efavirenz (Sustiva, EFV)
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Indications
- HIV infection
- for use in combination with:
Contraindications
- use during 1st trimester should be avoided[3]
- may be continued in pregnant with maintenance of viral suppression[11]
Dosage
- 600 mg PO QD
- may be taken with or without food (avoid dosing with high fat meals)
- neuropsychiatric advers effects during initial weeks of therapy can be diminished by increasing dose incrementally[8]
Tabs: 50 mg, 100 mg, 200 mg.
Pharmacokinetics
- metabolized to inactive metabolites by cyt P450 3A4 & 2B6
- 0.7% of serum levels achieved in CSF
- serum levels of 5.6-12.9 uM achieved with doses of 600 mg QD
- protein-binding > 99%
- volume of distribution 2-4 L/kg
- metabolized by cytochrome P450 3A4 & cyt P450 2B6[7]
- polymorphism in cyt P450 2B6 may lead to accumulation & persistence after discontinuation*[7]
- 14-34% excreted in the urine
- 16-61% excreted in the feces
- elimination 1/2life: 40-55 hours (multiple doses)
- not dialyzable
* thus discontinuation of antiretroviral therapy in patients receiving efavirenz with the TT genotype amounts to monotherapy & possibly emergence of resistance[7]
elimination via liver
elimination via kidney
elimination by hemodialysis = -
1/2life = 40-55 hours
protein binding = >99 %
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
- rash (25-40%)
- may be severe with blistering
- mucosal involvement may occur
- CNS manifestations (56%): [5][6]
- lightheadedness, dizziness
- mood alterations
- psychiatric alterations
- insomnia, vivid dreams, nightmares
- hallucinations[9]
- genotoxicity
- GI affects:
- dyslipidemia[9]
- 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 adverse effects of antiretroviral agents
- drug adverse effects of non-nucleoside reverse transcriptase inhibitors (NNRTI)
Drug interactions
- astemizole
- cisapride
- midazolam
- ergot alkaloids
- clarithromycin (possible)
- any drug that inhibits cyt P450 3A4 may increase levels of evafirenz
- any drug that induces cyt P450 3A4 may diminish levels of efavirenz
- 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
More general terms
Additional terms
- 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)
Component of
References
- ↑ Micromedex
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 3.0 3.1 3.2 FDA MedWatch Sustiva (efavirenz) Capsules and Tablets http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Sustiva
- ↑ Department of Veterans Affairs, VA National Formulary
- ↑ 5.0 5.1 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: https://www.ncbi.nlm.nih.gov/pubmed/
- ↑ 6.0 6.1 Clifford DB et al Impact of efavirenz on neuropsychological performance and symptoms of HIV-infected individuals Ann Intern Med 2005; 143:714
- ↑ 7.0 7.1 7.2 7.3 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: https://www.ncbi.nlm.nih.gov/pubmed/16392089
Nolan D et al, Efavirenz and CYP2B6 polymorphism: Implications for drug toxicity and resistance. Clin Infect Dis 2006; 42:408 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16392090 - ↑ 8.0 8.1 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: https://www.ncbi.nlm.nih.gov/pubmed/19581631
- ↑ 9.0 9.1 9.2 Medical Knowledge Self Assessment Program (MKSAP) 14, 17. American College of Physicians, Philadelphia 2006, 2015.
- ↑ 10.0 10.1 Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 11.0 11.1 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) - ↑ 12.0 12.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24979445 <Internet> http://annals.org/article.aspx?articleid=1884528