clopidogrel	↓ clopidogrel active metabolite	Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel.
Antipsychotics: pimozide	↑ pimozide	Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
lurasidone	REYATAZ with ritonavir ↑ lurasidone	REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4)].
	REYATAZ ↑ lurasidone	REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.
quetiapine	↑ quetiapine	Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Benzodiazepines: midazolam (oral) triazolam	↑ midazolam ↑ triazolam	Coadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4)].
parenterally administered midazolam^b	↑ midazolam	Coadministration with parenteral midazolam 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.
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 diltiazem and REYATAZ with ritonavir has not been studied.
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.
Corticosteroids: dexamethasone and other corticosteroids (all routes of administration)	↓ atazanavir ↑ corticosteroids	Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information.
Endothelin receptor antagonists: bosentan	REYATAZ ↓ atazanavir REYATAZ with ritonavir ↑ bosentan	Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine	↑ ergot derivatives	Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)].
GI Motility Agents: cisapride	↑ cisapride	Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix	↓ atazanavir ↑ elagolix	Coadministration of elagolix and REYATAZ with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response.
Herbal Products: St. John’s wort (Hypericum perforatum)	↓ atazanavir	Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4)].
Kinase inhibitors: fostamatinib	↑ R406 (active metabolite of fostamatinib)	When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.
Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin	↑ lovastatin ↑ simvastatin	Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)].
atorvastatin, rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
Other Lipid Modifying Agents: lomitapide	↑ lomitapide	Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4)].
H₂ - Receptor antagonists	↓ atazanavir	Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult 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 (H2RA). An H2RA 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 H2RA. No single dose of the H2RA 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 use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA.
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone	↓ ethinyl estradiol ↑ norgestimate^c ↑ ethinyl estradiol ↑ norethindrone^d	Use caution if considering coadministration of oral contraceptives with REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, 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 with ritonavir and 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: cyclosporine, sirolimus, tacrolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ.
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 reactions 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 should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
	REYATAZ with ritonavir ↑ fluticasone	With concomitant use of fluticasone propionate and REYATAZ with ritonavir 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 with 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 with ritonavir and clarithromycin has not been studied.
Opioids: buprenorphine	REYATAZ or REYATAZ with ritonavir ↑ buprenorphine ↑ norbuprenorphine	Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.
	REYATAZ ↓ atazanavir	The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended.
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 reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO^®(sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4)] .
Proton-pump inhibitors: omeprazole	↓ atazanavir	Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) 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 HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended.

7.4 Drugs with No Observed Interactions with REYATAZ

[see Clinical Pharmacology, Tables 21 and 22 (12.3)]

for sildenafil when dosed as VIAGRA^® for erectile dysfunction.

Drug Class

Drugs within class that are contraindicated with REYATAZ

Alpha 1-adrenoreceptor antagonist

Alfuzosin

Anticonvulsants

Carbamazepine, phenobarbital, phenytoin

Antiarrhythmics

Amiodarone (with ritonavir), quinidine (with ritonavir)

Antimycobacterials

Rifampin

Antineoplastics

Apalutamide, encorafenib, irinotecan, ivosidenib

Antipsychotics

Lurasidone (with ritonavir), pimozide

Benzodiazepines

Orally administered midazolam^a, triazolam

Ergot Derivatives

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

GI Motility Agent

Cisapride

Hepatitis C Direct-Acting Antivirals

Elbasvir/grazoprevir; glecaprevir/pibrentasvir

Herbal Products

St. John’s wort (

Hypericum perforatum

)

Lipid-Modifying Agents:

Lomitapide, lovastatin, simvastatin

Phosphodiesterase-5 (PDE-5) Inhibitor

Sildenafil^b when dosed as REVATIO^® for the treatment of pulmonary arterial hypertension

Protease Inhibitors

Indinavir

Non-nucleoside Reverse Transcriptase Inhibitors

Nevirapine

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