Efavirenz

Synonyms :
(-)-6-CHLORO-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, (S)-6-chloro-4-(Cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one, (S)-6-chloro-4-Cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-benzo[D][1,3]oxazin-2-one, 6-chloro-4-(2-Cyclopropyl-1-ethynyl)-4-trifluoromethyl-(4S)-1,4-dihydro-2H-benzo[D][1,3]oxazin-2-one, Efavirenz, Éfavirenz, Efavirenzum

Status : approved

Category

Anti-HIV Agents

Therapeutic Classification

DIRECT ACTING ANTIVIRALS

ANTIINFECTIVES FOR SYSTEMIC USE
ANTIVIRALS FOR SYSTEMIC USE
DIRECT ACTING ANTIVIRALS
Reverse Transcriptase Inhibitors

Description

Efavirenz (brand names Sustiva® and Stocrin®) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1. For HIV infection that has not previously been treated, efavirenz and lamivudine in combination with zidovudine or tenofovir is the preferred NNRTI-based regimen. Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to prevent HIV transmission for those exposed to materials associated with a high risk for HIV transmission.

Used

For use in combination treatment of HIV infection (AIDS)

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.

Dosage

Form Route Strength
Tablet oral 600 mg
Tablet, film coated oral 600; 200; 300 mg/1; mg/1; mg
Capsule, gelatin coated oral 200 mg
Capsule, gelatin coated oral 50 mg
Tablet, film coated oral 600 mg
Capsule oral 100 mg
Capsule oral 200 mg
Capsule oral 50 mg
Tablet oral 600 mg

Pharmacodynamics

Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI). 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.

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.

Half Life

40-55 hours

Protein Binding

99.5-99.75%

Elimination Route

Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites.

Chemical Classification

This compound belongs to the class of organic compounds known as benzoxazines. These are organic compounds containing a benzene fused to an oxazine ring (a six-membered aliphatic ring with four carbon atoms, one oxygen atom, and one nitrogen atom).

Benzoxazines

Organic compounds

Organoheterocyclic compounds

Benzoxazines

Chemical Name

(-)-6-CHLORO-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Brands

name Dosage form Country
Atripla tablet Canada
Atripla tablet, film coated US
Atripla tablet, film coated US
Atripla tablet, film coated US
Atripla tablet, film coated US
Auro-efavirenz tablet Canada
Mylan-efavirenz tablet Canada
Sustiva tablet, film coated US
Sustiva capsule, gelatin coated US
Sustiva capsule, gelatin coated US
Sustiva tablet, film coated US
Sustiva 100mg capsule Canada
Sustiva 200mg capsule Canada
Sustiva 50mg capsule Canada
Sustiva Tablets tablet Canada
Teva-efavirenz tablet Canada

Drug Drug Interactions

  •  Acenocoumarol  : May decrease the serum concentration of Vitamin K Antagonists. Efavirenz may increase the serum concentration of Vitamin K Antagonists.
  •  Amlodipine  : May decrease the serum concentration of Calcium Channel Blockers.
  •  Amodiaquine  : Efavirenz may enhance the hepatotoxic effect of Amodiaquine. Efavirenz may increase the serum concentration of Amodiaquine.
  •  Amrinone  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Aripiprazole  : CYP3A4 Inducers may decrease the serum concentration of Aripiprazole.
  •  Artemether  : Efavirenz may decrease the serum concentration of Artemether. Concentrations of dihydroartemisinin (active metabolite of artemether) may also be decreased by efavirenz
  •  Atazanavir  : Efavirenz may decrease the serum concentration of Atazanavir.
  •  Atorvastatin  : Efavirenz may decrease the serum concentration of Atorvastatin.
  •  Atovaquone  : Efavirenz may decrease the serum concentration of Atovaquone.
  •  Axitinib  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib.
  •  Bedaquiline  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline.
  •  Bepridil  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Boceprevir  : Efavirenz may decrease the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Efavirenz.
  •  Bosentan  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Bosentan  : CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan.
  •  Bosutinib  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib.
  •  Buprenorphine  : Efavirenz may decrease serum concentrations of the active metabolite(s) of Buprenorphine. Efavirenz may decrease the serum concentration of Buprenorphine.
  •  Bupropion  : Efavirenz may decrease the serum concentration of Bupropion.
  •  Canagliflozin  : Efavirenz may decrease the serum concentration of Canagliflozin.
  •  Carbamazepine  : May decrease the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Carbamazepine. This mechanism applies specifically to Efavirenz.
  •  Carvedilol  : CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased.
  •  Caspofungin  : Inducers of Drug Clearance may decrease the serum concentration of Caspofungin.
  •  Cilostazol  : CYP2C19 Inhibitors may increase the serum concentration of Cilostazol.
  •  Citalopram  : CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram.
  •  Clarithromycin  : Efavirenz may decrease the serum concentration of Clarithromycin.
  •  Clevidipine  : May decrease the serum concentration of Calcium Channel Blockers.
  •  Clopidogrel  : CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel.
  •  Cyclosporine  : May decrease the serum concentration of Cyclosporine (Systemic).
  •  Dabrafenib  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Dabrafenib  : May decrease the serum concentration of CYP2B6 Substrates.
  •  Daclatasvir  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir.
  •  Darunavir  : May increase the serum concentration of Efavirenz. Efavirenz may decrease the serum concentration of Darunavir.
  •  Deferasirox  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Delavirdine  : Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz.
  •  Desogestrel  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Dienogest  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Diltiazem  : Efavirenz may decrease the serum concentration of Diltiazem.
  •  Dolutegravir  : Efavirenz may decrease the serum concentration of Dolutegravir.
  •  Doxylamine  : May enhance the CNS depressant effect of CNS Depressants.
  •  Dronabinol  : CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.
  •  Dronabinol  : May enhance the CNS depressant effect of CNS Depressants.
  •  Dronabinol  : CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol.
  •  Dronabinol  : May enhance the CNS depressant effect of CNS Depressants.
  •  Droperidol  : May enhance the CNS depressant effect of CNS Depressants.
  •  Drospirenone  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Elvitegravir  : Efavirenz may decrease the serum concentration of Elvitegravir.
  •  Enzalutamide  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Enzalutamide.
  •  Ethinyl Estradiol  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Ethynodiol  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Etonogestrel  : Efavirenz may diminish the therapeutic effect of Etonogestrel.
  •  Etravirine  : Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Etravirine. This has been observed with the NNRTIs Efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine.
  •  Everolimus  : Efavirenz may decrease the serum concentration of Everolimus.
  •  Felodipine  : May decrease the serum concentration of Calcium Channel Blockers.
  •  Fentanyl  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fentanyl.
  •  Flibanserin  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin.
  •  Flunarizine  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Fosamprenavir  : Efavirenz may decrease serum concentrations of the active metabolite(s) of Fosamprenavir.
  •  Fosphenytoin  : May decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Fosphenytoin.
  •  Gabapentin  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Ginkgo biloba  : May decrease the serum concentration of Efavirenz.
  •  Hydrocodone  : CNS Depressants may enhance the CNS depressant effect of Hydrocodone.
  •  Hydroxyzine  : May enhance the CNS depressant effect of CNS Depressants.
  •  Ibrutinib  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib.
  •  Ifosfamide  : CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide.
  •  Indinavir  : Efavirenz may decrease the serum concentration of Indinavir.
  •  Isradipine  : May decrease the serum concentration of Calcium Channel Blockers.
  •  Itraconazole  : Efavirenz may decrease the serum concentration of Itraconazole.
  •  Ketoconazole  : May decrease the serum concentration of Ketoconazole (Systemic).
  •  Lamotrigine  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Lercanidipine  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Levonorgestrel  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Lopinavir  : Efavirenz may decrease the serum concentration of Lopinavir.
  •  Lovastatin  : Efavirenz may decrease the serum concentration of Lovastatin.
  •  Lumefantrine  : May decrease the serum concentration of Artemether. Concentrations of dihydroartemisinin (active metabolite of artemether) may also be decreased by Efavirenz
  •  Magnesium Sulfate  : May enhance the CNS depressant effect of CNS Depressants.
  •  Maraviroc  : Efavirenz may decrease the serum concentration of Maraviroc. Of note, this effect only applies in the absence of a strong CYP3A4 inhibitor
  •  Medroxyprogesterone Acetate  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Mestranol  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Methadone  : Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone.
  •  Methotrimeprazine  : CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.
  •  Metyrosine  : CNS Depressants may enhance the sedative effect of Metyrosine.
  •  Mifepristone  : May increase the serum concentration of Efavirenz.
  •  Minocycline  : May enhance the CNS depressant effect of CNS Depressants.
  •  Mirtazapine  : CNS Depressants may enhance the CNS depressant effect of Mirtazapine.
  •  Mitotane  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Nabilone  : May enhance the CNS depressant effect of CNS Depressants.
  •  Nevirapine  : Efavirenz may enhance the adverse/toxic effect of Nevirapine. Nevirapine may enhance the adverse/toxic effect of Efavirenz. Nevirapine may decrease the serum concentration of Efavirenz.
  •  Nicardipine  : May decrease the serum concentration of Calcium Channel Blockers.
  •  Nifedipine  : May decrease the serum concentration of Calcium Channel Blockers.
  •  Nimodipine  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nimodipine.
  •  Nisoldipine  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine.
  •  Nitrendipine  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Norethindrone  : May decrease the serum concentration of Contraceptives (Progestins).
  •  Norgestimate  : Efavirenz may decrease serum concentrations of the active metabolite(s) of Norgestimate.
  •  Olaparib  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib.
  •  Orphenadrine  : CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
  •  Palbociclib  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib.
  •  Paraldehyde  : CNS Depressants may enhance the CNS depressant effect of Paraldehyde.
  •  Perampanel  : May enhance the CNS depressant effect of CNS Depressants.
  •  Perhexiline  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Phenytoin  : May decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Phenytoin.
  •  Posaconazole  : Efavirenz may decrease the serum concentration of Posaconazole.
  •  Pramipexole  : CNS Depressants may enhance the sedative effect of Pramipexole.
  •  Pravastatin  : Efavirenz may decrease the serum concentration of Pravastatin.
  •  Prenylamine  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Proguanil  : Efavirenz may decrease the serum concentration of Proguanil.
  •  Quazepam  : May increase the serum concentration of CYP2B6 Substrates.
  •  Ranolazine  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine.
  •  Rifabutin  : Efavirenz may decrease the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Efavirenz.
  •  Rifampicin  : May decrease the serum concentration of Efavirenz.
  •  Rilpivirine  : Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of Efavirenz, etravirine, and nevirapine.
  •  Risedronate  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Ritonavir  : Efavirenz may enhance the adverse/toxic effect of Ritonavir. Efavirenz may increase the serum concentration of Ritonavir. Ritonavir may increase the serum concentration of Efavirenz.
  •  Ropinirole  : CNS Depressants may enhance the sedative effect of Ropinirole.
  •  Rotigotine  : CNS Depressants may enhance the sedative effect of Rotigotine.
  •  Rufinamide  : May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
  •  Saquinavir  : May enhance the adverse/toxic effect of Efavirenz. Efavirenz may decrease the serum concentration of Saquinavir.
  •  Saxagliptin  : CYP3A4 Inducers may decrease the serum concentration of Saxagliptin.
  •  Sertraline  : Efavirenz may decrease the serum concentration of Sertraline.
  •  Siltuximab  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Simeprevir  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir.
  •  Simvastatin  : Efavirenz may decrease the serum concentration of Simvastatin.
  •  Sirolimus  : Efavirenz may decrease the serum concentration of Sirolimus.
  •  Sodium oxybate  : May enhance the CNS depressant effect of CNS Depressants.
  •  Sonidegib  : CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib.
  •  Suvorexant  : CNS Depressants may enhance the CNS depressant effect of Suvorexant.
  •  Tacrolimus  : May decrease the serum concentration of Tacrolimus (Systemic).
  •  Tapentadol  : May enhance the CNS depressant effect of CNS Depressants.
  •  Telaprevir  : Efavirenz may decrease the serum concentration of Telaprevir. Telaprevir may decrease the serum concentration of Efavirenz.
  •  Thalidomide  : CNS Depressants may enhance the CNS depressant effect of Thalidomide.
  •  Tocilizumab  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Ulipristal  : Efavirenz may decrease the serum concentration of Ulipristal.
  •  Verapamil  : May decrease the serum concentration of Calcium Channel Blockers.
  •  Voriconazole  : Efavirenz may decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Efavirenz.
  •  Warfarin  : May decrease the serum concentration of Vitamin K Antagonists. Efavirenz may increase the serum concentration of Vitamin K Antagonists.
  •  Zolpidem  : CNS Depressants may enhance the CNS depressant effect of Zolpidem.

Food Interactions

  • Avoid excessive or chronic alcohol consumption., Take without regard to meals.

Calculated Property

kind Value Source
logP 3.89 ALOGPS
logS -4.6 ALOGPS
Water Solubility 8.55e-03 g/l ALOGPS
logP 4.46 ChemAxon
IUPAC Name (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one ChemAxon
Traditional IUPAC Name efavirenz ChemAxon
Molecular Weight 315.675 ChemAxon
Monoisotopic Weight 315.027390859 ChemAxon
SMILES FC(F)(F)[C@]1(OC(=O)NC2=C1C=C(Cl)C=C2)C#CC1CC1 ChemAxon
Molecular Formula C14H9ClF3NO2 ChemAxon
InChI InChI=1S/C14H9ClF3NO2/c15-9-3-4-11-10(7-9)13(14(16,17)18,21-12(20)19-11)6-5-8-1-2-8/h3-4,7-8H,1-2H2,(H,19,20)/t13-/m0/s1 ChemAxon
InChIKey InChIKey=XPOQHMRABVBWPR-ZDUSSCGKSA-N ChemAxon
Polar Surface Area (PSA) 38.33 ChemAxon
Refractivity 71.34 ChemAxon
Polarizability 26.81 ChemAxon
Rotatable Bond Count 3 ChemAxon
H Bond Acceptor Count 2 ChemAxon
H Bond Donor Count 1 ChemAxon
pKa (strongest acidic) 12.52 ChemAxon
pKa (strongest basic) -1.5 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 3 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 1 ChemAxon
MDDR-Like Rule 0 ChemAxon

Affected organism

Human Immunodeficiency Virus

Target within organism

  • Reverse Transcriptase : in Human immunodeficiency virus 1