Reyataz
(Atazanavir)Dosage & Administration
Reyataz Prescribing Information
Contraindications REYATAZ is contraindicated:
Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6:
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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 UseREYATAZ 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)]. SeeDosage 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 MicrobiologyMechanism of ActionAtazanavir (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 CultureAtazanavir 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.
ResistanceIn 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 Failuresaat 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 mgwithritonavir 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 96c
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-ResistanceCross-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 AnalysesGenotypic 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/mLbNumber and Type of Baseline PISubstitutionsaatazanavir with ritonavir(n=110)lopinavir/ritonavirc(n=113)3 or more primary PI substitutions includingd: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 substitutionsaAll 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/mLbBaseline Phenotypeaatazanavir with ritonavir(n=111)lopinavir/ritonavirc(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)
• 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.
• 50 mg of atazanavir as an oral powder in a packet.
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 ReactionsIn 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 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) 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. 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) ] .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.
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)] .b See 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) 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. 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) ] .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.
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)] . | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 midazolama, 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 | Sildenafilb when dosed as REVATIO® for the treatment of pulmonary arterial hypertension | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Protease Inhibitors | Indinavir | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Non-nucleoside Reverse Transcriptase Inhibitors | Nevirapine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||