Basic Profile / Key Facts
Drug Category
- Anti-HIV Agents
- Nonnucleoside Reverse Transcriptase Inhibitors
Dosage Forms
Indications
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.
Absorption
Not Available
Toxicity
Not Available
Biotrnasformation / Drug Metabolism
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.
Contraindications
SUSTIVA (efavirenz) is contraindicated in patients with clinically significant hypersensitivity to any
of its components.
SUSTIVA should not be administered concurrently with astemizole, cisapride, midazolam, triazolam, or
ergot derivatives because competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs
and create the potential for serious and/or life-threatening adverse events (eg, cardiac arrhythmias, prolonged
sedation, or respiratory depression). SUSTIVA should not be administered concurrently with voriconazole because
SUSTIVA significantly decreases voriconazole plasma concentrations.
Drug Interactions
Efavirenz has been shown in vivo to induce CYP3A4. Other compounds that are substrates of
CYP3A4 may have decreased plasma concentrations when coadministered with SUSTIVA (efavirenz). In vitro studies
have demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma
concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in
altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary
for these drugs.
Drugs which induce CYP3A4 activity (eg, phenobarbital, rifampin, rifabutin) would be expected to
increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interactions with SUSTIVA are
summarized in Table 5.
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Table 5a: Drugs That Should Not Be Coadministered With SUSTIVA
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Drug Class
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Drugs Within Class Not To Be Coadministered With SUSTIVA
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Antihistamines Benzodiazepines GI Motility Agents Anti-Migraine Antifungal
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astemizole midazolam, triazolam
cisapride ergot derivatives voriconazole
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Established Drug Interactions
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Drug Name
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Effect
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Clinical Comment
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Atazanavir
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¯atazanavir
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When coadministered with SUSTIVA in treatment-naive patients, the recommended dose of atazanavir
is 300 mg with ritonavir 100 mg and SUSTIVA 600 mg (all once daily). Dosing recommendations for SUSTIVA and
atazanavir in treatment-experienced patients have not been established.
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Established Drug Interactions (continued)
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Drug Name
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Effect
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Clinical Comment
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Clarithromycin
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¯clarithromycin concentration
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Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected
volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is
recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be
considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with
SUSTIVA.
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14-OH metabolite concentration
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Indinavir
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¯indinavir concentration
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The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing
the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to
SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once
daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively,
compared to when indinavir (800 mg every 8 hours) was given alone.
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Lopinavir/ritonavir
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¯lopinavir concentration
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A dose increase of lopinavir/ritonavir to 533/133 mg (4 capsules or 6.5 mL) twice daily taken
with food is recommended when used in combination with SUSTIVA.
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Methadone
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¯methadone concentration
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Coadministration in HIV-infected individuals with a history of injection drug use resulted in
decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of
22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone
dose increased as required to alleviate withdrawal symptoms.
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Ethinyl estradiol
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ethinyl estradiol concentration
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Plasma concentrations increased by SUSTIVA (efavirenz); clinical significance unknown. Because
the potential interaction of efavirenz with oral contraceptives has not been fully characterized, a reliable
method of barrier contraception should be used in addition to oral contraceptives.
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Rifabutin
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¯rifabutin concentration
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Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where
rifabutin is given 2 or 3 times a week.
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Rifampin
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¯efavirenz concentration
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Clinical significance of reduced efavirenz concentrations unknown.
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Ritonavir
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ritonavir concentration
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Combination was associated with a higher frequency of adverse clinical experiences (eg,
dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver
enzymes is recommended when SUSTIVA is used in combination with ritonavir.
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efavirenz concentration
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Saquinavir
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¯saquinavir
concentration
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Should not be used as sole protease inhibitor in combination with SUSTIVA.
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Sertraline
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¯sertraline concentration
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Increases in sertraline dose should be guided by clinical response.
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Other Potentially Clinically Significant Drug or Herbal Product Interactions With
SUSTIVAb
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Anticoagulants: Warfarin
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Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
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Anticonvulsants: Phenytoin Phenobarbital Carbamazepine
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Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of
anticonvulsant plasma levels should be conducted.
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Antifungals: Itraconazole Ketoconazole
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Drug interaction studies with SUSTIVA and these imidazole and triazole antifungals have not been
conducted. SUSTIVA has the potential to decrease plasma concentrations of itraconazole and ketoconazole.
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Anti-HIV protease inhibitors: Saquinavir/ritonavir combination
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No pharmacokinetic data are available.
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Amprenavir
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SUSTIVAhas the potential to decrease serum concentrations of amprenavir.
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Non-nucleoside reverse transcriptase inhibitors
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No studies have been performed with other NNRTIs.
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St. Johnís wort (Hypericum perforatum)
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Expected to substantially decrease plasma levels of efavirenz;has not been studied in
combination with SUSTIVA.
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a See Tables 1 and 2.
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b This table is not all-inclusive.
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Other Drugs: Based on the results of drug interaction studies, no dosage adjustment is
recommended when SUSTIVA (efavirenz) is given with the following: aluminum/magnesium hydroxide antacids,
azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, and zidovudine.
Specific drug interaction studies have not been performed with SUSTIVA and NRTIs other than lamivudine
and zidovudine. Clinically significant interactions would not be expected since the NRTIs are metabolized via a
different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination
pathways.
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