Efavirenz

(BAN, rINN)
Efavirenz Chemical formula
Synonyms: 5B706; DMP-266; Efavirentsi; Éfavirenz; Efavirenzum; L-743; L743726. (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
Cyrillic synonym: Эфавиренз.

💊 Chemical information

Chemical formula: C14H9ClF3NO2 = 315.7.
CAS — 154598-52-4.
ATC — J05AG03.
ATC Vet — QJ05AG03.

💊 Adverse Effects

The most common adverse effects associated with antiretroviral regimens containing efavirenz are skin rashes and psychiatric or CNS disturbances. Mild to moderate rashes (usually maculopapular eruptions) generally appear within the first 2 weeks of starting therapy and may resolve within a month of continued treatment; of severe forms including erythema multiforme and Stevens-Johnson syndrome have been reported occasionally. CNS symptoms include agitation, amnesia, confusion, dizziness, euphoria, headache, insomnia or somnolence, impaired concentration, abnormal thinking or dreaming, convulsions, depersonalisation, and hallucinations. Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2 to 4 weeks; they may occur more frequently when efavirenz is taken with meals, possibly due to increased efavirenz plasma concentrations. Serious psychiatric adverse effects include severe depression, suicidal ideation and attempts, aggressive behaviour, and psychotic reactions including paranoia and mania. Other adverse effects include nausea and vomiting, diarrhoea, fatigue, and pancreatitis. Raised liver enzyme values and raised serum-cholesterol and -triglyceride concentrations have been reported. Hepatic failure and photoallergic dermatitis have occurred. Immune reconstitution syndrome (an inflammatory immune response resulting in clinical deterioration) has been reported during the initial phase of treatment with combination antiretroviral therapy, including efavirenz, in HIV-infected patients with severe immune deficiency. Accumulation or redistribution of body fat (lipodystrophy) including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been seen in patients receiving antiretroviral therapy, including efavirenz. Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia have also been reported.
1. Clifford DB, et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med 2005; 143: 714–21.

Effects on the mouth.

Burning mouth syndrome was diagnosed in a patient 2 weeks after adding efavirenz to her longstanding combination antiretroviral treatment regimen.1 Efavirenz was stopped and the syndrome resolved within 1 week.
1. Borrás-Blasco J, et al. Burning mouth syndrome due to efavirenz therapy. Ann Pharmacother 2006; 40: 1471–2.

💊 Precautions

Efavirenz is contra-indicated in patients with severe hepatic impairment (Child-Pugh class C), and should be used with caution, and liver enzymes values monitored, in patients with mild to moderate liver disease. Patients co-infected with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. Caution should be exercised in patients with a history of seizures or psychiatric disorders including depression. Efavirenz should be stopped if a severe skin rash, associated with blistering, desquamation, mucosal involvement, or fever, develops. Monitoring of serum lipids and blood-glucose may be considered during efavirenz treatment. Food may increase exposure to efavirenz and lead to an increase in the frequency of undesirable effects. False-positive results in some urinary cannabinoid tests have been reported in subjects receiving efavirenz.

Pregnancy.

Licensed product information states that efavirenz has been associated with teratogenicity in animals. No specific malformation pattern was noted in more than 200 pregnancies with first-trimester exposure to efavirenz as part of a combination antiretroviral regimen. However, retrospective analysis of these pregnancies noted a few cases of neural tube defects, including meningomyelocele. The use of adequate contraceptive measures is recommended during, and for 12 weeks after, treatment with regimens containing efavirenz.

💊 Interactions

Efavirenz is metabolised mainly by cytochrome P450 isoenzymes including CYP3A4. Consequently, it may compete with other drugs metabolised by this system, potentially resulting in mutually increased plasma concentrations and toxicity. Enzyme inducers may decrease plasma concentrations of efavirenz; efavirenz itself acts as an enzyme inducer and can reduce plasma concentrations of other drugs. Inhibition of some P450 isoenzymes has also been found in vitro. Efavirenz is contra-indicated with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious or life-threatening events. These drugs include antihistamines (astemizole and terfenadine), calciumchannel blockers (bepridil), ergot derivatives (dihydroergotamine, ergometrine, ergotamine, methylergometrine), gastrointestinal prokinetics (cisapride), antipsychotics (pimozide), and sedatives and hypnotics (midazolam and triazolam). St John’s wort decreases the concentration of efavirenz; use with the antiretroviral is not recommended due to the possible loss of its activity and development of resistance.

Antibacterials.

Plasma concentrations of efavirenz may be reduced by rifampicin and may necessitate an increase in the dose of efavirenz. A similar interaction might occur with rifabutin. Use of efavirenz with clarithromycin has resulted in a decrease in the plasma concentration of clarithromycin and an increase in its active hydroxy metabolite. The combination has been associated with a high incidence of skin rashes.

Antifungals.

Giving efavirenz with voriconazole results in a 2way interaction; efavirenz decreases the concentration of voriconazole and voriconazole increases the concentration of efavirenz. When efavirenz is given with voriconazole, licensed product information for efavirenz suggests the voriconazole maintenance dose should be increased to 400 mg twice daily and the efavirenz dose reduced to 300 mg once daily.

Antivirals.

For the effect of efavirenz on HIV-protease inhibitors.

Grapefruit.

The metabolism of efavirenz may be inhibited by concomitant ingestion of grapefruit juice.

💊 Antiviral Action

Efavirenz acts by non-competitive inhibition of HIV-1 reverse transcriptase; it binds to the enzyme, disrupting the conformation of its catalytic site and impairing its RNA- and DNA-dependent polymerase activity. Resistance to efavirenz and emergence of cross-resistance to other non-nucleoside reverse transcriptase inhibitors has been seen.

💊 Pharmacokinetics

Efavirenz is absorbed after oral doses with peak plasma concentrations being achieved after about 3 to 5 hours. Steady-state plasma concentrations are reached in 6 to 7 days after multiple dosing. Bioavailability is increased after a high-fat meal. Efavirenz is more than 99% bound to plasma proteins and is distributed into the CSF. It is metabolised mainly by hepatic cytochrome P450 isoenzymes CYP3A4 and CYP2B6 into inactive hydroxylated, metabolites. Efavirenz acts as an enzyme inducer and induces its own metabolism resulting in a terminal half-life of 40 to 55 hours after multiple doses compared with 52 to 76 hours after a single dose. About 14 to 34% of a dose is excreted in the urine (less than 1% unchanged), and 16 to 61% in the faeces (primarily as unchanged drug).
1. Kappelhoff BS, et al. Population pharmacokinetics of efavirenz in an unselected cohort of HIV-1-infected individuals. Clin Pharmacokinet 2005; 44: 849–61
2. Almond LM, et al. Intracellular and plasma pharmacokinetics of efavirenz in HIV-infected individuals. J Antimicrob Chemother 2005; 56: 738–44
3. Burger D, et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 2006; 61: 148–54
4. Back DJ, et al. Population pharmacokinetics of efavirenz in an unselected cohort of HIV-1-infected individuals. Clin Pharmacokinet 2006; 45: 213–14.

💊 Uses and Administration

Efavirenz is a non-nucleoside reverse transcriptase inhibitor with activity against HIV. It is used with other antiretrovirals for combination therapy of HIV infection and AIDS. Efavirenz is given orally as capsules or tablets in a dose of 600 mg once daily; alternatively, it may be given as an oral solution in a dose of 720 mg once daily. Efavirenz tablets and capsules should be given on an empty stomach. Dosing at bedtime is recommended during the first 2 to 4 weeks of therapy to improve tolerability. Bioavailability of efavirenz from the oral solution is less than that from the capsule and so proportionately higher doses of the solution are used. For details of doses in children and adolescents, see below. Fixed-dose combination products have been developed in order to improve patient adherence and avoid monotherapy, thereby decreasing the risk of acquired drug resistance. Products containing efavirenz in combination with emtricitabine and tenofovir are available in some countries.
1. Adkins JC, Noble S. Efavirenz. Drugs 1998; 56: 1055–64
2. Gazzard BG. Efavirenz in the management of HIV infection. Int J Clin Pract 1999; 53: 60–4
3. Frampton JE, Croom KF. Efavirenz/emtricitabine/tenofovir disoproxil fumarate: triple combination tablet. Drugs 2006; 66: 1501–12.

Administration in children.

For the treatment of HIV infection in children 3 years of age and older and adolescents efavirenz is given daily with other antiretroviral drugs. In the USA oral capsules and tablets are available and the dose is based on body-weight:
10 to 14 kg: 200 mg once daily
15 to 19 kg: 250 mg once daily
20 to 24 kg: 300 mg once daily
25 to 32.4 kg: 350 mg once daily
32.5 to 39 kg: 400 mg once daily
40 kg or more: as for adults (above)
Capsules are also available in the UK for use in children and adolescents; doses are similar to those used in the USA. In the UK an oral solution is also available; the dose ranges, which are again calculated in terms of body-weight, also depend on the age range:
13 to 14 kg: children less than 5 years, 360 mg daily; children 5 years and older, 270 mg once daily
15 to 19 kg: children less than 5 years, 390 mg daily; children 5 years and older, 300 mg once daily
20 to 24 kg: children less than 5 years, 450 mg daily; children 5 years and older, 360 mg once daily
25 to 32.4 kg: children less than 5 years, 510 mg daily; children 5 years and older, 450 mg once daily
32.5 to 39 kg: children 5 years and older, 510 mg once daily
40 kg or more: children 5 years and older, as for adults, above

💊 Preparations

Proprietary Preparations

Arg.: Efavilea; Filginase; Stocrin; Sulfinav; Virorrever; Austral.: Stocrin; Austria: Stocrin; Belg.: Stocrin; Braz.: Stocrin; Canad.: Sustiva; Chile: Stocrin; Cz.: Stocrin; Sustiva; Denm.: Stocrin; Fin.: Stocrin; Fr.: Sustiva; Ger.: Sustiva; Gr.: Stocrin; Hong Kong: Stocrin; Hung.: Stocrin; India: Efavir; Irl.: Sustiva; Israel: Stocrin; Ital.: Sustiva; Malaysia: Stocrin; Mex.: Stocrin; Neth.: Stocrin; Sustiva; Norw.: Stocrin; NZ: Stocrin; Pol.: Stocrin; Port.: Stocrin; Sustiva; Rus.: Stocrin (Стокрин); S.Afr.: Stocrin; Singapore: Stocrin; Spain: Sustiva; Swed.: Stocrin; Switz.: Stocrin; Thai.: Stocrin; UK: Sustiva; USA: Sustiva; Venez.: Efavir; Stocrin. Multi-ingredient: India: Odivir Kit; UK: Atripla; USA: Atripla.
Published November 07, 2018.