Efavirenz (Systemic)


VA CLASSIFICATION
Primary: AM840

Commonly used brand name(s): Sustiva.

Another commonly use name is
EFV{03}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral (systemic)—

Indications

General considerations
The use of efavirenz for the treatment of human immunodeficiency virus type 1 (HIV-1) infection is based on analyses of plasma HIV-RNA levels and CD4 cell counts in controlled studies of up to 24 weeks duration. {01} Results from controlled trials evaluating the long-term suppression of HIV-RNA with efavirenz have not yet been obtained. {01}

When non-nucleoside reverse transcriptase inhibitors (NNRTIs) are administered as monotherapy, viral resistance occurs over a short period of time. {01} Therefore, efavirenz should not be given as a single agent or added by itself to a failing regimen. {01} Efavirenz should be initiated in combination with at least one new antiretroviral agent to which the patient has not been previously exposed. {01}

Accepted

Human immunodeficiency virus (HIV) (treatment)—Efavirenz is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. {01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    315.68 {01}

Solubility
    Practically insoluble in water (< 10 mcg/mL). {01}

Mechanism of action/Effect:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). {01} The action of efavirenz is through noncompetitive inhibition of HIV-1 reverse transcriptase. {01} Efavirenz has no inhibitory effect on human immunodeficiency virus type 2 (HIV-2) reverse transcriptase or human cellular DNA polymerases alpha, beta, gamma, or delta. {01}

Absorption:

Dose-related increases in peak plasma concentration (C max) and area under the curve (AUC) were seen for doses up to 1600 mg. {01} The increases were less than proportional, suggesting diminished absorption at higher doses. {01}

Meals of normal composition had no significant effect on the bioavailability of 100 mg of an investigational efavirenz formulation administered twice a day for 10 days with meals. {01} The relative bioavailability of a single 1200 mg dose of an investigational efavirenz formulation in uninfected volunteers was increased by 50% (range 11 to 126%) following a high fat meal. {01} Efavirenz may be taken with or without meals; however, it should not be taken with meals with a high fat content. {01}

Distribution:

In HIV-1 infected patients who received efavirenz 200 to 600 mg once a day for at least 1 month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. {01} This proportion is approximately threefold higher than the non–protein-bound (free) fraction of efavirenz in plasma. {01}

Protein binding:

Very high (approximately 99.5 to 99.75%); primarily bound to albumin. {01}

Biotransformation:

Efavirenz is metabolized primarily by the hepatic cytochrome P450 system into hydroxylated, inactive metabolites. {01} These metabolites undergo subsequent glucuronidation. {01} In vitro studies suggest that CYP3A4 and CYP2B6 are the principal isoenzymes responsible for the metabolism of efavirenz {01}. Efavirenz is an inducer of cytochrome P450 enzymes, resulting in the induction of its own metabolism. {01} Ten days of therapy with 200 to 400 mg of efavirenz daily resulted in a lower-than-expected accumulation of medication (22 to 42% lower) and a shorter terminal half-life, 40 to 55 hours compared with the single-dose half-life of 52 to 76 hours. {01}

Half-life:


Elimination:

Terminal half-life:

• Single dose—52 to 76 hours. {01}


• Multiple doses—40 to 55 hours. {01}



Time to peak concentration:

3 to 5 hours. {01}

Peak serum concentration:

12.9 ± 3.7 micromoles at steady state; 1.6 to 9.1 micromoles following single oral doses of 100 to 1600 mg. {01}

Elimination:
    Renal; 14 to 34% of a radiolabeled dose of efavirenz was recovered in the urine, nearly all in the form of metabolites. {01}
    Fecal; 16 to 61% of a radiolabeled dose was recovered, primarily unchanged, in the feces. {01}


Precautions to Consider

Carcinogenicity

Long-term carcinogenicity studies of efavirenz in rats and mice are currently in progress. {01}

Mutagenicity

Efavirenz was not shown to be mutagenic or genotoxic in either in vitro or in vivo genotoxicity assays. {01} The assays included bacterial mutation assays in Salmonella typhimurium and Escherichia coli , mammalian mutation assays in Chinese hamster ovary cells, chromosomal aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. {01}

Pregnancy/Reproduction
Fertility—
Efavirenz did not impair the mating or fertility of male or female rats {01}. Sperm of male rats treated with efavirenz were not affected. The reproductive performance of offspring born to females given efavirenz was not affected. {01} Rapid clearance of efavirenz occurs in rats. As a result, the systemic drug exposures achieved in these fertility studies were either equivalent to or below those achieved in humans on therapeutic doses of efavirenz. {01}

Pregnancy—
No adequate and well-controlled studies have been performed in pregnant women. {01}

In animal studies, malformations have been observed in cynomolgus monkey fetuses whose mothers received doses of efavirenz throughout pregnancy (postcoital days 20 to 150) that resulted in plasma concentrations similar to those seen in humans at a 600 mg per day dose. {01} The malformations occurred at a rate of 3 fetuses with malformations out of 20. The malformations included anencephaly and unilateral anophthalmia in one fetus, microophthalmia in another fetus, and cleft palate in a third fetus. {01} Efavirenz crosses the placenta in cynomolgus monkeys and results in fetal blood concentrations that are similar to maternal blood concentrations. {01} Efavirenz also has been shown to cross the placenta in both rats and rabbits, producing fetal blood concentrations similar to those of maternal concentrations. {01} An increase in fetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in rats equivalent to or lower than those achieved in humans at doses of 600 mg daily. {01} No reproductive toxicities were seen when efavirenz was given to pregnant rabbits at doses that produced peak plasma concentrations that were similar to, and AUC values that were approximately half of, those achieved in humans at doses of 600 mg daily. {01}

Pregnancy should be avoided in women receiving efavirenz due to the teratogenic effects observed in primates at plasma concentrations similar to those in humans. {01} Two methods of birth control, a method of barrier contraception in combination with another method of contraception, such as an oral or other hormonal contraceptive, should be used to avoid pregnancy. {01} Before initiating therapy with efavirenz, women of childbearing potential should undergo pregnancy testing. It is recommended that efavirenz not be given to pregnant women except in a situation in which there are no therapeutic alternatives. {01}

An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to efavirenz. Physicians are encouraged by the manufacturer to register patients by calling (800) 258-4263. {01}

FDA Pregnancy Category C. {01}

Breast-feeding

It is not known whether efavirenz is distributed into breast milk in humans. However, efavirenz is distributed into the milk of lactating rats. {01} In addition, the Centers for Disease Control and Prevention recommends that HIV-infected mothers refrain from breast-feeding their infants to avoid risking postnatal transmission of HIV. Breast-feeding is not recommended during therapy with efavirenz. {01}

Pediatrics

Safety and efficacy have not been established in children up to 3 years of age or those who weigh less than 13 kg. {01} The types and severity of adverse reactions generally were similar to those of adults; however, children experienced a higher incidence of rash (40% of children compared with 28% of adults). {01} In addition, the incidence of severe rash (Grade 3 or 4) was higher in children; 7% of children developed a severe rash compared with 0.7% of adults. {01} The median time to onset of rash in children was 8 days. {01} Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz should be considered. {01}


Geriatrics


No information is available on the relationship of age to the effects of efavirenz in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol or
Psychoactive drugs    (concurrent use may have an additive effect on the central nervous system [CNS] effects of efavirenz {01})


» Amprenavir    (efavirenz may decrease the plasma concentrations of amprenavir; no specific dosage adjustment can be recommended until additional studies are conducted {02})


» Astemizole or
» Cisapride    (efavirenz may inhibit the metabolism of these medications through competition for the CYP3A4 isoenzyme, which may increase the potential for cardiac arrythmias; use is contraindicated {01})


Clarithromycin    (efavirenz may decrease the plasma concentration of clarithromycin; consideration of alternatives to clarithromycin, such as azithromycin, is recommended since coadministration of azithromycin with efavirenz did not result in any clinically significant pharmacokinetic interactions; other macrolide antibiotics, such as erythromycin, have not been studied in combination with efavirenz {01})


» Ergot derivatives    (efavirenz may inhibit the metabolism of these medications, increasing the potential for respiratory depression; use is contraindicated {01})


Ethinyl estradiol    (plasma concentrations of this medication may be increased by efavirenz; the clinical significance is unknown; the addition of a reliable method of barrier contraception is recommended {01})


» Indinavir    (efavirenz may decrease plasma concentrations of indinavir through enzyme induction; it is recommended that the dose of indinavir be increased from 800 milligrams every 8 hours to 1000 milligrams every 8 hours when used concurrently with efavirenz)


Medications metabolized by hepatic enzymes 2C9, 2C19, and 3A4    (concurrent use of efavirenz with medications primarily metabolized by the isoenzymes 2C9, 2C19, and 3A4 may result in altered plasma concentrations of the coadministered medication due to induction or inhibition of these enzymes by efavirenz {01})


» Midazolam or
» Triazolam    (efavirenz may inhibit the metabolism of these medications through competition for the CYP3A4 isoenzyme, increasing the potential for prolonged sedation; use is contraindicated {01})


Phenobarbital    (concurrent use of phenobarbital may increase the clearance of efavirenz due to induction of CYP3A4 activity and result in lower plasma concentrations {01})


» Rifabutin    (plasma concentrations of rifabutin may be decreased by efavirenz; increasing the dose of rifabutin by at least 50% may be considered for concurrent administration; adjustment of efavirenz dosage is not necessary {02})


Rifampin    (concurrent use of rifampin may decrease efavirenz plasma concentrations; the clinical significance of decreased efavirenz concentrations is unknown; adjustment of efavirenz or rifampin dosage is not recommended {01})


» Ritonavir    (concurrent use of efavirenz with ritonavir may result in a higher frequency of adverse effects [dizziness, nausea, and paresthesia] and laboratory abnormalities [elevated liver enzymes]; monitoring of liver enzymes is recommended {01})


» Saquinavir    (plasma concentrations of saquinavir may be decreased by efavirenz; it should not be used as the sole protease inhibitor in combination with efavirenz {01})


» Warfarin    (plasma concentrations and clinical effects may be either increased or decreased when the medication is used concurrently with efavirenz {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Cannabinoid test    (although efavirenz does not bind to cannabinoid receptors, false positive urine cannabinoid test results have been reported in uninfected volunteers who received efavirenz; the false-positive test results have been observed only with the CEDIA DAU Multi-Level THC assay, used for screening, and were not observed with other cannabinoid assays, including those used for confirmation of positive results {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to efavirenz{01}
Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment or{01}
» Hepatitis B or C, confirmed or suspected history of{01}    (caution is recommended because of the lack of experience with efavirenz in hepatic function impairment and the necessary metabolism of efavirenz by the cytochrome P450 system {01}; liver enzymes should be monitored periodically {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Liver enzymes    (monitoring of liver enzymes is recommended in patients in whom a history of hepatitis B or C is confirmed or suspected and in patients treated with other medications associated with liver toxicity {01})


Lipids    (efavirenz may increase total cholesterol or serum triglycerides; clinical significance is not yet known {01})




Side/Adverse Effects

Note: Fifty-two percent of patients treated with efavirenz reported CNS or psychiatric symptoms {01}. In 2.6% of patients these symptoms were severe and resulted in discontinuation of therapy with efavirenz. {01} The CNS and psychiatric symptoms usually appear within the first or second day of treatment and generally resolve after 2 to 4 weeks of therapy. {01}
Skin rashes usually appear as mild or moderate maculopapular skin eruptions that occur within the first 2 weeks of therapy with efavirenz. {01}
The side/adverse effects listed below were observed when efavirenz was used in combination with other antiretrovirals. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Depression{01}
    
pruritus{01} (itching)
    
skin rash{01} —incidence 27% in adults, 40% in children

Incidence less frequent
    
Hematuria{01} (blood in urine)
    
increase in total cholesterol concentration —asymptomatic
    
renal calculus{01} (difficult or painful urination; pain in lower back and/or side)

Incidence rare
    
Abnormal vision{01} (changes in vision)
    
allergic reaction{01} (skin rash or hives; fever; troubled breathing; tightness in chest; wheezing)
    
asthma{01} (cough; difficulty breathing; tightness in chest; wheezing)
    
ataxia{01} (clumsiness or unsteadiness)
    
confusion{01}
    
convulsions{01}
    
depression, severe acute
    
diplopia{01} (double vision)
    
elevated liver enzymes{01} —asymptomatic
    
erythema multiforme (possible prodrome of chills, fever, sore throat, muscle aches or pains, or nausea or vomiting; sores, ulcers, or white spots in mouth or on lips; skin rash or sores, hives, or itching)
    
fever{01}
    
hepatitis{01} (yellow eyes or skin; loss of appetite; unusual tiredness; weight loss; fever; skin rash or itching; nausea or vomiting; dark urine)
    
impaired coordination{01} (difficulty with coordination)
    
migraine headache{01} (headache, severe and throbbing)
    
neuralgia{01} (nerve pain)
    
pancreatitis{01} (abdominal pain; fever with or without chills; swelling and/or tenderness in upper abdominal or stomach area)
    
paresthesia{01} (tingling, burning, or prickling sensations)
    
peripheral edema{01} (swelling of hands, arms, feet, or legs; rapid weight gain)
    
peripheral neuropathy{01} (tingling, burning, numbness, or pain in the hands, arms, feet, or legs)
    
psychological reactions, such as
delusions or inappropriate behavior{01} —primarily in patients with a history of mental illness or substance abuse (incidence 0.1 to 0.2%)
hallucinations{01} (seeing, hearing, or feeling things that are not there), psychosis{01} (severe mood or mental changes)
    
speech disorder{01}
    
Stevens-Johnson syndrome
    
suicidal ideation or attempts (thoughts of suicide or attempts at suicide)
    
syncope (fainting)
    
tachycardia or palpitations{01} (fast or pounding heartbeat)
    
thrombophlebitis{01} (pain, tenderness, bluish color, or swelling of leg or foot)
    
skin rash, severe, associated with blistering, moist desquamation, or ulceration (blistering; open sores; ulcers)—incidence 1%
    
tremor{01}
    
urticaria{01} (hives)
    
vertigo{01} (sense of constant movement of self or surroundings)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea{01}
    
dizziness{01}
    
fatigue{01}
    
headache{01}
    
impaired concentration{01} (poor concentration)
    
increased sweating{01}
    
insomnia{01} (trouble in sleeping)
    
nausea or vomiting{01}
    
somnolence{01} (drowsiness)

Incidence less frequent
    
Abdominal pain or dyspepsia{01} (abdominal pain; heartburn; indigestion; stomach discomfort)
    
abnormal dreams{01}
    
anorexia{01} (loss of appetite)
    
flatulence{01} (belching; excessive gas)
    
hypoesthesia{01} (abnormally decreased sensitivity, particularly to touch)
    
nervousness{01}

Incidence rare
    
Agitation or anxiety{01}
    
alopecia{01} (loss of hair)
    
amnesia{01} (loss of memory)
    
apathy{01} (lack of feeling or emotion)
    
arthralgia or myalgia{01} (joint or muscle pain)
    
asthenia{01} (weakness)
    
depersonalization{01} (loss of sense of reality)
    
dry mouth{01}
    
eczema{01} (skin rash)
    
emotional lability{01} (mood changes)
    
euphoria{01} (false sense of well-being)
    
folliculitis{01} (painful, red, hot, or irritated hair follicles)
    
flushing{01}
    
malaise{01} (general feeling of discomfort)
    
parosmia{01} (change in sense of smell)
    
skin exfoliation{01} (flaking and falling off of skin)
    
taste perversion{01} (change in sense of taste)
    
tinnitus{01} (ringing in the ears)





Overdose
Some patients who accidentally took twice the recommended adult daily dose reported increased CNS symptoms. {01} One patient experienced involuntary muscle contractions. {01}

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
There is no specific antidote for overdose of efavirenz. {01} Treatment of overdose should consist of general supportive measures, including monitoring the patient's vital signs and clinical status. {01}

To decrease absorption—Activated charcoal may be administered to aid the removal of unabsorbed efavirenz {01}. Dialysis is not expected to significantly remove efavirenz from the blood since the drug is highly protein bound {01}.

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Efavirenz (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to efavirenz

Pregnancy—Birth defects and other problems have been observed in animal studies





Breast-feeding—Breast-feeding is not recommended due to the potential for postnatal transmission of the HIV-1 virus; it is unknown whether efavirenz is distributed into human breast milk; however, it is distributed into the milk of rats





Use in children—Children are at an increased risk for skin rash, which may be severe; the appearance of a rash should be reported to the physician as soon as possible

Other medications, especially amprenavir, astemizole, cisapride, ergot derivatives, indinavir, midazolam, rifabutin, ritonavir, saquinavir, triazolam, or warfarin
Other medical problems, especially liver function impairment or history of hepatitis B or C

Proper use of this medication
» Importance of not taking more medication than prescribed; importance of not discontinuing efavirenz without checking with physician

» Compliance with full course of therapy with efavirenz and with any other medications prescribed for HIV infection

Taking efavirenz with or without meals; not taking with high fat meals because they may increase the absorption of the medication

Being aware that the CNS and psychiatric side effects are likely to decrease with continued therapy; dosing at bedtime, especially during the first 2 to 4 weeks of treatment, may make these side effects more tolerable

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Avoiding potentially hazardous tasks such as driving or operating machinery since efavirenz may cause dizziness, impaired concentration, and/or drowsiness

» Checking with physician before taking efavirenz with alcohol or other psychoactive medications since concurrent use may exacerbate the CNS effects

» Being aware that efavirenz therapy does not reduce the risk of transmitting HIV to others through sexual contact or contamination through blood

» Using two methods of contraception, a reliable barrier method and an oral or other hormonal contraceptive, when the potential for pregnancy exists


Side/adverse effects
Signs of potential side effects, especially depression; pruritus; skin rash; hematuria; renal calculus; abnormal vision; allergic reaction; asthma; ataxia; confusion; convulsions; diplopia; erythema multiforme; fever; hepatitis; impaired coordination; migraine headache; neuralgia; pancreatitis; paresthesia; peripheral edema; peripheral neuropathy; psychological reactions, such as delusions, inappropriate behavior, hallucinations, or psychosis; speech disorder; Stevens-Johnson syndrome; suicidal ideation or attempts; syncope; tachycardia or palpitations; thrombophlebitis; tremor; urticaria; and vertigo


General Dosing Information
When non-nucleoside reverse transcriptase inhibitors (NNRTIs) are administered as monotherapy, viral resistance occurs over a short period of time. {01} Therefore, efavirenz should not be given as a single agent or added solely to a failing regimen. {01} Efavirenz should be initiated in combination with at least one new antiretroviral agent to which the patient has not previously been exposed. {01}

Treatment with efavirenz may be reinitiated in patients whose therapy was interrupted by a skin rash. The use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is restarted. {01}

Prophylaxis with antihistamines is recommended in children before initiating therapy with efavirenz due to the high incidence of skin rash, which may be severe, in this population. {01}

For treatment of adverse effects
Recommended treatment consists of the following:    • Discontinuation of efavirenz in patients who experience skin rash associated with blistering, desquamation, mucosal involvement, or fever. {01} Treatment with antihistamines and/or corticosteroids may increase the tolerability of symptoms and shorten the time to resolution of the rash. {01}



Oral Dosage Forms

EFAVIRENZ CAPSULES

Usual adult and adolescent dose
Antiviral
Oral, 600 mg once a day. {01}


Usual pediatric dose
Antiviral
Children up to 3 years of age: Safety and efficacy have not been established. {01}
Children 3 years of age and older (by weight) {01}:

• 10 to 15 kg—Oral, 200 mg once a day.


• 15 to 20 kg—Oral, 250 mg once a day.


• 20 to 25 kg—Oral, 300 mg once a day.


• 25 to 32.5 kg—Oral, 350 mg once a day.


• 32.5 to 40 kg—Oral, 400 mg once a day.


• ³ 40 kg—See Usual adult and adolescent dose .



Usual geriatric dose
Antiviral
See Usual adult and adolescent dose .


Strength(s) usually available
U.S.—


50 mg (Rx) [Sustiva{01}]


100 mg (Rx) [Sustiva{01}]


200 mg (Rx) [Sustiva{01}]

Packaging and storage:
Store at 25 ºC (77 ºF); brief deviations between 15 and 30 ºC (59 and 86 ºF) are allowed. {01}

Auxiliary labeling:
   • May cause dizziness or drowsiness.
   • Take at bedtime.
   • Caution with alcoholic beverages.



Developed: 12/14/1998
Revised: 02/10/2003



References
  1. Sustiva package insert (DuPont—US), Issued 9/98, Rec 10/98.
  1. Fiske WD, Benedek IH, Joshi AS, et al. Summary of pharmacokinetic drug interaction studies with efavirenz. Presented at the 36th Annual Meeting of Infectious Disease Society of America. 1998 Nov 12-15; Denver, Colorado. DuPont Pharmaceuticals.
  1. Feinberg, William, R.Ph.,M.B.A., 2002 Update Pharmacy Perspective: Acquired Immune Deficiency Disease. CE PRN®2002; 13-18.
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