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efavirenz (Sustiva, EFV)

Indications: 1) HIV infection 2) for use in combination with: a) zidovudine & lamivudine (Combivir) b) indinavir Contraindications: - use during 1st trimester should be avoided [3] - may be continued in pregnant with maintenance of viral suppression [11] Dosage: 1) 600 mg PO QD 2) may be taken with or without food (avoid dosing with high fat meals) 3) neuropsychiatric advers effects during initial weeks of therapy can be diminished by increasing dose incrementally [8] Tabs: 50 mg, 100 mg, 200 mg. Pharmacokinetics: 1) metabolized to inactive metabolites by cyt P450 3A4 & 2B6 2) 0.7% of serum levels achieved in CSF 3) serum levels of 5.6-12.9 uM achieved with doses of 600 mg QD 4) protein-binding > 99% 5) volume of distribution 2-4 L/kg 6) metabolized by cytochrome P450 3A4 & cyt P450 2B6 [7] - polymorphism in cyt P450 2B6 may lead to accumulation & persistence after discontinuation* [7] 7) 14-34% excreted in the urine 8) 16-61% excreted in the feces 9) elimination 1/2life: 40-55 hours (multiple doses) 10) not dialyzable * thus discontinuation of antiretroviral therapy in patients receiving efavirenz with the TT genotype amounts to monotherapy & possibly emergence of resistance [7] Monitor: - liver function tests at baseline & periodically in patients with preexisting hepatic disease (i.e. viral hepatitis), & patients taking other potentially hepatotoxic medications - should be considered for all patients [10] Adverse effects: 1) rash (25-40%) a) may be severe with blistering b) mucosal involvement may occur 2) CNS manifestations (56%): [5,6] a) lightheadedness, dizziness b) mood alterations - increased risk of suicide (RR=2.2) [12] c) psychiatric alterations d) insomnia, vivid dreams, nightmares e) hallucinations [9] 3) genotoxicity 4) GI affects: - nausea/vomiting, diarrhea 5) dyslipidemia [9] 6) neural tube defects in infants born to women using Sustiva during the 1st trimester (4 cases) [3] - 3 cases of meningomyelocele - 1 case of Dandy Walker Syndrome Drug interactions: 1) astemizole 2) cisapride 3) midazolam 4) ergot alkaloids 5) clarithromycin (possible) 6) any drug that inhibits cyt P450 3A4 may increase levels of evafirenz 7) any drug that induces cyt P450 3A4 may diminish levels of efavirenz 8) both induces & inhibits cyt P450 3A4, thus unpredicatable effects on metabolism of other cyt P450 3A4 substrates Laboratory: mininal therapeutic level (serum) 1.0 ug/mL Mechanism of action: 1) non nucleoside reverse transcriptase inhibitor

Interactions

drug interactions drug adverse effects (more general classes)

Related

Acquired Immuno-Deficiency Syndrome (HIV infection stage 3, AIDS) cytochrome P450 2B6 (cytochrome P450 2B1, phenobarbital-inducible, CYP2B6) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

non-nucleoside reverse transcriptase inhibitor (NNRTI)

Properties

MISC-INFO: elimination route LIVER KIDNEY elimination by hemodialysis - 1/2life 40-55 HOURS protein-binding >99% pregnancy-category D safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. Micromedex
  2. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  3. FDA MedWatch Sustiva (efavirenz) Capsules and Tablets http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Sustiva
  4. Department of Veterans Affairs, VA National Formulary
  5. Gutierrez F et al, Prediction of neuropsychatric adverse effects associated with long-term efaviranz therapy, using plasma frug level monitoring. Clin Infect Disease 2005; 41:1648 PMID:
  6. Clifford DB et al Impact of efavirenz on neuropsychological performance and symptoms of HIV-infected individuals Ann Intern Med 2005; 143:714
  7. Ribaudo HJ et al, Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: An adult AIDS Clinical Trial Group Study. Clin Infect Dis 2006; 42:401 PMID: 16392089 - Nolan D et al, Efavirenz and CYP2B6 polymorphism: Implications for drug toxicity and resistance. Clin Infect Dis 2006; 42:408 PMID: 16392090
  8. Gutierrez-Valencia A et al Stepped-dose vs. full-dose efavirenz for HIV infection and neuropsychiatric adverse events: A randomized trial. Ann Intern Med 2009 Jul 7 PMID: 19581631
  9. Medical Knowledge Self Assessment Program (MKSAP) 14, 17. American College of Physicians, Philadelphia 2006, 2015.
  10. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  11. Zuger A Use of Antiretroviral Drugs in Pregnancy. Physician's First Watch, April 22, 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. 2014. AIDSinfo. Clinical Guidelines Portal. March 28, 2014. http://aidsinfo.nih.gov/Guidelines/HTML/3/perinatal-guidelines/0 (corresponding NGC guideline withdrawn March 2016)
  12. Mollan KR et al Association Between Efavirenz as Initial Therapy for HIV-1 Infection and Increased Risk for Suicidal Ideation or Attempted or Completed Suicide: An Analysis of Trial Data. Ann Intern Med. 2014;161(1):1-10 PMID: 24979445 http://annals.org/article.aspx?articleid=1884528

Component-of

efavirenz/emtricitabine/tenofovir (Atripla) efavirenz/lamivudine/tenofovir