Drug interactions

Like other protease inhibitors, atazanavir (Reyataz) is metabolised through the cytochrome P450 system, and is a specific inhibitor of the CYP3A4 enzyme. This means that it may interact with a wide variety of drugs also metabolised through this pathway .

Many other drugs using the CYP3A4 enzyme should not be given with atazanavir, as their levels may be increased in the body. These include:

  • Alfuzosin

  • Astemizole

  • Bepridil

  • Cisapride

  • Colchicine in patients with renal or hepatic impairment
  • Ergotamine tartrate (Cafergot/Migril)
  • Flecainide acetate (Tambocor)
  • Fluticasone propionate (Flixotide)
  • Halofantrine
  • Hypericin (St John’s wort)
  • Lovastatin
  • Lumefantrine
  • Midazolam (Hypnovel)
  • Pimozide (Orap)
  • Propafenone (Arythmol)
  • Quinidine (Kinidin Durules)
  • Rifampicin (Rifadin / Rimactane)
  • Simvastatin (Zocor)
  • Terfenadine
  • Triazolam
  • Voriconazole (Vfend).

Atazanavir also inhibits P-glycoprotein and the multidrug resistance-associated protein, which pump foreign substances, including some drugs, out of cells. This could explain the observation that the blood disorders caused by many chemotherapy drugs are more severe in patients taking protease inhibitors.

When atazanavir is taken with drugs to treat acid reflux disease and related symptoms, the AUC of atazanavir decreases significantly. Studies have shown that taking atazanavir with proton-pump inhibitors such as omeprazole (Losec) and esomeprazole (Nexium) or H2-receptor blockers (e.g. ranitidine/Zantac and cimetidine/Dyspamet, Tagamet)) results in lowered blood atazanavir concentrations in HIV-negative patients.

Proton-pump inhibitors should not be used in treatment-experienced patients receiving atazanavir. In treatment-naive patients, the proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20mg and must be taken approximately 12 hours prior to the atazanavir/ritonavir 300/100mg dose.

According to the Bristol-Myers Squibb package insert, ARV-naive patients taking omeprazole (or other proton pump inhibitor drugs) with an atazanavir-containing regimen decrease atazanavir exposure by 30 to 65%. When use of the two drugs is unavoidable, the drugs should be taken 12 hours apart, close clinical monitoring is recommended, and an increase in the atazanavir dose to 400mg boosted with 100mg ritonavir is recommended.

In ARV-experienced patients on an atazanavir-containing regimen, the H2-receptor antagonist dose should not exceed the dose-equivalent of 20mg famotidine taken twice daily. Atazanavir and ritonavir should be administered simultaneously with, or at least 10 hours after, the H2-receptor antagonist.

This advisory was issued despite an earlier study carried out in HIV-positive patients that failed to show reduced atazanavir levels when combined with low-dose ritonavir.1 In that study, PPIs did not have a significant effect on the outcomes of antiretroviral therapy containing ritonavir-boosted atazanavir.2 The study investigators claim that the effects of omeprazole may be less important in patients with HIV because of possible reduced stomach acid levels. Differences in study design and variability in drug levels may have also led to confusion over the relationship between these drugs.3 [ref Regardless, current (as of July 2008) directives on co-administration of atazanavir with acid-reducing medications have now been made clear.

Atazanavir slows the clearance of saquinavir (Invirase), resulting in elevated levels of saquinavir.4 A double-boosted protease inhibitor regimen of atazanavir, saquinavir and ritonavir results in elevated levels of saquinavir and ritonavir and may be useful in salvage therapy.5 6 7

Atazanavir should not be taken with indinavir, since both drugs can cause elevated bilirubin levels. Although it has not been tested in human trials, taking both drugs together is expected to increase drug levels and the risk of this side-effect occurring. Nevirapine use is also not recommended with atazanavir.

When atazanavir is dosed with efavirenz (Sustiva), atazanavir levels are reduced by around 70%. Adding low-dose ritonavir counteracts this effect in HIV-negative volunteers, but a small study has found that this may not be the case in people with HIV.8 9 10 A similar effect of nevirapine has also been seen in a small study. Both drugs are CYP3A4 inducers, which means that they speed up metabolism of other drugs metabolised by the same route.10

Combining atazanavir with tenofovir (Viread) may put a patient at risk of treatment failure, since tenofovir can reduce atazanavir levels by up to 40%.11 12 Atazanavir can also increase the likelihood of tenofovir-associated adverse events, including kidney disorders. Doctors should consider boosting atazanavir levels with ritonavir, if atazanavir and tenofovir must be used together, although studies have shown that this is not always successful in restoring atazanavir levels.13 10

Given the poor results of the ACTG 5175 study arm looking at atazanavir with enteric-coated didanosine and emtricitabine, an alternative regimen is recommended.14 If this is the only treatment option, patients are advised to take the ec-ddI/FTC on an empty stomach and at least two hours before or after taking atazanavir with food.

Sildenafil is contraindicated when used for treatment of pulmonary arterial hypertension.

Some drugs require dose adjustments when taken with atazanavir. The following drugs need to be taken at lower doses:

  • Clarithromycin (Klaricid / Klaricid EC): the dose should be halved.
  • Diltiazem (Tildiem / Angiozem / Optil): the dose should be halved.
  • Rifabutin (Mycobutin): the dose should be reduced by up to 75% (150mg every day or three times a week) when atazanavir is dosed at 400mg once daily.15

Atazanavir has been observed to increase levels of the hormonal contraceptives ethinylestradiol and norethindrone. No guidance is available at present on appropriate dose reductions or interactions with other contraceptives. There have also been at least three case reports of elevated levels of buprenorphine, which is used to treat opiate addiction, in patients taking atazanavir.16 A dose reduction may be necessary. In contrast, no dose adjustment of methadone (Methadose) is needed.17

References

  1. Guiard-Schmid JB et al. Proton pump inhibitors do not reduce atazanavir concentrations in HIV-infected patients treated with ritonavir-boosted atazanavir. AIDS 19: 1937-1938, 2005
  2. Furtek KJ et al. Proton pump inhibitor therapy in atazanavir-treated patients: contraindicated? J Acquir Immune Defic Syndr 41: 394-395, 2006
  3. Guiard-Schmid JB et al. Lack of interaction between atazanavir and proton pump inhibitors in HIV-infected patients treated with ritonavir-boosted atazanavir. J Acquir Immune Defic Syndr 41: 393-394, 2006
  4. Haas DW et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS 17: 1339-1349, 2003
  5. von Hentig NH et al. The ATSAQ-1 cohort study: pharmacokinetic interactions of atazanavir (AZV) and saquinavir (SQV) in a ritonavir (RTV) boosted protease inhibitor therapy regimen. 15th International AIDS Conference, Bangkok, abstract WeOrB1235, 2004
  6. Boffito M et al. Atazanavir but not ritonavir impacts the elimination half-life of saquinavir hard gel in HIV+ subjects. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract A-452, 2004
  7. Boffito M et al. Pharmacokinetics of saquinavir hard-gel / ritonavir and atazanavir when combined once daily in HIV type 1-infected individuals administered different atazanavir doses. AIDS Res Hum Retroviruses 22: 749-756, 2006
  8. Tackett D et al. Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 543, 2003
  9. Poirier JM et al. Critical drug interaction between ritonavir-boosted atazanavir regimen and non-nucleoside reverse transcriptase inhibitors. AIDS 20: 1087-1089, 2006
  10. Dailly E et al. Influence of tenofovir, nevirapine and efavirenz on ritonavir-boosted atazanavir pharmacokinetics in HIV-infected patients. Eur J Clin Pharmacol 62: 523-526, 2006
  11. Kaul S et al. Pharmacokentic evaluation of the combination of atazanavir (ATV), enteric coated didanosine (ddI-EC), and tenofovir disoproxil fumarate (TDF) for a once-daily antiretroviral regimen. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract A-1616, 2003
  12. Agarwala S et al. Pharmacokinetic interaction between tenofovir and atazanavir in healthy subjects. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WePe3.3C07, 2005
  13. Taburet AM et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 48: 2091-2096, 2004
  14. National Institute of Allergy and Infectious Disease Monitoring Board recommends stopping experimental treatment regimen in international study of patients new to HIV treatment. NIAID Bulletin, available online at www3.niaid.nih.gov/news/newsreleases/2008/ACTG_5175 [accessed 28 October 2008], 2008
  15. Agarwala S et al. Pharmacokinetic (PK) effect of rifabutin (RIF) on atazanavir (ATV) with and without ritonavir (RTV) in healthy subjects. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 445, 2002
  16. Bruce RD et al. Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS 20: 783-784, 2006
  17. Friedland G et al. Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction. AIDS 19: 1635-1641, 2005
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