Efavirenz

Oral
HIV-1 infection

Patients taking voriconazole: Reduce efavirenz dose by 50% (e.g. 300 mg once daily) and increase voriconazole maintenance dose to 400 mg every 12 hours. May restore initial efavirenz dose when voriconazole treatment is discontinued.

Patients taking rifampicin: ≥50 kg: Increase efavirenz dose to 800 mg once daily.

Pharmacogenomics

Efavirenz is mainly metabolised into inactive metabolites by CYP3A4 and CYP2B6 isoenzymes. Individuals with certain CYP2B6 genetic variants may be at increased risk of CNS adverse effects and possible treatment discontinuation.

Allele frequencies among individuals of different populations and ethnic backgrounds may be a considering factor that can cause potential uncertainty in genotyping and phenotype predictions. CYP2B6*18 and other rare variants are relatively common in black population but have considerably lower prevalence or even absent in Caucasians or European ancestry, and the frequency of CYP2B6*29 and CYP2B6*30 alleles is very low in African Americans and Asians (approx 0.005%).

Genetic testing may serve as a factor to be considered when prescribing efavirenz. Thus, the alleles that should be tested may considerably vary for a given population. Therapeutic drug monitoring may also be used as a guide to ensure the therapeutic plasma efavirenz concentrations.

CYP2B6 ultrarapid metabolisers (carriers of 2 increased function alleles e.g. *4/*4, *22/*22, *4/*22)
Patients may experience slightly lower dose-adjusted trough concentrations compared with normal metabolisers.
Adult and children ≥40 kg: Initiate therapy with standard dosing (600 mg once daily).

CYP2B6 rapid metabolisers (carriers of 1 normal function allele and 1 increased function allele e.g. *1/*4, *1/*22)
Patients may experience slightly lower dose-adjusted trough concentrations compared with normal metabolisers.
Adult and children ≥40 kg: Initiate therapy with standard dosing (600 mg once daily).

CYP2B6 normal metabolisers (carriers of 2 normal function alleles e.g. *1/*1)
Patients have normal metabolism and achieve therapeutic concentration with standard dosing.
Adult and children ≥40 kg: Initiate therapy with standard dosing (600 mg once daily).

CYP2B6 intermediate metabolisers (carriers of 1 normal function allele and 1 decreased function allele, or 1 normal function allele and 1 no function allele, or 1 increased function allele and 1 decreased function allele, or 1 increased function allele and 1 no function allele e.g. *1/*6, *1/*18, *4/*6, *4/*18, *6/*22, *18/*22)
Patients may experience higher dose-adjusted trough concentrations compared with normal metabolisers (1.3-fold increased risk of adverse effects).
Adult and children ≥40 kg: Consider decreasing initial dose to 400 mg once daily.

CYP2B6 poor metabolisers (carriers of 2 decreased function alleles, or 2 no function alleles, or 1 decreased function allele and 1 no function allele e.g. *6/*6, *18/*18, *6/*18)
Patients are at greatest risk for higher dose-adjusted trough concentrations compared with normal and intermediate metabolisers, and greater overall plasma efavirenz exposure (4.8-fold significantly increased risk for adverse CNS effects and treatment discontinuation).
Adult and children ≥40 kg: Consider decreasing initial dose to 400 mg or 200 mg once daily.

Moderate: Not recommended. Severe (Child Pugh Class C): Contraindicated.

Should be taken on an empty stomach. Take preferably at bedtime.

Hypersensitivity. History of severe cutaneous reaction (e.g. Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions); family history of sudden death, or of congenital QTc interval prolongation, or with any other clinical condition known to prolong the QTc interval; history of symptomatic cardiac arrhythmias, or with clinically relevant bradycardia, or with CHF accompanied by reduced LVEF; severe electrolyte balance disturbances (e.g. hypokalaemia, hypomagnesaemia). Severe hepatic impairment (Child Pugh Class C). Pregnancy (1st trimester) and lactation. Concomitant use with terfenadine, astemizole, cisapride, flecainide, methadone, midazolam, triazolam, pimozide, bepridil, ergot alkaloids, elbasvir, grazoprevir, St. John’s wort, classes IA and III antiarrhythmics, neuroleptics, antidepressants, certain antibiotics (e.g. some macrolides, fluoroquinolones, imidazole and triazole antifungals), certain antimalarials.

Patients with history of seizure, psychiatric disorders (including depression), or drug abuse; HIV-associated dementia, chronic hepatitis B or C infection. Not intended to be used as a single agent to treat HIV or add on as a sole agent to a failing regimen. Not recommended in moderate hepatic impairment. Severe renal and mild hepatic impairment. Children. Pregnancy (2nd-3rd trimester). CYP2B6 ultrarapid, rapid, intermediate, and poor metabolisers.

Significant: QTc prolongation, CNS effects (e.g. dizziness, insomnia, somnolence, impaired concentration, abnormal dreams), psychiatric effects (e.g. aggression, delusions, severe depression, paranoia, psychosis-like behaviour, mania), fat redistribution or accumulation (e.g. central obesity, buffalo hump, peripheral and facial wasting, breast enlargement, cushingoid appearance), hypercholesterolaemia, immune reconstitution syndrome (e.g. activation of Graves’ disease, polymyositis, Guillain-Barré syndrome), osteonecrosis, seizures.
Blood and lymphatic system disorders: Neutropenia.
Ear and labyrinth disorders: Tinnitus.
Eye disorders: Blurred vision.
Gastrointestinal disorders: Abdominal pain, diarrhoea, nausea, vomiting, pancreatitis.
General disorders and admin site conditions: Fatigue, ataxia.
Investigations: Increased ALT and AST, elevated gamma-glutamyl transferase.
Metabolism and nutrition disorders: Hypertriglyceridaemia, hyperglycaemia.
Nervous system disorders: Abnormal coordination, balance and attention disturbances, headache, vertigo, amnesia, abnormal thinking, tremor.
Psychiatric disorders: Anxiety, affect lability, confusion, euphoria, hallucination, catatonia.
Reproductive system and breast disorders: Gynaecomastia.
Respiratory, thoracic and mediastinal disorders: Dyspnoea.
Skin and subcutaneous tissue disorders: Rash, pruritus. Rarely, photoallergic dermatitis.
Vascular disorders: Flushing.
Potentially Fatal: Stevens-Johnson syndrome, fulminant hepatitis progressing to hepatic failure, fatal suicide attempts.

This drug may cause dizziness, somnolence or impaired concentration, if affected, do not drive or operate machinery. Efavirenz does not reduce your risk of passing HIV infection through sexual contact. Avoid sexual intercourse and follow your doctor’s advise on ways to prevent passing the disease to others. Use an effective barrier contraception in addition to hormonal contraceptives during and for 12 weeks after treatment.

Monitor viral load, CD4 count, serum transaminases, blood glucose, serum cholesterol and triglycerides at baseline and periodically during treatment. Assess for signs and symptoms of infection and psychiatric effects.

Symptoms: Increased CNS effects including involuntary muscle contractions. Management: Symptomatic and supportive treatment. May administer activated charcoal.

May reduce plasma concentrations of voriconazole, rifampicin, HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs), HIV integrase inhibitors, Ca channel blockers, HMG-CoA reductase inhibitors (e.g. atorvastatin, pravastatin, simvastatin), immunosuppressants (e.g. ciclosporin, tacrolimus, sirolimus). May increase CNS effects with psychoactive drugs. May alter plasma warfarin concentrations resulting to increased or decreased anticoagulant effect.
Potentially Fatal: Increased risk of QTc interval prolongation and torsade de pointes with classes IA and III antiarrhythmics, neuroleptics, antidepressants, certain antibiotics (e.g. some macrolides, fluoroquinolones, imidazole and triazole antifungals), certain non-sedating antihistamines (e.g. terfenadine, astemizole), cisapride, flecainide, certain anti-malarial (e.g. atovaquone/proguanil) and methadone. Increased risk of serious reactions (e.g. prolonged sedation, respiratory depression) with midazolam, triazolam, pimozide, bepridil, ergot alkaloids (e.g. ergotamine, ergonovine). May significantly decrease plasma concentrations leading to loss of virologic response of elbasvir/grazoprevir.

Reduced plasma concentrations with St. John’s wort and Gingko biloba extracts. Increased exposure and frequency of adverse reactions with food and grapefruit juice. May enhance toxic effects of alcohol.

May lead to false-positive test results for cannabinoid and benzodiazepine.

Description:
Mechanism of Action: Efavirenz is a non-nucleoside reverse transcriptase inhibitor with  activity against HIV-1. It blocks the RNA- and DNA-dependent polymerase activities including HIV-1 replication.
Pharmacokinetics:
Absorption: Increased absorption with high-fat or high-caloric meal. Time to peak plasma concentration: Approx 3-5 hours.
Distribution: Distributed into CSF. Enters breast milk. Bioavailability: 42%. Plasma protein binding: >99% mainly to albumin.
Metabolism: Metabolised mainly by hepatic CYP3A4 and CYP2B6 isoenzymes to inactive hydroxylated metabolites which then undergo glucuronidation.
Excretion: Via faeces (16-61% mainly as unchanged drug); urine (approx 14-34% as metabolites; <1% as unchanged drug). Elimination half-life: 52-76 hours (single dose); 40-55 hours (multiple doses).

Source: National Center for Biotechnology Information. PubChem Database. Efavirenz, CID=64139, https://pubchem.ncbi.nlm.nih.gov/compound/Efavirenz (accessed on Jan. 22, 2020)

Store at 25°C.

Antivirals

J05AG03 - efavirenz ; Belongs to the class of non-nucleoside reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

Desta Z, Gammal R, Gong L et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy. Clinical Pharmacology and Therapeutics. 2019 Oct;106(4):726-733. doi: 10.1002/cpt.1477. Accessed 12/07/2019. PMID: 31006110

Desta Z, Gammal R, Gong L et al. Supplement to: CPIC Guideline for CYP2B6 and Efavirenz-containing Antiretroviral Therapy. Clinical Pharmacology & Therapeutics. Accessed 12/07/2019

Annotation of CPIC Guideline for Efavirenz and CYP2B6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 12/07/2019.

Annotation of DPWG Guideline for Efavirenz and CYP2B6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 12/07/2019.

Anon. Efavirenz. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 12/07/2019.

Buckingham R (ed). Efavirenz. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 12/07/2019.

CPIC Guideline for CYP2B6 and Efavirenz-containing Antiretroviral Therapy. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 12/07/2019.

Efavirenz Capsule (Aurobindo Pharma Limited). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 12/07/2019.

Supplement to: CPIC Guideline for CYP2B6 and Efavirenz-containing Antiretroviral Therapy. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 12/07/2019.