Efavirenz
Efavirenz Prescribing Information
Efavirenz in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg.
• Efavirenz should be taken orally once daily on an empty stomach, preferably at bedtime. (
• Efavirenz should be taken orally once daily on an empty stomach, preferably at bedtime.
• Recommended adult dose: 600 mg.
• With rifampin, increase efavirenz dose to 800 mg once daily for patients weighing 50 kg or more.
• Pediatric dosing is based on weight.
Monitor hepatic function prior to and during treatment with efavirenz [
Efavirenz is not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C) [
The recommended dosage of efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions
Concomitant Antiretroviral Therapy
Efavirenz must be given in combination with other antiretroviral medications
If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). Efavirenz tablets must not be broken.
Table 1: Efavirenz Dosing in Pediatric Patients | ||
|---|---|---|
Patient Body Weight | Efavirenz Daily Dose | Number of Capsulesaor Tabletsband Strength to Administer |
| 3.5 kg to less than 5 kg | 100 mg | two 50 mg capsules |
| 5 kg to less than 7.5 kg | 150 mg | three 50 mg capsule |
| 7.5 kg to less than 15 kg | 200 mg | one 200 mg capsule |
| 15 kg to less than 20 kg | 250 mg | one 200 mg + one 50 mg capsule |
| 20 kg to less than 25 kg | 300 mg | one 200 mg + two 50 mg capsules |
| 25 kg to less than 32.5 kg | 350 mg | one 200 mg + three 50 mg capsules |
| 32.5 kg to less than 40 kg | 400 mg | two 200 mg capsules |
| at least 40 kg | 600 mg | one 600 mg tablet OR three 200 mg capsules |
aCapsules can be administered intact or as sprinkles
bTablets must not be crushed
• Recommended adult dose: 600 mg. (
The recommended dosage of efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions
Concomitant Antiretroviral Therapy
Efavirenz must be given in combination with other antiretroviral medications
If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). Efavirenz tablets must not be broken.
Concomitant Antiretroviral Therapy
Efavirenz must be given in combination with other antiretroviral medications
If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). Efavirenz tablets must not be broken.
Table 1: Efavirenz Dosing in Pediatric Patients | ||
|---|---|---|
Patient Body Weight | Efavirenz Daily Dose | Number of Capsulesaor Tabletsband Strength to Administer |
| 3.5 kg to less than 5 kg | 100 mg | two 50 mg capsules |
| 5 kg to less than 7.5 kg | 150 mg | three 50 mg capsule |
| 7.5 kg to less than 15 kg | 200 mg | one 200 mg capsule |
| 15 kg to less than 20 kg | 250 mg | one 200 mg + one 50 mg capsule |
| 20 kg to less than 25 kg | 300 mg | one 200 mg + two 50 mg capsules |
| 25 kg to less than 32.5 kg | 350 mg | one 200 mg + three 50 mg capsules |
| 32.5 kg to less than 40 kg | 400 mg | two 200 mg capsules |
| at least 40 kg | 600 mg | one 600 mg tablet OR three 200 mg capsules |
aCapsules can be administered intact or as sprinkles
bTablets must not be crushed
• Efavirenz Tablets, USP 600 mg
600-mg tablets are yellow, biconvex, capsule-shaped, film-coated tablets, engraved with "ML 12" on one side and plain on the other side.
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Because of potential teratogenic effects, pregnancy should be avoided in women receiving efavirenz
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Efavirenz is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering Efavirenz to these patients
•
In controlled clinical trials, 26% (266/1008) of adult patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups
Rash was reported in 59 of 182 pediatric patients (32%) treated with efavirenz
Efavirenz can generally be reinitiated in patients interrupting therapy because of rash. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered
The following adverse reactions have been identified during postapproval use of efavirenz tablets. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Central and Peripheral Nervous
The safety, pharmacokinetic profile, and virologic and immunologic responses of efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials
• Efavirenz is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product.
• Coadministration of efavirenz with elbasvir and grazoprevir is contraindicated [
Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. The most prominent effect of efavirenz at steady-state is induction of CYP3A and CYP2B6
Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with efavirenz
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QTc prolongation has been observed with the use of efavirenz [
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Efavirenz must not be used as a single agent to treat HIV-1 infection or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance.
•Not recommended with ATRIPLA, which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (
Coadministration of efavirenz with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (e.g., with rifampin), since efavirenz is one of its active ingredients.
•
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz -treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior although a causal relationship to the use of efavirenz cannot be determined from these reports. Postmarketing cases of catatonia have also been reported and may be associated with increased efavirenz exposure. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Drug Interactions
A statement to patients and healthcare providers is included on the product's bottle labels:
Efavirenz tablets may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, nonprescription medication.
General Information for Patients
Infom patients that efavirenz tablets is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician while taking efavirenz tablets.
Advised patients to avoid doing things that can spread HIV-1 infection to others.
Dosing Instructions
Advised patients to take efavirenz tablets. every day as prescribed. If a patient forgets to take efavirenz tablets, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Advise the patient to ask a healthcare provider if he/she needs help in planning the best times to take his/her medicine.
Efavirenz tablets must always be used in combination with other antiretroviral drugs. Advised patients to take efavirenz tablets on an empty stomach, preferably at bedtime. Taking efavirenz tablets with food increases efavirenz concentrations and may increase the frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms
For adult and pediatric patients who cannot swallow capsules or tablets, patients or their caregivers should be advised to read and carefully follow the instructions for administering the capsule contents in a small amount of food or infant formula [see Dosage and Administration and
Nervous System Symptoms
Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with efavirenz tablets
Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy which may occur months to years after beginning efavirenz tablets therapy
Psychiatric Symptoms
Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms and catatonia have been reported in patients receiving efavirenz tablets
Rash
Inform patients that a common side effect is rash
Hepatotoxicity
Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets during pregnancy
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known
The brands listed herein are trademarks of their respective owners.
Manufactured for :
Princeton, NJ 08540
Manufactured by:
Revised: 06/2024
.
•
Fifty-three percent (531/1008) of patients receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens
Patients receiving efavirenz should be alerted to the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs.
Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
Adverse Reactions in Adults.
The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting
Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials are presented in Table 2
Table 2: Selected Treatment-EmergentaAdverse Reactions of Moderate or Severe Intensity Reported in ≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 | ||||||
|---|---|---|---|---|---|---|
Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients | Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients | |||||
Adverse Reactions | Efavirenzb + ZDV/LAM (n=412) | Efavirenzb+ Indinavir (n=415) | Indinavir + ZDV/LAM (n=401) | Efavirenzb + Nelfinavir + NRTIs (n=64) | Efavirenzb + NRTIs (n=65) | Nelfinavir + NRTIs (n=66) |
180 weeksc | 102 weeksc | 76 weeksc | 71.1 weeksc | 70.9 weeksc | 62.7 weeksc | |
| Psychiatric | ||||||
| Body as a Whole | ||||||
| Fatigue | 8% | 5% | 9% | 0 | 2% | 3% |
| Pain | 1% | 2% | 8% | 13% | 6% | 17% |
Central and Peripheral Nervous System | ||||||
| Dizziness | 9% | 9% | 2% | 2% | 6% | 6% |
| Headache | 8% | 5% | 3% | 5% | 2% | 3% |
| Insomnia | 7% | 7% | 2% | 0 | 0 | 2% |
| Concentration impaired | 5% | 3% | <1% | 0 | 0 | 0 |
| Abnormal dreams | 3% | 1% | 0 | — | — | — |
| Somnolence | 2% | 2% | <1% | 0 | 0 | 0 |
| Anorexia | 1% | <1% | <1% | 0 | 2% | 2% |
Gastrointestinal | ||||||
| Nausea | 10% | 6% | 24% | 3% | 2% | 2% |
| Vomiting | 6% | 3% | 14% | — | — | — |
| Diarrhea | 3% | 5% | 6% | 14% | 3% | 9% |
| Dyspepsia | 4% | 4% | 6% | 0 | 0 | 2% |
| Abdominal pain | 2% | 2% | 5% | 3% | 3% | 3% |
| Anxiety | 2% | 4% | <1% | — | — | — |
| Depression | 5% | 4% | <1% | 3% | 0 | 5% |
| Nervousness | 2% | 2% | 0 | 2% | 0 | 2% |
Skin & Appendages | ||||||
| Rashd | 11% | 16% | 5% | 9% | 5% | 9% |
| Pruritis | <1% | 1% | 1% | 9% | 5% | 9% |
aIncludes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364. bEfavirenz tablets provided as 600 mg once daily. cMedian duration of treatment. dIncludes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified. ZDV = zidovudine, LAM=lamivudine. | ||||||
Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients (
Nervous System Symptoms
For 1008 patients treated with regimens containing efavirenz and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization
Table 3: Percent of Patients with One or More Selected Nervous System Symptomsa,b | ||
|---|---|---|
Percent of Patients with: | EFAVIRENZ TABLETS 600 mg Once Daily (n=1008) | Control Groups (n=635) |
% | % | |
Symptoms of any severity | 52.7 | 24.6 |
Mild symptomsc | 33.3 | 15.6 |
Moderate symptomsd | 17.4 | 7.7 |
Severe symptomse | 2.0 | 1.3 |
Treatment discontinuation as a result of symptoms | 2.1 | 1.1 |
aIncludes events reported regardless of causality.
bData from Study 006 and three Phase 2/3 studies.
c"Mild" = Symptoms which do not interfere with patient’s daily activities.
d"Moderate" = Symptoms which may interfere with daily activities.
e"Severe" = Events which interrupt patient’s usual daily activities.
Psychiatric Symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials, psychiatric symptoms observed at a frequency of greater than 2% among patients treated with efavirenz or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).
Rash
In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing efavirenz and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz -treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz -treated patients and 0.3% for control groups
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.
Laboratory Abnormalities
Selected Grade 3-4 laboratory abnormalities reported in greater than 2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4.
Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients | Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients | ||||||||
Variable | Limit | EFAVI RENZa+ ZDV/ LAM (n=412) | EFAVI RENZa+ Indinavir (n=415) | Indina vir + ZDV/ LAM (n=401) | EFAVI RENZa+ Nelfinavir + NRTIs (n=64) | EFAVI RENZa+ NRTIs (n=65) | Nelfi navir + NRTIs (n=66) | ||
180 weeksb | 102 weeksb | 76 weeksb | 71.1 weeksb | 70.9 weeksb | 62.7 weeksb | ||||
| Chemistry | |||||||||
| ALT | >5 x ULN | 5% | 8% | 5% | 2% | 6% | 3% | ||
| AST | >5 x ULN | 5% | 6% | 5% | 6% | 8% | 8% | ||
| GGTc | >5 x ULN | 8% | 7% | 3% | 5% | 0 | 5% | ||
| Amylase | >2 x ULN | 4% | 4% | 1% | 0 | 6% | 2% | ||
| Glucose | >250 mg/dL | 3% | 3% | 3% | 5% | 2% | 3% | ||
| Triglyce ridesd | ≥751 mg/dL | 9% | 6% | 6% | 11% | 8% | 17% | ||
| Hematology | |||||||||
| Neutrophils | <750/mm3 | 10% | 3% | 5% | 2% | 3% | 2% | ||
aEfairenz tablets provided as 600 mg once daily. bMedian duration of treatment. cIsolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity. dNonfasting. ZDV = zidovudine, LAM = lamivudine, ULN = Upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase | |||||||||
Patients Coinfected with Hepatitis B or C
Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz -containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders
Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received efavirenz in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Drug Interactions
A statement to patients and healthcare providers is included on the product's bottle labels:
Efavirenz tablets may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, nonprescription medication.
General Information for Patients
Infom patients that efavirenz tablets is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician while taking efavirenz tablets.
Advised patients to avoid doing things that can spread HIV-1 infection to others.
Dosing Instructions
Advised patients to take efavirenz tablets. every day as prescribed. If a patient forgets to take efavirenz tablets, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Advise the patient to ask a healthcare provider if he/she needs help in planning the best times to take his/her medicine.
Efavirenz tablets must always be used in combination with other antiretroviral drugs. Advised patients to take efavirenz tablets on an empty stomach, preferably at bedtime. Taking efavirenz tablets with food increases efavirenz concentrations and may increase the frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms
For adult and pediatric patients who cannot swallow capsules or tablets, patients or their caregivers should be advised to read and carefully follow the instructions for administering the capsule contents in a small amount of food or infant formula [see Dosage and Administration and
Nervous System Symptoms
Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with efavirenz tablets
Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy which may occur months to years after beginning efavirenz tablets therapy
Psychiatric Symptoms
Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms and catatonia have been reported in patients receiving efavirenz tablets
Rash
Inform patients that a common side effect is rash
Hepatotoxicity
Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets during pregnancy
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known
The brands listed herein are trademarks of their respective owners.
Manufactured for :
Princeton, NJ 08540
Manufactured by:
Revised: 06/2024
.
•
Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Advise females of reproductive potential who are receiving efavirenz to avoid pregnancy
There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the Antiretroviral Pregnancy Registry are not sufficient to adequately assess this risk. Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program(MACDP). Although a causal relationship has not been established between exposure to efavirenz in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose. In addition, fetal and embryonic toxicities occurred in rats, at a dose ten times less than the human exposure at recommended clinical dose. Because of the potential risk of neural tube defects, efavirenz should not be used in the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus.
There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to efavirenz-containing regimens in the first trimester.
Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of approximately 1000 live births following exposure to efavirenz-containing regimens (including over 800 live births exposed in the first trimester), there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4%-3.6%). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have a known association with anophthalmia.
Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternalsystemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately
0.7 times the maternal values. Three of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.
•
Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with efavirenz. Reports have included patients with underlying hepatic disease, including coinfection with hepatitis B or C, and patients without pre-existing hepatic disease or other identifiable risk factors.
Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving efavirenz. [
Monitoring of liver enzymes before and during treatment is recommended for all patients [
Discontinue efavirenz if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation.
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
Adverse Reactions in Adults.
The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting
Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials are presented in Table 2
Table 2: Selected Treatment-EmergentaAdverse Reactions of Moderate or Severe Intensity Reported in ≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 | ||||||
|---|---|---|---|---|---|---|
Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients | Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients | |||||
Adverse Reactions | Efavirenzb + ZDV/LAM (n=412) | Efavirenzb+ Indinavir (n=415) | Indinavir + ZDV/LAM (n=401) | Efavirenzb + Nelfinavir + NRTIs (n=64) | Efavirenzb + NRTIs (n=65) | Nelfinavir + NRTIs (n=66) |
180 weeksc | 102 weeksc | 76 weeksc | 71.1 weeksc | 70.9 weeksc | 62.7 weeksc | |
| Psychiatric | ||||||
| Body as a Whole | ||||||
| Fatigue | 8% | 5% | 9% | 0 | 2% | 3% |
| Pain | 1% | 2% | 8% | 13% | 6% | 17% |
Central and Peripheral Nervous System | ||||||
| Dizziness | 9% | 9% | 2% | 2% | 6% | 6% |
| Headache | 8% | 5% | 3% | 5% | 2% | 3% |
| Insomnia | 7% | 7% | 2% | 0 | 0 | 2% |
| Concentration impaired | 5% | 3% | <1% | 0 | 0 | 0 |
| Abnormal dreams | 3% | 1% | 0 | — | — | — |
| Somnolence | 2% | 2% | <1% | 0 | 0 | 0 |
| Anorexia | 1% | <1% | <1% | 0 | 2% | 2% |
Gastrointestinal | ||||||
| Nausea | 10% | 6% | 24% | 3% | 2% | 2% |
| Vomiting | 6% | 3% | 14% | — | — | — |
| Diarrhea | 3% | 5% | 6% | 14% | 3% | 9% |
| Dyspepsia | 4% | 4% | 6% | 0 | 0 | 2% |
| Abdominal pain | 2% | 2% | 5% | 3% | 3% | 3% |
| Anxiety | 2% | 4% | <1% | — | — | — |
| Depression | 5% | 4% | <1% | 3% | 0 | 5% |
| Nervousness | 2% | 2% | 0 | 2% | 0 | 2% |
Skin & Appendages | ||||||
| Rashd | 11% | 16% | 5% | 9% | 5% | 9% |
| Pruritis | <1% | 1% | 1% | 9% | 5% | 9% |
aIncludes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364. bEfavirenz tablets provided as 600 mg once daily. cMedian duration of treatment. dIncludes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified. ZDV = zidovudine, LAM=lamivudine. | ||||||
Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients (
Nervous System Symptoms
For 1008 patients treated with regimens containing efavirenz and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization
Table 3: Percent of Patients with One or More Selected Nervous System Symptomsa,b | ||
|---|---|---|
Percent of Patients with: | EFAVIRENZ TABLETS 600 mg Once Daily (n=1008) | Control Groups (n=635) |
% | % | |
Symptoms of any severity | 52.7 | 24.6 |
Mild symptomsc | 33.3 | 15.6 |
Moderate symptomsd | 17.4 | 7.7 |
Severe symptomse | 2.0 | 1.3 |
Treatment discontinuation as a result of symptoms | 2.1 | 1.1 |
aIncludes events reported regardless of causality.
bData from Study 006 and three Phase 2/3 studies.
c"Mild" = Symptoms which do not interfere with patient’s daily activities.
d"Moderate" = Symptoms which may interfere with daily activities.
e"Severe" = Events which interrupt patient’s usual daily activities.
Psychiatric Symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials, psychiatric symptoms observed at a frequency of greater than 2% among patients treated with efavirenz or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).
Rash
In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing efavirenz and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz -treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz -treated patients and 0.3% for control groups
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.
Laboratory Abnormalities
Selected Grade 3-4 laboratory abnormalities reported in greater than 2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4.
Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients | Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients | ||||||||
Variable | Limit | EFAVI RENZa+ ZDV/ LAM (n=412) | EFAVI RENZa+ Indinavir (n=415) | Indina vir + ZDV/ LAM (n=401) | EFAVI RENZa+ Nelfinavir + NRTIs (n=64) | EFAVI RENZa+ NRTIs (n=65) | Nelfi navir + NRTIs (n=66) | ||
180 weeksb | 102 weeksb | 76 weeksb | 71.1 weeksb | 70.9 weeksb | 62.7 weeksb | ||||
| Chemistry | |||||||||
| ALT | >5 x ULN | 5% | 8% | 5% | 2% | 6% | 3% | ||
| AST | >5 x ULN | 5% | 6% | 5% | 6% | 8% | 8% | ||
| GGTc | >5 x ULN | 8% | 7% | 3% | 5% | 0 | 5% | ||
| Amylase | >2 x ULN | 4% | 4% | 1% | 0 | 6% | 2% | ||
| Glucose | >250 mg/dL | 3% | 3% | 3% | 5% | 2% | 3% | ||
| Triglyce ridesd | ≥751 mg/dL | 9% | 6% | 6% | 11% | 8% | 17% | ||
| Hematology | |||||||||
| Neutrophils | <750/mm3 | 10% | 3% | 5% | 2% | 3% | 2% | ||
aEfairenz tablets provided as 600 mg once daily. bMedian duration of treatment. cIsolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity. dNonfasting. ZDV = zidovudine, LAM = lamivudine, ULN = Upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase | |||||||||
Patients Coinfected with Hepatitis B or C
Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz -containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders
Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received efavirenz in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash
Efavirenz is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering Efavirenz to these patients
•
In controlled clinical trials, 26% (266/1008) of adult patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups
Rash was reported in 59 of 182 pediatric patients (32%) treated with efavirenz
Efavirenz can generally be reinitiated in patients interrupting therapy because of rash. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
Adverse Reactions in Adults.
The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting
Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials are presented in Table 2
Table 2: Selected Treatment-EmergentaAdverse Reactions of Moderate or Severe Intensity Reported in ≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 | ||||||
|---|---|---|---|---|---|---|
Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients | Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients | |||||
Adverse Reactions | Efavirenzb + ZDV/LAM (n=412) | Efavirenzb+ Indinavir (n=415) | Indinavir + ZDV/LAM (n=401) | Efavirenzb + Nelfinavir + NRTIs (n=64) | Efavirenzb + NRTIs (n=65) | Nelfinavir + NRTIs (n=66) |
180 weeksc | 102 weeksc | 76 weeksc | 71.1 weeksc | 70.9 weeksc | 62.7 weeksc | |
| Psychiatric | ||||||
| Body as a Whole | ||||||
| Fatigue | 8% | 5% | 9% | 0 | 2% | 3% |
| Pain | 1% | 2% | 8% | 13% | 6% | 17% |
Central and Peripheral Nervous System | ||||||
| Dizziness | 9% | 9% | 2% | 2% | 6% | 6% |
| Headache | 8% | 5% | 3% | 5% | 2% | 3% |
| Insomnia | 7% | 7% | 2% | 0 | 0 | 2% |
| Concentration impaired | 5% | 3% | <1% | 0 | 0 | 0 |
| Abnormal dreams | 3% | 1% | 0 | — | — | — |
| Somnolence | 2% | 2% | <1% | 0 | 0 | 0 |
| Anorexia | 1% | <1% | <1% | 0 | 2% | 2% |
Gastrointestinal | ||||||
| Nausea | 10% | 6% | 24% | 3% | 2% | 2% |
| Vomiting | 6% | 3% | 14% | — | — | — |
| Diarrhea | 3% | 5% | 6% | 14% | 3% | 9% |
| Dyspepsia | 4% | 4% | 6% | 0 | 0 | 2% |
| Abdominal pain | 2% | 2% | 5% | 3% | 3% | 3% |
| Anxiety | 2% | 4% | <1% | — | — | — |
| Depression | 5% | 4% | <1% | 3% | 0 | 5% |
| Nervousness | 2% | 2% | 0 | 2% | 0 | 2% |
Skin & Appendages | ||||||
| Rashd | 11% | 16% | 5% | 9% | 5% | 9% |
| Pruritis | <1% | 1% | 1% | 9% | 5% | 9% |
aIncludes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364. bEfavirenz tablets provided as 600 mg once daily. cMedian duration of treatment. dIncludes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified. ZDV = zidovudine, LAM=lamivudine. | ||||||
Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients (
Nervous System Symptoms
For 1008 patients treated with regimens containing efavirenz and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization
Table 3: Percent of Patients with One or More Selected Nervous System Symptomsa,b | ||
|---|---|---|
Percent of Patients with: | EFAVIRENZ TABLETS 600 mg Once Daily (n=1008) | Control Groups (n=635) |
% | % | |
Symptoms of any severity | 52.7 | 24.6 |
Mild symptomsc | 33.3 | 15.6 |
Moderate symptomsd | 17.4 | 7.7 |
Severe symptomse | 2.0 | 1.3 |
Treatment discontinuation as a result of symptoms | 2.1 | 1.1 |
aIncludes events reported regardless of causality.
bData from Study 006 and three Phase 2/3 studies.
c"Mild" = Symptoms which do not interfere with patient’s daily activities.
d"Moderate" = Symptoms which may interfere with daily activities.
e"Severe" = Events which interrupt patient’s usual daily activities.
Psychiatric Symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials, psychiatric symptoms observed at a frequency of greater than 2% among patients treated with efavirenz or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).
Rash
In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing efavirenz and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz -treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz -treated patients and 0.3% for control groups
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.
Laboratory Abnormalities
Selected Grade 3-4 laboratory abnormalities reported in greater than 2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4.
Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients | Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients | ||||||||
Variable | Limit | EFAVI RENZa+ ZDV/ LAM (n=412) | EFAVI RENZa+ Indinavir (n=415) | Indina vir + ZDV/ LAM (n=401) | EFAVI RENZa+ Nelfinavir + NRTIs (n=64) | EFAVI RENZa+ NRTIs (n=65) | Nelfi navir + NRTIs (n=66) | ||
180 weeksb | 102 weeksb | 76 weeksb | 71.1 weeksb | 70.9 weeksb | 62.7 weeksb | ||||
| Chemistry | |||||||||
| ALT | >5 x ULN | 5% | 8% | 5% | 2% | 6% | 3% | ||
| AST | >5 x ULN | 5% | 6% | 5% | 6% | 8% | 8% | ||
| GGTc | >5 x ULN | 8% | 7% | 3% | 5% | 0 | 5% | ||
| Amylase | >2 x ULN | 4% | 4% | 1% | 0 | 6% | 2% | ||
| Glucose | >250 mg/dL | 3% | 3% | 3% | 5% | 2% | 3% | ||
| Triglyce ridesd | ≥751 mg/dL | 9% | 6% | 6% | 11% | 8% | 17% | ||
| Hematology | |||||||||
| Neutrophils | <750/mm3 | 10% | 3% | 5% | 2% | 3% | 2% | ||
aEfairenz tablets provided as 600 mg once daily. bMedian duration of treatment. cIsolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity. dNonfasting. ZDV = zidovudine, LAM = lamivudine, ULN = Upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase | |||||||||
Patients Coinfected with Hepatitis B or C
Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz -containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders
Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received efavirenz in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Drug Interactions
A statement to patients and healthcare providers is included on the product's bottle labels:
Efavirenz tablets may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, nonprescription medication.
General Information for Patients
Infom patients that efavirenz tablets is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician while taking efavirenz tablets.
Advised patients to avoid doing things that can spread HIV-1 infection to others.
Dosing Instructions
Advised patients to take efavirenz tablets. every day as prescribed. If a patient forgets to take efavirenz tablets, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Advise the patient to ask a healthcare provider if he/she needs help in planning the best times to take his/her medicine.
Efavirenz tablets must always be used in combination with other antiretroviral drugs. Advised patients to take efavirenz tablets on an empty stomach, preferably at bedtime. Taking efavirenz tablets with food increases efavirenz concentrations and may increase the frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms
For adult and pediatric patients who cannot swallow capsules or tablets, patients or their caregivers should be advised to read and carefully follow the instructions for administering the capsule contents in a small amount of food or infant formula [see Dosage and Administration and
Nervous System Symptoms
Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with efavirenz tablets
Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy which may occur months to years after beginning efavirenz tablets therapy
Psychiatric Symptoms
Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms and catatonia have been reported in patients receiving efavirenz tablets
Rash
Inform patients that a common side effect is rash
Hepatotoxicity
Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets during pregnancy
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known
The brands listed herein are trademarks of their respective owners.
Manufactured for :
Princeton, NJ 08540
Manufactured by:
Revised: 06/2024
.
•
Convulsions have been observed in adult and pediatric patients receiving efavirenz, generally in the presence of known medical history of seizures [
•
Treatment with efavirenz has resulted in increases in the concentration of total cholesterol and triglycerides
•
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as
•
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Drug Interactions
A statement to patients and healthcare providers is included on the product's bottle labels:
Efavirenz tablets may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, nonprescription medication.
General Information for Patients
Infom patients that efavirenz tablets is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician while taking efavirenz tablets.
Advised patients to avoid doing things that can spread HIV-1 infection to others.
Dosing Instructions
Advised patients to take efavirenz tablets. every day as prescribed. If a patient forgets to take efavirenz tablets, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Advise the patient to ask a healthcare provider if he/she needs help in planning the best times to take his/her medicine.
Efavirenz tablets must always be used in combination with other antiretroviral drugs. Advised patients to take efavirenz tablets on an empty stomach, preferably at bedtime. Taking efavirenz tablets with food increases efavirenz concentrations and may increase the frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms
For adult and pediatric patients who cannot swallow capsules or tablets, patients or their caregivers should be advised to read and carefully follow the instructions for administering the capsule contents in a small amount of food or infant formula [see Dosage and Administration and
Nervous System Symptoms
Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with efavirenz tablets
Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy which may occur months to years after beginning efavirenz tablets therapy
Psychiatric Symptoms
Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms and catatonia have been reported in patients receiving efavirenz tablets
Rash
Inform patients that a common side effect is rash
Hepatotoxicity
Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets during pregnancy
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known
The brands listed herein are trademarks of their respective owners.
Manufactured for :
Princeton, NJ 08540
Manufactured by:
Revised: 06/2024
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