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Efavirenz is a non- nucleoside reverse transcriptase (RT) inhibitor of human immunodeficiency virus type 1 (HIV-1).
Efavirenz activity is mediated predominantly by non- competitive inhibition of HIV-1 RT. HIV-2 RT and human cellular
DNA polymerases alpha, beta, gamma, and delta are not inhibited by efavirenz.
Absorption: Peak efavirenz plasma concentrations of 1.6-9.1 m M were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose- related increases in C max and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In HIV- infected patients at steady- state, mean C max , mean C min , and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time- to- peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving efavirenz 600 mg QD, steady- state C max was 12.9 ± 3.7 m M (mean ± S. D.), steady-state C min was 5.6 ± 3.2 m M, and AUC was 184 ± 73 m M"" h. Effect of Food on Oral Absorption: In uninfected volunteers, meals of normal composition had no appreciable effect on the bioavailability of 100 mg of an investigational efavirenz formulation administered twice a day for 10 days with meals (Breakfast: 662 kcal, 13.8 g protein, 27.9 g fat, 94.6 g carbohydrate; Dinner: 567 kcal, 44.5 g protein, 12.5 g fat, 73.8 g carbohydrate). The relative bioavailability of a single 1200 mg dose of an investigational efavirenz formulation in uninfected volunteers (N= 5) was increased 50% (range 11%- 126%) following a high fat meal (1070 kcal, 82 g fat, 69% of calories from fat)
Distribution: Efavirenz is highly bound (approximately 99.5- 99.75%) to human plasma proteins, predominantly
albumin. In HIV- 1 infected patients (N= 9) who received efavirenz 200 to 600 mg once daily for at least one month,
cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration.
This proportion is approximately 3- fold higher than the non-protein- bound (free) fraction of efavirenz in plasma.
Metabolism: Studies in humans and in vitro studies using human liver microsomes have demonstrated that 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.
The in vitro studies suggest that C.P.A. and CYP2B6 are the major isozymes responsible for efavirenz metabolism.
Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism. Multiple doses of
200- 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter
terminal half- life of 40-55 hours (single dose half-life 52-76 hours).
Elimination: Efavirenz has a terminal half- life of 52- 76 hours after single doses and 40- 55 hours after multiple doses. A
one-month mass balance/ excretion study was conducted using 400 mg per day with a 14 C-labeled dose administered on
Day 8. Approximately 14- 34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces.
Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the
majority of the total radioactivity measured in feaces.
Efavirenz is indicated for the treatment of HIV infection in children and adults. Efavirenz is most effective when used as
part of a triple combination therapy regimen with two other anti-HIV drugs.
DOSAGE AND DIRECTION OF USE:
Adults: Orally 600mg once daily. It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime.
Increased absorption occurs when efavirenz is taken with food and may lead to adverse events. Taking efavirenz before
bedtime may improve the tolerability of neurological side effects.
Paediatric: For children older than 3 years, administered efavirenz once daily as follows: 200mg (10 to <15kg); 250mg (
15 to <20kg); 300mg ( 20 to <25kg); 350mg ( 25 to < 32.5kg); 400mg ( 32.5 to 40kg) ; 600mg ( >40kg).
Previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin
eruptions) to efavirenz.
For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the
potential for serious and/or life-threatening adverse reactions (e.g., cardiac arrhythmias, prolonged sedation, or
Hepatic Impairment: The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic
Renal Impairment: The pharmacokinetics of efavirenz have not been studied in patients with renalinsufficiency;
however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz
elimination should be minimal.
Gender and Race: The pharmacokinetics of efavirenz in patients appear to be similar between men and women and
among the racial groups studied.
Efavirenz must not be used as a single agent to treat HIV or added on a a sole agent to a failing regimen. As with all other
non – nucleoside reverse transcriptase inhibitors, resistance virus emerges rapidly when efavirenz is administered as
monotheraphy. The choice of new antiretroviral agent to be used in combination with efavirenz should take into
consideration the potential for viral cross-resistance.
Grapefruit juice may effect plasma efavirenz concentration.
Antibacterials: increased risk of rash with clarithromycin. Rifampicin reduces plasma concentration of efavirenz.
Antidepressants: avoid concomitant use of st. john’s wort
Antihistaminics: increased risk of ventricular arrhythmias when used with terfenadine. Other antivirals: Efavirenz
reduces plasma concentration of amprenavir, indinavir and lipinavir. Efavirenz reduces plasma concentration of
Anxiolytics: Risk of prolonged sedation with midazolam.
Oestrogen and progestogens: possibly reduced efficacy of oral contraceptives.
SIDE EFFECTS AND PRECAUTIONS:
side effects included dizziness; sleep disturbance, vivid dreams, nightmares, hallucinations, and confusion. These lasted for a median 21 days and occurred in more than 50% of patients. In the expanded access program involving 4,000 individuals, serious depression (requiring hospitalization) was reported in six patients; treatment-related psychosis was reported in four patients. The serious psychiatric episodes occurred in patients with past depression or psychotic illness.
Patients with a history of psychiatric symptoms or suicidal thoughts should be warned about the probable CNS effects of efavirenz and the potential for their symptoms to worsen. Rash was reported in more than 30% of patients. It was mainly grade 1 or 2 maculopapular skin eruptions; most cases resolved when treatment was interrupted and did not recur when drug was resumed. Greater incidence and severity of rash have been reported in children (including grade 4 in 3.5%). According to one study, Hispanics or people with a history of sulfa rash had a greater risk of rash upon beginning NNRTI therapy (Derisi). Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered efavirenz at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600-mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, efavirenz showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies.
These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of efavirenz, the relevance to humans of neoplasms in efavirenz-treated mice is not known.
Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of efavirenz.
Use in Pregnancy and the Neonatal Period
Reproductive Risk Potential: Pregnancy Category D. Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving Efavirenz. Barrier contraception should always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing before initiation of Efavirenz. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
There are no adequate and well-controlled studies in pregnant women. Efavirenz should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. As of July 2004, the Antiretroviral Pregnancy Registry has received prospective reports of 237 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (232 pregnancies). Birth defects occurred in 5 of 188 live births (first-trimester exposure) and 0 of 13 live births (second/third-trimester exposure). None of these prospectively reported defects were neural tube defects. However, there have been four retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of Efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz. Malformations have been observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20-150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those in humans given 600 mg/day of Efavirenz. Anencephaly and unilateral anophthalmia were observed in one fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations.
Efavirenz has been shown to cross the placenta in rats and rabbits and produces fetal blood concentrations of efavirenz similar to maternal concentrations. An increase in fetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of Efavirenz. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of Efavirenz.
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Although it is not known if efavirenz is secreted in human milk, efavirenz is secreted into the milk of lactating rats. Because of the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breast-feed if they are receiving Efavirenz.
ACTG 382 is an ongoing, open-label study in 57 NRTI-experienced pediatric patients to characterize the safety, pharmacokinetics, and antiviral activity of Efavirenz in combination with nelfinavir (20-30 mg/kg TID) and NRTIs. Mean age was 8 years (range 3-16). Efavirenz has not been studied in pediatric patients below 3 years of age or who weigh less than 13 kg. At 48 weeks, the type and frequency of adverse experiences was generally similar to that of adult patients with the exception of a higher incidence of rash, which was reported in 46% (26/57) of pediatric patients compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 5% (3/57) of pediatric patients
compared to 0.9% of adults.
The starting dose of Efavirenz was 600 mg once daily adjusted to body size, based on weight, targeting AUC levels in the range of 190-380 μM•h. The pharmacokinetics of efavirenz in pediatric patients were similar to the pharmacokinetics in adults who received 600-mg daily doses of Efavirenz. In 48 pediatric patients receiving the equivalent of a 600-mg dose of Efavirenz, steady-state Cmax was 14.2 ± 5.8 μM (mean ± SD), steady-state Cmin was 5.6 ± 4.1 μM, and AUC was 218 ± 104 μM•h.
Clinical studies of Efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.
Animal carcinogenicity studies
Long-term animal carcinogenicity studies with efavirenz in rats and mice are not completed; in vitro screening tests have been negative.
Reproduction/fertility animal studies
No effect of efavirenz on reproduction or fertility in rodents has been seen. An increase in fetal resorptions has been observed in rats at doses comparable to or lower than those used to achieve human therapeutic exposure.
Teratogenicity/developmental toxicity animal studies
Malformations were observed in three of 20 infants born to pregnant cynomolgus monkeys receiving efavirenz from gestational days 20 to 150 at a dose of 30 mg/kg twice daily (resulting in plasma concentrations comparable to systemic human therapeutic exposure). The malformations included anencephaly and unilateral anophthalmia in one; microphthalmia in another; and cleft palate in the third. Primate teratogenicity studies have not been conducted for delavirdine or nevirapine.
Placental and breast milk passage in animal studies
Efavirenz crosses the placenta in rats, rabbits, and primates, producing cord blood concentrations similar to concentrations in maternal plasma. It is unknown whether efavirenz is excreted in human breast milk.
Human studies in pregnancy
No studies with efavirenz in pregnant humans are planned at this time. Because teratogenic effects were seen in primates at drug exposures similar to those representing human therapeutic exposure, pregnancy should be avoided in women receiving efavirenz.
Efavirenz has not been formally studied in pregnant women, but preliminary studies indicate that women should avoid becoming pregnant while on this drug. A study conducted in pregnant monkeys showed that there were malformations in fetuses the monkeys were given a dose similar to the recommended human dose.
Women should also be cautions of breast feeding while taking efavirenz because it may be passed through breast milk resulting in potential toxicity to the child. A study is planned to look at whether efavirenz can prevent or reduce the risk of transmission of HIV from moter to child.
Some patients accidently taking 600mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
Efavirenz: Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions must be considered before and during therapy.
Store in a cool & dry place, protected from light.
Keep out of reach of children.
30/60 tablets packed in HDPE Bottles.