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| Pronunciation | /ɪˈfævɪrɛnz/i-FAV-i-renz or/ˌɛfəˈvaɪrɛnz/EF-ə-VY-renz |
| Trade names | Sustiva, Stocrin, others[1] |
| Other names | EFV |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a699004 |
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| Routes of administration | By mouth (capsules,tablets) |
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| Bioavailability | 40–45% (under fasting conditions) |
| Protein binding | 99.5–99.75% |
| Metabolism | Liver (CYP2A6 andCYP2B6-mediated) |
| Onset of action | 3–5 hours |
| Eliminationhalf-life | Single-dose: 52–76 h[5] Multi-dose: 40–55 h[5] |
| Excretion | Kidney (14–34%) and feces (16–61%) |
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| ECHA InfoCard | 100.149.346 |
| Chemical and physical data | |
| Formula | C14H9ClF3NO2 |
| Molar mass | 315.68 g·mol−1 |
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Efavirenz (EFV), sold under the brand namesSustiva among others, is anantiretroviral medication used to treat and preventHIV/AIDS.[1] It is generally recommended for use with other antiretrovirals.[1] It may be used for prevention after aneedlestick injury or other potential exposure.[1] It is sold both by itself and in combination asefavirenz/emtricitabine/tenofovir.[1] It is taken by mouth.[1]
Common side effects includerash,nausea,headache, feeling tired, and trouble sleeping.[1] Some of the rashes may be serious such asStevens–Johnson syndrome.[1] Other serious side effects includedepression,thoughts of suicide,liver problems, andseizures.[1] It is not safe for use duringpregnancy.[1] It is anon-nucleoside reverse transcriptase inhibitor (NNRTI) and works by blocking the function ofreverse transcriptase.[1]
Efavirenz was approved for medical use in the United States in 1998,[1] and in the European Union in 1999.[4] It is on theWorld Health Organization's List of Essential Medicines.[6] As of 2016, it is available as ageneric medication.[7][8]
For HIV infection that has not previously been treated, theUnited States Department of Health and Human Services Panel on Antiretroviral Guidelines recommends the use of efavirenz in combination withtenofovir/emtricitabine (Truvada) as one of the preferred NNRTI-based regimens in adults and adolescents[9] and children.[10]
Efavirenz is also used in combination with otherantiretroviral agents as part of an expandedpost-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.).[11][12]
Efavirenz is safe to use during the first trimester of pregnancy.[13] Efavirenz passes into breast milk and breast-fed infants may be exposed to efavirenz.[14]
People who have taken this medication before and experienced an allergic reaction should avoid taking further efavirenz dosages. Hypersensitivity reactions includeStevens–Johnson syndrome, toxic skin eruptions, anderythema multiforme.[3]
Neuropsychiatric effects are the most common adverse effects, and include disturbed sleep (includingnightmares,insomnia,disrupted sleep, anddaytime fatigue),dizziness,headaches,vertigo,blurred vision,anxiety, and cognitive impairment (includingfatigue,confusion, and memory and concentration problems), anddepression, including suicidal thinking.[15][16] Some people experienceeuphoria.[15]
Use of efavirenz can produce afalse positive result in some urine tests formarijuana.[17][18]
Efavirenz may lengthen theQT interval so should not be used in people with or at risk oftorsades de pointes.[19]
Efavirenz may cause convulsions in adult and pediatric populations who have a history ofseizures.[3]
Efavirenz is broken down in the liver byenzymes that belong to thecytochrome P450 system, which include both CYP2B6 and CYP3A4.[3] Efavirenz is a substrate of these enzymes and can decrease themetabolism of other drugs that require the same enzymes.[3] 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.[3] 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, includingamprenavir,atazanavir, andindinavir.[3] 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 affectsantifungal drugs, which are used for fungal infections such asurinary tract infections. Similar to the effect seen with protease inhibitors, efavirenz lowers the blood levels of antifungal drugs likevoriconazole,itraconazole,ketoconazole, andposaconazole.[3] 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.
Efavirenz has also been reported to interact withtubulin and inhibit its polymerization.[20]
Efavirenz falls in the NNRTI class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, thereverse transcriptase enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside RTIs, which bind at the enzyme's active site, NNRTIs actallosterically 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.[21]
As most NNRTIs bind within the same pocket, viral strains which are resistant to efavirenz are usually also resistant to the other NNRTIs,nevirapine anddelavirdine. The most common mutation observed after efavirenz treatment is K103N, which is also observed with other NNRTIs.[3] Nucleosidereverse-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]
Efavirenz has been found to haveaffinity for a variety oftargets to varying degrees and appears to act as anantagonist of the serotonin 5-HT2A (specificallyGq signaling),5-HT2B,5-HT2C, and5-HT3 receptors, as aninverse agonist of the serotonin5-HT6 receptor, as a dualGABAA receptorpositive allosteric modulator andorthosteric site antagonist, as aserotonin–dopamine reuptake inhibitor (SDRI), as avesicular monoamine transporter 2 (VMAT2) inhibitor, as amonoamine oxidase inhibitor (MAOI) ofMAO-A, and as an antagonist of themuscarinic acetylcholineM1 andM3 receptors.[22][23][24] Efavirenz produces thehead-twitch response, a behavioral proxy ofserotonergic psychedelic effects, in animals, and can partially substitute forLSD andMDMA in animaldrug discrimination tests.[22][25][23] Induction of the head-twitch response and substitution for LSD by efavirenz can be abolished by serotonin 5-HT2A receptor antagonists or serotonin 5-HT2A receptorknockout.[25] Efavirenz does not substitute forcocaine orcarisoprodol.[22] The drug is notself-administered and does not produceconditioned place preference (CPP) in animals.[22]
As of 2016 the mechanism of efavirenz's neuropsychiatric adverse effects was not clear.[15][16] It appears to produceneurotoxicity, possibly by interfering withmitochondrial function, which may in turn possibly be caused by inhibitingcreatine kinase but also possibly by disrupting mitochondrialmembranes or by interfering withnitric oxide signalling.[15] Some neuropsychiatric adverse effects may be mediated throughcannabinoid receptors, or through activity at theserotonin5-HT2A receptor, but efavirenz interacts with manycentral nervous systemtargets, so this is not clear.[15] The neuropsychiatric adverse effects are dose-dependent.[15] Although efavirenz appears to act as a serotonin 5-HT2A receptor antagonist, it has been suggested that it might exertfunctional selectivity and act as an agonist of the receptor for certainsignaling pathways, which could in turn explain its hallucinogenic and LSD-like effects.[22][25] However, this hypothesis remains to be evaluated.[22] Conversely, research suggests that efavirenz may actually be apartial agonist of the serotonin 5-HT2A receptor.[26] The effects of efavirenz in animals and humans are consistent with it being a serotonergic psychedelic.[25][23][27][28][29]
Theonset of action of efavirenz is 3 to 5 hours[citation needed] and itselimination half-life is 52 to 76 hours with a single dose and 40 to 55 hours with continuous administration.[5] The shorter half-life with chronic administration may be due to induction ofcytochrome P450enzymes by efavirenz.[5]
Efavirenz is chemically described as (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-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 practicallyinsoluble in water (<10 μg/mL).
Efavirenz was approved by the FDA on 21 September 1998.[30]
On 17 February 2016, the FDA approved the generic tablet formulation to be produced byMylan.[7][8]
In late 2018, Thailand'sGovernment Pharmaceutical Organization (GPO) announced that it will produce efavirenz after receivingWHO approval.[31]
Efavirenz code name is DMP 266, discovered by Du pont Pharma. European countries are set to receive the license for manufacturing of Efavirenz in May 1999.[32]
A one-month supply of 600 mg tablets costs approximately US$1,010 in July 2016.[33] In 2007, Merck provided Efavirenz in certain developing countries and countries largely affected by HIV for about US$0.65 per day.[34] Some emerging countries have opted to purchase Indian generics.[35]
In Thailand, a one-month supply of efavirenz + Truvada, as of June 2012, cost 2,900baht (US$90), and there is a social program for patients who cannot afford the medication. As of 2018[update] Thailand will produce efavirenz domestically. ItsGovernment Pharmaceutical Organization product costs 180baht per bottle of thirty 600 mg tablets. The imported version in Thailand retails for more than 1,000 baht per bottle. GPO will devote 2.5 percent of its manufacturing capacity to make 42 million efavirenz pills in 2018, allowing it to serve export markets as well as domestic. The Philippines alone will order about 300,000 bottles of efavirenz for 51 million baht.[31]
In South Africa, a license has been granted to generics giantAspen Pharmacare to manufacture, and distribute tosub-Saharan Africa, a cost-effectiveantiretroviral drug.[36]
Abuse of efavirenz by crushing and smoking the tablets for supposedhallucinogenic anddissociative effects has been reported inSouth Africa, where it is used in a mixture known aswhoonga andnyaope.[37][38][39][40] ResearcherHamilton Morris described efavirenz as "classically psychedelic."[27]
As of 2016, efavirenz is 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.[41]
As of 2016, the combination of efavirenz,tenofovir, andemtricitabine is marketed in various jurisdictions under the brand names Atripla, Atroiza, Citenvir, Oditec, Teevir, Trustiva, Viraday, and Vonavir.[41]
As of 2016, the combination of efavirenz, tenofovir, andlamivudine is marketed under the brand name Eflaten.[41]
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