Efavirenz

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Efavirenz
Efavirenz.svg
Efavirenz ball-and-stick model.png
Clinical data
Pronunciation e-FAV-irr-enz
Trade names Atripla, Sustiva, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a699004
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
By mouth (capsules, tablets)
ATC code J05AG03 (WHO)
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: ℞-only
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 40–45% (under fasting conditions)
Protein binding 99.5–99.75%
Metabolism Hepatic (CYP2A6 and CYP2B6-mediated)
Onset of action 3–5 hours
Biological half-life 40–55 hours
Excretion Urine (14–34%) and feces (16–61%)
Identifiers
CAS Number 154598-52-4 YesY
PubChem (CID) 64139
DrugBank DB00625 YesY
ChemSpider 57715 YesY
UNII JE6H2O27P8 YesY
KEGG D00896 YesY
ChEBI CHEBI:119486 YesY
ChEMBL CHEMBL223228 YesY
NIAID ChemDB 032934
PDB ligand ID EFZ (PDBe, RCSB PDB)
Chemical and physical data
Formula C14H9ClF3NO2
Molar mass 315.675 g/mol
3D model (Jmol) Interactive image
  (verify)

Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is sold both by itself and in combination as efavirenz/emtricitabine/tenofovir. It is taken by mouth once a day.[1]

Common side effects include rash, nausea, headache, feeling tired, and trouble sleeping. Some of the rashes may be serious such as Stevens-Johnson syndrome. Other serious side effects include depression, thoughts of suicide, liver problems, and seizures. It is not safe for use during pregnancy. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and works by blocking the function of reverse transcriptase.[1]

Efavirenz was approved for medical use in the United States in 1998.[1] It is on the WHO Model List of Essential Medicines, the most important medication needed in a basic health system.[2] As of 2015 it is not avaliable as a generic medication.[3] The wholesale cost in the developing world is about 3.27 to 9.15 USD per month.[4] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[3]

Medical uses[edit]

For HIV infection that has not previously been treated, the United States Department of Health and Human Services Panel on Antiretroviral Guidelines recommends the use of efavirenz in combination with tenofovir/emtricitabine (Truvada) as one of the preferred NNRTI-based regimens in adults and adolescents[5] and children.[6]

Efavirenz is also used in combination with other antiretroviral agents as part of an expanded post-exposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex, etc.).[7][8]

Pregnancy and breastfeeding[edit]

Efavirenz is safe to use during the first trimester of pregnancy.[9] Efavirenz passes into breast milk and breast-fed infants may be exposed to efavirenz.[10]

Contraindications[edit]

People who have taken this medication before and experienced an allergic reaction should avoid taking further efavirenz dosages. Hypersensitivity reactions include Steven-Johnson syndrome, toxic skin eruptions, and erythema multiforme.[11]

Adverse effects[edit]

Neuropsychiatric effects are the most common adverse effects, and include include disturbed sleep (including nightmares, insomnia, disrupted sleep, and daytime fatigue), dizziness, headaches, vertigo, blurred vision, anxiety, and cognitive impairment (including fatigue, confusion, and memory and concentration problems), and depression, including suicidal thinking.[12][13] Some people experience euphoria, which makes the drug liable to abuse and diversion.[12]

Rash and nausea may occur.[11]

Use of efavirenz can produce a false positive result in some urine tests for marijuana. [14][15]

Efavirenz may lengthen the QT interval so should not be used in people with or at risk of Torsades de Pointes.[16]

Efavirenz may cause convulsions in adult and pediatric populations who have a history of seizures.[11]

Drug interactions[edit]

Efavirenz is broken down in the liver by enzymes that belong to the cytochrome P450 system, which include both CYP2B6 and CYP3A4.[11] Efavirenz is a substrate of these enzymes and can decrease the metabolism of other drugs that require the same enzymes.[11] However, efavirenz also induces these enzymes, which means the enzyme activity is enhanced and the metabolism of other drugs broken down by CYP2B6 and CYP3A4 can be increased.[11] People who are taking both efavirenz and other drugs metabolized by the same enzymes might need the dose of their drugs to be increased or decreased.

One group of drugs that efavirenz affects is protease inhibitors, which are used for HIV/AIDS. Efavirenz will lower the blood levels of most protease inhibitors, including aprenavir, atazanavir, and indinavir.[11] At lowered levels, protease inhibitors may not be effective in people taking both drugs, which means the virus that causes HIV/AIDS won’t be stopped from replicating and may become resistant to the protease inhibitor.

Efavirenz also affects antifungal drugs, which are used for fungal infections such as urinary tract infections. Similar to the effect seen with protease inhibitors, efavirenz lowers the blood levels of antifungal drugs like voriconazole, itraconazole, ketoconazole, and posaconazole.[11] As a result of lowered levels, antifungal drugs may not be effective in people taking both drugs, which means that the fungi that cause the infection may become resistant to the antifungal.

Mechanism of action[edit]

Anti-HIV effects[edit]

Efavirenz falls in the NNRTI class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, the reverse transcriptase enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside RTIs, which bind at the enzyme's active site, NNRTIs act allosterically by binding to a distinct site away from the active site known as the NNRTI pocket.

Efavirenz is not effective against HIV-2, as the pocket of the HIV-2 reverse transcriptase has a different structure, which confers intrinsic resistance to the NNRTI class.[17]

As most NNRTIs bind within the same pocket, viral strains which are resistant to efavirenz are usually also resistant to the other NNRTIs, nevirapine and delavirdine. The most common mutation observed after efavirenz treatment is K103N, which is also observed with other NNRTIs.[11] Nucleoside reverse-transcriptase inhibitors (NRTIs) and efavirenz have different binding targets, so cross-resistance is unlikely; the same is true with regard to efavirenz and protease inhibitors.[1]

Neuropsychiatric effects[edit]

As of 2016 the mechanism of efavirenz' neuropsychiatric adverse effects was not clear.[12][13] Efavirenz appears to have neurotoxicity, possibly by interfering with mitochondrial function, which may in turn possibly be caused by inhibiting creatine kinase but also possibly by disrupting mitochondrial membranes or by interfering with nitric oxide signalling.[12] Some neuropsychiatric adverse effects may be mediated through cannabinoid receptors, or through activity at the 5-HT2A receptor, but efavirenz interacts with many CNS receptors, so this is not clear.[12] The neuropsychiatric adverse effects are dose-dependent.[12]

Chemical properties[edit]

Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C14H9ClF3NO2. Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68 g/mol. It is practically insoluble in water (<10 µg/mL).

History[edit]

Efavirenz was approved by the FDA on September 21, 1998, making it the 14th approved antiretroviral drug.

On February 17, 2016, the FDA approved the generic tablet formulation to be produced by Mylan.[18]

Society and culture[edit]

Pricing information[edit]

A one-month supply of 600 mg tablets costs approximately $1,010 in July 2016.[19] In 2007, Merck provided efavirenz in certain developing countries and countries largely affected by HIV for about $0.65 per day.[20] Some emerging countries have opted to purchase Indian generics.[21] In Thailand, one month supply of efavirenz + truvada, as of June 2012, costs THB 2900 ($90), and there is a social program for patients who cannot afford the medication. In South Africa, a license has been granted to generics giant Aspen Pharmacare to manufacture, and distribute to Sub-Saharan Africa, a cost-effective antiretroviral drug.[22]

Recreational use[edit]

Abuse of efavirenz by crushing and smoking the tablets for supposed hallucinogenic and dissociative effects has been reported in South Africa, where it is used in a mixture known as whoonga and nyaope.[23][24][25][26]

Brands[edit]

As of 2016, efavirenz was marketed in various jurisdictions under the brand names Adiva, Avifanz, Efamat, Efatec, Efavir, Efavirenz , Efcure, Eferven, Efrin, Erige, Estiva, Evirenz, Filginase, Stocrin, Sulfina V, Sustiva, Virorrever, and Zuletel.[27]

As of 2016, the combination of efavirenz, tenofovir, and emtricitabine was marketed in various jurisdictions under the brand names Atripla, Atroiza, Citenvir, Oditec, Teevir, Trustiva, Viraday, and Vonavir.[27]

As of 2016, the combination of efavirenz, tenofovir, and lamivudine was marketed under the brand name Eflaten.[27]

References[edit]

  1. ^ a b c d e "Efavirenz". The American Society of Health-System Pharmacists. Retrieved 28 November 2016. 
  2. ^ "WHO Model List of Essential Medicines (19th)" (PDF). World Health Organization. April 2015. Retrieved 6 December 2016. 
  3. ^ a b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 62. ISBN 9781284057560. 
  4. ^ "Efavirenz". International Drug Price Indicator Guide. Retrieved 28 November 2016. 
  5. ^ "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents". July 14, 2016. 
  6. ^ "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection". NIH AIDSinfo. March 1, 2016. 
  7. ^ Kuhar, David T.; Henderson, David K.; Struble, Kimberly A.; Heneine, Walid; Thomas, Vasavi; Cheever, Laura W.; Gomaa, Ahmed; Panlilio, Adelisa L. (2013-09-01). "Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis". Infection Control & Hospital Epidemiology. 34 (9): 875–892. doi:10.1086/672271. ISSN 0899-823X. 
  8. ^ "Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States" (PDF). Centers for Disease Control and Prevention. Retrieved November 7, 2016. 
  9. ^ Ford, N; Mofenson, L; Shubber, Z; Calmy, A; Andrieux-Meyer, I; Vitoria, M; Shaffer, N; Renaud, F (March 2014). "Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis.". AIDS (London, England). 28 Suppl 2: S123–31. PMID 24849471. 
  10. ^ Waitt, Catriona John; Garner, Paul; Bonnett, Laura Jayne; Khoo, Saye Hock; Else, Laura Jayne (2015-07-01). "Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies". The Journal of Antimicrobial Chemotherapy. 70 (7): 1928–1941. doi:10.1093/jac/dkv080. ISSN 1460-2091. PMC 4472329Freely accessible. PMID 25858354. 
  11. ^ a b c d e f g h i "Efavirenz label" (PDF). FDA. October 2016. 
  12. ^ a b c d e f Treisman, GJ; Soudry, O (October 2016). "Neuropsychiatric Effects of HIV Antiviral Medications.". Drug safety. 39 (10): 945–57. PMID 27534750. 
  13. ^ a b Apostolova, N; Funes, HA; Blas-Garcia, A; Galindo, MJ; Alvarez, A; Esplugues, JV (October 2015). "Efavirenz and the CNS: what we already know and questions that need to be answered.". The Journal of antimicrobial chemotherapy. 70 (10): 2693–708. PMID 26203180. 
  14. ^ Rossi, S; Yaksh, T; Bentley, H; Van Den Brande, G; Grant, I; Ellis, R (2006). "Characterization of interference with 6 commercial delta9-tetrahydrocannabinol immunoassays by efavirenz (glucuronide) in urine". Clinical Chemistry. 52 (5): 896–7. doi:10.1373/clinchem.2006.067058. PMID 16638958. 
  15. ^ Röder, CS; Heinrich, T; Gehrig, AK; Mikus, G (2007). "Misleading results of screening for illicit drugs during efavirenz treatment". AIDS (London, England). 21 (10): 1390–1. doi:10.1097/QAD.0b013e32814e6b3e. PMID 17545727. 
  16. ^ Abdelhady, Ahmed M.; Shugg, Tyler; Thong, Nancy; Lu, Jessica Bo Li; Kreutz, Yvonne; Jaynes, Heather A.; Robarge, Jason D.; Tisdale, James E.; Desta, Zeruesenay (2016-10-01). "Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers". Journal of Cardiovascular Electrophysiology. 27 (10): 1206–1213. doi:10.1111/jce.13032. ISSN 1045-3873. PMC 5065384Freely accessible. PMID 27333947. 
  17. ^ Ren, J.; Bird, L. E.; Chamberlain, P. P.; Stewart-Jones, G. B.; Stuart, D. I.; Stammers, D. K. (2002-10-29). "Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors". Proceedings of the National Academy of Sciences of the United States of America. 99 (22): 14410–14415. doi:10.1073/pnas.222366699. ISSN 0027-8424. PMC 137897Freely accessible. PMID 12386343. 
  18. ^ "Efavirenz Drug Profile". DrugPatentWatch. Retrieved 2016-11-09. 
  19. ^ "Cost Considerations and Antiretroviral Therapy | Adult and Adolescent ARV Guidelines | AIDSinfo". AIDSinfo. Retrieved 2016-11-16. 
  20. ^ "Merck & Co., Inc., Again Reduces Price of Stocrin (efavirenz) for Patients in Least Developed Countries and Countries Hardest Hit by Epidemic - Drugs.com MedNews". 
  21. ^ IndiaDaily - A new trend in emerging nations - Brazil opts for Indian generic drug ignoring US pharmaceutical giant Merck’s patent on AIDS drug Efavirenz
  22. ^ Patrick Lumumba Osewe; Yvonne Korkoi Nkrumah; Emmanuel K. Sackey (15 June 2008). Improving Access to HIV/AIDS Medicines in Africa: Trade-Related Aspects of Intellectual Property Rights (TRIPS) Flexibilities Utilization. World Bank Publications. pp. 35–39. ISBN 978-0-8213-7544-0. Retrieved 30 June 2012. 
  23. ^ IOL: Thugs get high on stolen Aids drugs IOL News May 12, 2007
  24. ^ Getting high on HIV drugs in S Africa. BBC News, 8 December 2008.
  25. ^ 'No Turning Back': Teens Abuse HIV Drugs. ABC News, April 6, 2009.
  26. ^ Getting High On HIV Medication Vice 7.04.2014.
  27. ^ a b c "International brands for Efavirenz". Drugs.com. Retrieved 10 November 2016.