indication

For use in combination treatment of HIV infection (AIDS)

pharmacology

Efavirenz (dideoxyinosine, ddI) is an oral nucleoside reverse transcriptase inhibitor (NRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection.

mechanism of action

Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity.

biotransformation

Efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1.

half life

40-55 hours

route of elimination

Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites.

drug interactions

Alprazolam: The antiviral agent, efavirenz, may increase the effect and toxicity of the benzodiazepine, alprazolam.

Astemizole: Increased risk of cardiotoxicity and arrhythmias

Atazanavir: Efavirenz decreases the levels/effects of atazanavir

Atorvastatin: Efavirenz may decrease the serum concentration of atorvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if efavirenz is initiated, discontinued or dose changed.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clarithromycin: Efavirenz decreases levels of clarithromycin

Cyclosporine: Efavirenz decreases the levels of cyclosporine

Dihydroergotamine: Efavirenze may increase the adverse/toxic effects of dihydroergotamine. Concomitant therapy is contraindicated.

Dihydroergotoxine: The antiretroviral agent may increase the ergot derivative toxicity

Ergotamine: The antiretroviral agent may increase the ergot derivative toxicity

Indinavir: Efavirenz decreases the effect of indinavir

Lovastatin: Efavirenz may decrease the serum concentration of lovastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if efavirenz is initiated, discontinued or dose changed.

Methadone: Efavirenz may decrease the serum concentration of methadone by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of methadone if efavirenz is initiated, discontinued or dose changed.

Methylergonovine: The antiretroviral agent may increase the ergot derivative toxicity

Methysergide: The antiretroviral agent may increase the ergot derivative toxicity

Midazolam: The antiviral agent, efavirenz, may increase the effect and toxicity of the benzodiazepine, midazolam.

Saquinavir: Efavirenz decreases the effect of saquinavir

Simvastatin: Efavirenz may decrease the serum concentration of simvastatin. Monitor for changes in the therapeutic and adverse effects of simvastatin if efavirenz is initiated, discontinued or dose changed.

St. John's Wort: St. John's Wort decreases the antiretroviral effect

Tamsulosin: Efavirenz, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Efavirenz is initiated, discontinued, or dose changed.

Telithromycin: Efavirenz may decrease the plasma concentration of Telithromycin. Consider alternate therapy.

Temsirolimus: Efavirenz may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Tipranavir: Efavirenz may alter the serum concentration Tipranavir. Monitor for changes in Tipranavir therapeutic and adverse effects if Efavirenz is initiated, discontinued or dose changed.

Tolterodine: Efavirenz may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Tramadol: Efavirenz may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inhibitor and inducer, Efavirenz, may alter Trazodone efficacy/toxicity by altering Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Efavirenz is initiated, discontinued or dose changed.

Triazolam: The antiviral agent, efavirenz, may increase the effect and toxicity of the benzodiazepine, triazolam.

Voriconazole: Efavirenze may decrease the serum concentration of voriconazole likely by increasing its metabolism. Voriconazole may increase the serum concentration of efavirenz by decreasing its metabolism. Consider alternate therapy or adjust doses and monitor for reduced voriconazole efficacy and increased efavirenz adverse effects during concomitant therapy.