Efavirenz (Page 2 of 10)

5.7 Embryo-Fetal Toxicity

Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Advise females of reproductive potential who are receiving efavirenz tablets to avoid pregnancy. [See Use in Specific Populations (8.1and 8.3).]

5.8 Rash

In controlled clinical trials, 26% (266/1,008) of adult patients treated with 600 mg efavirenz tablets experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups [see Adverse Reactions (6.1)].Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1,008) of patients treated with efavirenz tablets. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in adult patients treated with efavirenz tablets in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1,008).
Rash was reported in 59 of 182 pediatric patients (32%) treated with efavirenz tablets [see Adverse Reactions (6.2)].Two pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 28 days (range 3 to 1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz tablets in pediatric patients should be considered. Efavirenz tablets can generally be reinitiated in patients interrupting therapy because of rash. Efavirenz tablets 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 (eg, Stevens-Johnson syndrome), alternative therapy should be considered [see Contraindications (4)].

5.9 Hepatotoxicity

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. [see Adverse Reactions (6.1) and Use in Specific Populations ( 8.6)].Monitoring of liver enzymes before and during treatment is recommended for all patients [see Dosage and Administration ( 2.1)].Consider discontinuing efavirenz in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range. Discontinue efavirenz if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation.

5.10 Convulsions

Convulsions have been observed in adult and pediatric patients receiving efavirenz, generally in the presence of known medical history of seizures [see Nonclinical Toxicology (13.2)].Caution should be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels [see Drug Interactions (7.1)].

5.11 Lipid Elevations

Treatment with efavirenz tablets has resulted in increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions ( 6.1)].Cholesterol and triglyceride testing should be performed before initiating efavirenz tablets therapy and at periodic intervals during therapy.

5.12 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz tablets. 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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.13 Fat Redistribution

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.

6 ADVERSE REACTIONS

The most significant adverse reactions observed in patients treated with efavirenz tablets are:
• psychiatric symptoms [see Warnings and Precautions (5.5)],
• nervous system symptoms [see Warnings and Precautions (5.6)],
• rash [see Warnings and Precautions (5.8)]. • hepatotoxicity [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

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 tablets 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 tablets-treated patients in two controlled clinical trials are presented in Table 2.Table 2: Selected Treatment-Emergenta Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364

Adverse Reactions Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
Efavirenz tabletsb + ZDV/LAM(n=412) 180 weeksc Efavirenz tabletsb + Indinavir(n=415)102 weeksc Indinavir+ZDV/LAM(n=401) 76 weeksc Efavirenz tabletsb + Nelfinavir+ NRTIs(n=64)71.1 weeksc Efavirenz tabletsb + NRTIs(n=65)70.9 weeksc Nelfinavir+ NRTIs(n=66) 62.7 weeksc
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%
Psychiatric
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%
Pruritus <1% 1% 1% 9% 5% 9%

a Includes 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.

b Efavirenz tablets provided as 600 mg once daily.
c Median duration of treatment.

d Includes 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 (see Laboratory Abnormalities).
Nervous System Symptoms
For 1,008 patients treated with regimens containing efavirenz tablets 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 [see Warnings and Precautions (5.6)].The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2.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=1,008) % 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 1.3
Treatment discontinuation as a result of symptoms 2.1 1.1

a Includes events reported regardless of causality.
b Data 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 greater than 2% among patients treated with efavirenz tablets 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 1,008 adults treated with regimens containing efavirenz tablets 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 tablets-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz tablets and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz tablets-treated patients and 0.3% for control groups [see Warnings and Precautions (5.8)].
Experience with efavirenz tablets 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 tablets. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz tablets, and two of these patients discontinued because of rash.
Laboratory Abnormalities
Selected Grade 3 to 4 laboratory abnormalities reported in ≥2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4.
Table 4: Selected Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Efavirenz-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 Efavirenz tabletsa +ZDV/LAM(n=412) 180 weeksb Efavirenz tabletsa +Indinavir(n=415) 102 weeksb Indinavir+ZDV/LAM(n=401)76 weeksb Efavirenz tabletsa +Nelfinavir+ NRTIs(n=64) 71.1 weeksb Efavirenz tabletsa +NRTIs(n=65) 70.9 weeksb Nelfinavir+ NRTIs(n=66) 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%
Triglyceridesd ³751mg/dL 9% 6% 6% 11% 8% 17%
Hematology
Neutrophils <750/mm3 10% 3% 5% 2% 3% 2%

a Efavirenz tablets provided as 600 mg once daily.
b Median duration of treatment.
c Isolated elevations of GGT in patients receiving efavirenz tablets may reflect enzyme induction not associated with liver toxicity.
d Nonfasting.
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 tablets-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 tablets 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 tablets arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz tablets-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions (5.9)].Lipids
Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz tablets + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz tablets + 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 tablets + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz tablets + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz tablets 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 [see Warnings and Precautions (5.11)].
Adverse Reactions in Pediatric Patients
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 tablets 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 [see Warnings and Precautions (5.8)].

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