Immunodeficiency Clinic > Drug Interaction Guide
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Evotaz® (Atazanavir/Cobicistat) & Morphine [class:yellow]
Summary/Recommendation:
Monitor for signs/symptoms of opiate toxicity.
Data:
Potential for increased morphine and M6G concentrations via P-glycoprotein inhibition. Clinical significance unknown.
Coadministration of itraconazole 200 mg daily with oral morphine resulted in 22-29% increase in morphine AUC, likely via inhibition of intestinal P-glycoprotein.2723
Monitor for signs/symptoms of opiate toxicity.
Extensively metabolized by CYP3A4. Atazanavir inhibits CYP3A and UGT1A1 at clinically relevant concentrations. Atazanavir is a weak inhibitor of CYP2C8. Caution when unboosted atazanavir is coadministered with drugs that are 2C8 substrates with narrow therapeutic indices (e.g., paclitaxel, repaglinide); clinically significant interactions with 2C8 substrates are not expected when atazanavir is boosted with ritonavir.
Atazanavir does not inhibit CYP2C19 or CYP2E1 at clinically relevant concentrations.
Avoid concomitant administration with antacids, proton-pump inhibitors, or H2-blockers, as atazanavir absorption is significantly compromised.
Atazanavir is an inhibitor of CYP3A and UGT1A1. Atazanavir is a weak inhibitor of CYP2C8. With boosted atazanavir, ritonavir appears to induce CYP2C8 and offset inhibition by ATV.1463
Recommended Atazanavir and Ritonavir Dosage in Adults
Atazanavir Once Daily Dosage | Ritonavir Once Daily Dosage | |
Treatment-Naive Adult Patients | ||
recommended regimen | 300 mg | 100 mg |
unable to tolerate ritonavir | 400 mg | N/A |
in combination with efavirenz | 400 mg | 100 mg |
Treatment-Experienced Adult Patients | ||
recommended regimen | 300 mg | 100 mg |
in combination with both H2RA and tenofovir | 400 mg | 100 mg |
Recommended Dosage of Atazanavir and Ritonavir in Pregnant Patients
Atazanavir Once Daily Dosage | Ritonavir Once Daily Dosage | |
Treatment-Naive and Treatment-Experienced | ||
Recommended Regimen | 300 mg | 100 mg |
Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir | ||
In combination with either H2RA or tenofovir | 400 mg | 100 mg |
Atazanavir/cobocistat: 1 tablet (atazanavir 300mg, cobicistat 150mg) once daily with food.
Steady-state atazanavir concentrations in HIV-positive subjects after 400 mg QD administration with food:
Cmax 3152 ng/mL, Cmin 273 ng/mL, AUC 22262 ng.h/mL
Atazanavir plasma concentrations after 300/100 mg ritonavir QD: Cmax 5233 ng/mL, Cmin 862 ng/mL, AUC 53761 ng.h/mL
Atazanavir administered in a fixed-dose tablet (300 mg atazanavir/150 mg cobicistat) demonstrated bioequivalence to coadministration of the individual components when given with a light meal in healthy adult subjects.2892
10 HIV positive patients on ATV 400mg daily switched to ATV 200mg BID, atazanavir kinetics assessed at baseline and after 10 days of BID regimen. Atazanavir 200mg BID led to higher plasma Ctrough, lower Cmax and similar AUC compared to standard ATV 400mg daily dose.2910 2895
| Mean plasma levels | ATV 400 mg daily (Baseline) | ATV 200 mg BID | Mean plasma GM ratios (ATV 200 BID:ATV 400 mg QD) |
| Ctrough (ng/ml) | 138 | 305 | 2.19 |
| Cmax (ng/ml) | 2786 | 1314 | 0.48 |
| AUC24h (ng.h/ml) | 20780 | 16904 | 0.8 |
| Mean intracellular levels | ATV 400 mg daily (Baseline) | ATV 200 mg BID | Mean intracellular GM ratios (ATV 200 BID:ATV 400 mg QD) |
| Ctrough (ng/ml) | 465 | 2.93 | |
| Cmax (ng/ml) | 4058 | 1.27 | |
| AUC24h (ng.h/ml) | 35958 | 1.51 |
Increased bilirubin levels with BID regimen not clinically important. Atazanavir accumulates within the cell to a slightly greater extent versus plasma.
Open label, prospective, single center study to investigate kinetics of lower dose ATV/r. 22 Thai HIV infected adult patients suppressed on ATV/r 300mg/100mg daily were changed to 200mg/100mg daily (7 pts were also on TDF).
| Median | ATV/r 300/100mg at baseline | ATV/r 200mg/100mg at day 14 | p |
| AUC 0-12hr (mg.h/L) | 65.4 | 35.5 | < 0.001 |
| Cmax (mg/L) | 6.1 | 3.9 | < 0.001 |
| Cmin (mg/L) | 1 | 0.5 | < 0.001 |
No patients had subtherapeutic levels (< 0.15mg/L).2896 Results of ATV/r 200/100mg daily in Thai subjects comparable to Caucasian population on standard dose.2896
In 29 HIV-infected patients receiving atazanavir-based therapy (14 unboosted, 15 boosted), median intracellular atazanavir Ctrough concentrations were higher for boosted vs. unboosted atazanavir, and intracellular concentrations were higher than median plasma Ctrough:
| Median (+IQR) | Unboosted ATV | Boosted ATV | p |
| Plasma Ctrough (ng/mL) | 132 (111-184) | 543 (393-1081) | |
| Intracellular Ctrough (ng/mL) | 328 (168-440) | 1032 (819-3091) | 0.001 |
| p=0.001 | p=0.005 |
In 416 HIV-positive subjects on atazanavir-based regimens, routine atazanavir Ctrough was not significantly different between smokers (n=246) and non-/ex-smokers (n=170)2903. In healthy subjects taking either atazanavir or atazanavir/ritonavir, moderate tobacco use (up to 10 cigarettes per day) was not associated with a significant difference in atazanavir pharmacokinetics.2898
In 18 HIV-infected women on ≥ 6 months of cART (tenofovir, emtricitabine, atazanavir, and ritonavir) with plasma viral loads < 50 copies/mL, blood and cervicovaginal samples were collected twice weekly for three weeks following menses. The ratio of cervicovaginal to plasma drug concentrations (geometric mean) was 11.6 for emtricitabine (CI 8.1-16.6), 3.18 for tenofovir (CI 1.94-5.21), 2.59 for atazanavir (CI 1.81-3.71), and 1.52 for ritonavir (CI 1.04-2.23). HIV-1 RNA was detected in 14 cervicovaginal samples (13.7%, CI 7.7%-24.1%) from 8 (44%) women; all virus-positive samples had virus loads < 500 copies/10 mL CVL.2899
Atazanavir total and unbound concentrations were measured in HIV-positive subjects with compensated cirrhosis (n=8, median MELD 11, Child score A, n=7 or B n=1) and HIV-positive subjects without hepatic disease (n=3). In patients with compensated cirrhosis, total and unbound atazanavir concentrations were similar to controls and historical data.2900
A case report of a 37 year old HIV/HCV coinfected male (60 kg) who ingested 8700 mg atazanavir without ritonavir; last ritonavir 100 mg dose was taken ~24 hours prior to overdose. Transient elevation in total bilirubin and Scr and asymptomatic increases in PR and QTc intervals were observed at 24-48 hours post-overdose; values returned to baseline at one-month follow-up. Atazanavir plasma concentrations were 5400 ng/mL and 594 ng/mL at 22 and 62 hours post-overdose.2901
Atazanavir/cobicistat: In a trial where HIV-infected subjects (n=22) were instructed to take atazanavir 300 mg with cobicistat 150 mg once daily with food, the steady-state atazanavir Cmax, AUCtau and Ctau (mean ± SD) values were 3.9 ± 1.9 μg/ml, 46.1 ± 26.2 μg•hr/ml and 0.80 ± 0.72 μg/ml, respectively. Steady-state cobicistat Cmax, AUCtau and Ctau (mean ± SD) values were 1.5 ± 0.5 μg/ml, 11.1 ± 4.5 μg•hr/ml and 0.05 ± 0.07 μg/ml, respectively (n=22).2889
Parent: UGT. Active metabolite: morphine-6-glucuronide (renal). Morphine and morphine-6-glucuronide are also P-glycoprotein substrates.
Alternative Options: Interaction Check with Drugs from Similar Classes
HIV Protease Inhibitor with morphine
[yellow] 5
- Atazanavir (Reyataz®) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
- Prezcobix®(Darunavir/Cobicistat) (Darunavir/Cobicistat) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
- Lopinavir/Ritonavir (Lopinavir/Ritonavir) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
- Atazanavir/Ritonavir (Reyataz®, Norvir® ) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
- Darunavir/Ritonavir (Prezista®, Norvir®) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
Evotaz® with Opioid
[red] 2[yellow] 10[green] 4
- Evotaz® (Atazanavir/Cobicistat) & alfentanil (Alfenta®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & codeine (Codeine Contin®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & diphenoxylate (Lomotil®)[class:green]
- Evotaz® (Atazanavir/Cobicistat) & fentanyl (prescribed) (Duragesic®)[class:red]
- Evotaz® (Atazanavir/Cobicistat) & heroin [class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & hydrocodone (Hycodan®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & hydromorphone (Dilaudid, Jurnista®)[class:green]
- Evotaz® (Atazanavir/Cobicistat) & levomethadyl (LAAM) (Orlaam®)[class:red]
- Evotaz® (Atazanavir/Cobicistat) & loperamide (Imodium®)[class:green]
- Evotaz® (Atazanavir/Cobicistat) & meperidine (Demerol®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & Methadone (Metadol, Metadol-D, Methadose®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & oxycodone (Oxycontin, OxyNEO, Supeudol®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & propoxyphene (Darvon-N®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & tramadol (Ralivia, Tridural, Ultram, Zytram XL®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & sufentanil (Sufenta®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & remifentanil (Ultiva®)[class:green]
HIV Protease Inhibitor with morphine [yellow] 5
- Atazanavir (Reyataz®) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
- Prezcobix®(Darunavir/Cobicistat) (Darunavir/Cobicistat) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
- Lopinavir/Ritonavir (Lopinavir/Ritonavir) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
- Atazanavir/Ritonavir (Reyataz®, Norvir® ) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
- Darunavir/Ritonavir (Prezista®, Norvir®) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
Evotaz® with Opioid [red] 2[yellow] 10[green] 4
- Evotaz® (Atazanavir/Cobicistat) & alfentanil (Alfenta®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & codeine (Codeine Contin®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & diphenoxylate (Lomotil®)[class:green]
- Evotaz® (Atazanavir/Cobicistat) & fentanyl (prescribed) (Duragesic®)[class:red]
- Evotaz® (Atazanavir/Cobicistat) & heroin [class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & hydrocodone (Hycodan®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & hydromorphone (Dilaudid, Jurnista®)[class:green]
- Evotaz® (Atazanavir/Cobicistat) & levomethadyl (LAAM) (Orlaam®)[class:red]
- Evotaz® (Atazanavir/Cobicistat) & loperamide (Imodium®)[class:green]
- Evotaz® (Atazanavir/Cobicistat) & meperidine (Demerol®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & Methadone (Metadol, Metadol-D, Methadose®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & oxycodone (Oxycontin, OxyNEO, Supeudol®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & propoxyphene (Darvon-N®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & tramadol (Ralivia, Tridural, Ultram, Zytram XL®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & sufentanil (Sufenta®)[class:yellow]
- Evotaz® (Atazanavir/Cobicistat) & remifentanil (Ultiva®)[class:green]
Interaction Classification
- These Drugs should not be coadministered[class:red]
- Potential interaction - may require close monitoring, alteration of drug dosage or timing of administration[class:yellow]
- No clinically significant interaction expected[class:green]
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