The non-nucleoside reverse transcriptase inhibitors (NNRTIs, also known as "non-nukes") are drugs that attach to the reverse transcriptase enzyme. They bind in a site that is somewhat different than the "nukes", but essentially do the same thing. Although they bind on the same enzyme as the nukes, because they bind on a different site, they are safely (and recommended to be) combined with the nukes. Once bound, the virus can no longer convert its genetic makeup into your T-cells, thus preventing the virus from replicating.
There are three drugs in this class: Sustiva (efavirenz, EFV), Viramune (nevirapine, NVP) and less used Rescriptor (delavirdine, DLV). These drugs have differences but also similarities. Table 1 shows some unique factors. The similarities of the NNRTI class will also be reviewed.
Sustiva and Reyataz -- Because Sustiva may decrease the AUC of Reyataz by 74% and Cmin by 93% (see ABCs of Pharmacokinetics), it is recommended that 100 mg of Norvir is given once daily with the Reyataz and Sustiva combination. Also, Reyataz will need to be decreased from the usual 400 mg daily to 300 mg daily when Norvir is added (see Protease Inhibitors). Because you need to take Reyataz with food, you may want to separate your dose of Reyataz/Norvir and Sustiva. If you cannot or you simply want to take them all together, make sure you don't have a high fat snack when you take these medicines, as this may increase the concentrations of Sustiva in your body and the chance for side effects (see Table No. 1).
Sustiva and Lexiva -- Sustiva will decrease Lexiva's Cmin by 36%. If you are taking Lexiva once daily, it is recommended to take 300 mg (3 capsules) of Norvir with the Lexiva (2 tablets). This is more Norvir than is recommended to be taken with Lexiva without Sustiva (see Protease Inhibitors). Total dose will be Lexiva 1400 mg + Norvir 300 mg once daily with or without food. Remember that if you decide to eat when taking this combination, eat a low-fat or no-fat snack. This only applies to once-daily dosing of this combination. No additional Norvir dosing is needed if you are taking boosted Lexiva twice daily (see Protease Inhibitors).
Sustiva and Kaletra -- Sustiva will lower the Cmin of Kaletra by 39%. Thus you need to add an extra capsule of Kaletra for a total of 4 pills twice daily with food. Since Sustiva should be taken on an empty stomach, it is best to separate these medications by at least 2 hours. Remember that if you decide to eat when taking this combination, eat a low-fat or no-fat snack.
Sustiva and Crixivan -- Sustiva lowers the AUC of Crixivan ranging from 33-46%, and Cmin ranging from 39-57%. You have to either increase the Crixivan dose to 1,000 mg every 8 hours or, more recommended, use 100 mg?200 mg of Norvir twice daily (Crixivan 800 mg + Norvir 100 mg?200 mg twice daily). The latter regimen allows you to go from three times daily to twice daily dosing (by adding Norvir). Your doctor will let you know if you should take the 100 mg or 200 mg dose. If you take Crixivan/Norvir and Sustiva at the same time, make sure you take it on an empty stomach, to avoid high Sustiva concentrations. If you want to take your Crixivan/Norvir with some food, it is best to separate it from the Sustiva by at least 2 hours. Remember that if you decide to eat when taking this combination, eat a low-fat or no-fat snack.
Sustiva and Invirase and Fortovase -- When you take Sustiva with this drug, it will decrease the AUC by 62%, thus you cannot use this without boosting it! For both Invirase and Fortovase, there are two dosing regimens: Invirase/Fortovase 400 mg + Norvir 400 mg given twice daily with food or Invirase/Fortovase 1,000 mg + Norvir 100 mg given twice daily with food. Your doctor may have you take more Norvir to make sure you have adequate Invirase/ Fortovase in your body. Since Sustiva should be taken on an empty stomach, it is best to separate the Invirase or Fortovase with Norvir from Sustiva by at least 2 hours. Remember that if you decide to eat when taking this combination, eat a low-fat or no-fat snack.
Viramune and Reyataz -- There are no conclusive data with this combination, but the drug concentration of Reyataz is expected to decrease due to the inducing effects of Viramune. Thus, at this time, it is recommended to boost 300 mg of Reyataz with 100 mg of Norvir (see Protease Inhibitors).
Viramune and Lexiva -- There are no data with this combination, but the drug concentration of Lexiva is expected to decrease due to the inducing effects of Viramune. Thus you will likely need to use a boosted regimen. While 700 mg Lexiva + 100 mg Norvir is commonly used, it is unknown if this will be sufficient to offset the interaction. This may be one of the times where TDM would be useful (see Protease Inhibitors).
Viramune and Kaletra -- Like the interaction with Sustiva, if you take Viramune and Kaletra, we can see a decrease in the Kaletra AUC by 27% and Cmin by 51-55%. Thus, you need more Kaletra! For this interaction, you should be taking Kaletra 4 capsules twice daily with food (533 mg/133 mg).
Viramune and Crixivan -- When you take these two drugs together, the Cmin of Crixivan is decreased by 44%, so you need a different dose. You either have to increase Crixivan to 1000 mg every 8 hours or add 100 mg?200 mg of Norvir twice daily (Crixivan 800 mg + Norvir 100 mg?200 mg twice daily). If you add Norvir, this interaction allows you to go from three times daily to twice-daily dosing, taken with or without food. Your doctor will decide which dose of Norvir you should be taking.
Viramune and Invirase or Fortovase -- With this interaction, the AUC of Invirase/Fortovase is decreased by 38%, thus boosting is needed with Norvir. The amount of Norvir depends on the drug (Invirase or Fortovase) and amount of drug used as listed below.
Your doctor may have you take more Invirase, Fortovase and/or Norvir to make sure you have adequate Invirase/ Fortovase in your body. Your doctor may also decide to use TDM to make sure you are getting adequate drug in your body.
Switching from Viramune to Sustiva: Take the full dose of Sustiva on the first day of the switch.
Again, talk to your clinical pharmacist or doctor on how to plan this switch.
The metabolism of NNRTIs makes it very important when it comes to the potential drug interactions. The last thing you'd want is to lower the concentration of your HIV meds and risk developing resistance. Always check with your doctor or pharmacist whenever you are prescribed a new medication.
Jean Lee, Pharm.D. is an HIV Clinical Pharmacist working at the McAuley Health Center, Saint Mary's Health Care in Grand Rapids, MI.
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