SUSTIVA (Brand for EFAVIRENZ)

General Administration Information
For storage information, see the specific product information within the How Supplied section

-To reduce the nervous system side effects, bedtime dosing is recommended.

Route-Specific Administration

Oral Administration
-Administer on an empty stomach. Increased efavirenz concentrations observed following administration with food might lead to an increased frequency of adverse reactions.
Oral Solid Formulations
-Swallow capsules and tablets intact with liquid; DO NOT crush the tablets.

Capsule sprinkle method of administration
-For patients unable to swallow capsules or tablets.
-Open the capsule by holding horizontally over a small container and carefully twisting to open. Take precautions to avoid spillage or dispersion of the contents into the air.
-For patients able to tolerate solid foods, add a small amount (1-2 teaspoons) of age-appropriate soft food (applesauce, grape jelly, yogurt) to the container holding the entire capsule contents; gently mix and administer the dose.
-For young infants, the entire capsule contents is mixed in a medicine cup with 2 teaspoons (10 ml) of reconstituted, room temperature infant formula. After carefully stirring with a small spoon, the mixture is drawn up into a 10 ml oral syringe and administered.
-After administration, an additional small amount (2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse remaining drug residue, and administered to the patient.
-Administer the dose within 30 minutes of mixing.
-No additional food should be consumed for 2 hours after the dose.
-The mixture with grape jelly was rated as the most palatable formulation.

In general, CNS-related adverse reactions observed in pediatric patients were similar to those reported in adults. During clinical studies, 53% of efavirenz-treated patients experienced CNS symptoms compared to 25% of patients receiving control regimens. In a pediatric case series, 24% of patients experienced efavirenz-related CNS symptoms with 18% requiring drug discontinuation. Usually, these symptoms begin on the first or second day of therapy and resolve within 2 to 4 weeks; however, in some patients, late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. In one report, 37% of patients experienced persistent symptoms at 12 months, and in another report, half of treatment discontinuations occurred after 12 months. Reported nervous system adverse events included impaired concentration (8.3%), somnolence or drowsiness (7%), abnormal dreams/nightmares (6.2%), insomnia (16.3%, also reported as a general ADR in up to 7% of patients), and hallucinations (1.2%). Dizziness was reported in 28.1% of adults in trials. These symptoms were severe in 2% of patients, and 2.1% of patients discontinued treatment as a result. In clinical practice, up to 65% of patients experience CNS symptoms they describe as 'feeling stoned.' After 4 weeks of treatment, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9%. Dosing at bedtime may improve the tolerability of these reactions. Patients should be counseled regarding these symptoms and that they may spontaneously resolve after a few months. Additional CNS side effects reported with efavirenz include headache (2% to 8%), agitation, amnesia, anorexia (1% to 2%), confusion, depersonalization, euphoria, and stupor. Nervous system adverse events noted in postmarketing reports include abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, seizures, hypoesthesia, paresthesias, peripheral neuropathy, tremor, and vertigo, tinnitus, and visual impairment (abnormal vision). In one pediatric study in children younger than 36 months of age, 9% (n = 4/44) of patients experienced new onset-seizures; in 2 of these patients, seizures were due to alternative causes.

In general, adverse reactions observed in pediatric patients were similar to those reported in adults. Serious psychiatric adverse reactions have been reported with the use of efavirenz. Commonly reported psychiatric symptoms during efavirenz therapy in adults include depression (<= 19%; severe 2.4%), anxiety (<= 13%), and nervousness (<= 7%). In controlled trials (including 1,008 efavirenz-treated patients and 635 patients treated with control regimens), the frequency of specific serious psychiatric reactions among adult patients who received efavirenz included suicidal ideation (0.7%), nonfatal suicide attempts (0.5%), aggressive behavior (0.4%), paranoid reactions (paranoia/psychosis) (0.4%), and manic reactions (mania) (0.2%). Patients with a history of psychiatric disorders appear to be at greater risk for these serious psychiatric reactions. There have also been occasional postmarketing reports of aggressive reactions, catatonia, death by suicide, delusions, emotional lability, neurosis and psychosis-like behavior. Patients who experience serious psychiatric reactions 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.

In general, adverse reactions observed in pediatric patients were similar to those reported in adults; however, compared with adults, children tend to have more frequent and severe rashes. Rash (unspecified) was reported in 32% of pediatric patients. During clinical trials, Grade 3 rash (confluent rash with pyrexia, generalized rash) occurred in 1.1% of pediatric patients. Grade 4 rash (erythema multiforme, Stevens-Johnson syndrome) was reported in 2.2% of pediatric patients. The discontinuation rate for rash was 2.7% of pediatric patients in trials. Other dermatologic reactions reported in 5% to 16% of adults during clinical trials included allergic rash, erythema, erythematous rash, follicular rash, hives, inflammation, maculopapular rash, petechial rash, pruritus, pustular rash, urticaria, and welts. During postmarketing experience with efavirenz, photosensitivity (photoallergic dermatitis) was reported. Efavirenz associated skin rashes are usually mild-to-moderate maculopapular rashes that occur with the first 2 weeks of initiating therapy. In most cases, the rash resolves within 1 month while continuing therapy. Efavirenz can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids may be considered when efavirenz is restarted. Discontinue efavirenz in patients with blistering, desquamation, mucosal involvement, or high temperatures.

In general, adverse reactions observed in pediatric patients were similar to those reported in adults. Elevated hepatic enzymes have been observed in patients treated with efavirenz. Among adult patients treated with 600 mg of efavirenz in controlled clinical trials, 2% to 8% developed AST and ALT concentrations greater than 5-times the upper limit of normal (ULN). In adult patients treated with efavirenz who were seropositive for hepatitis B and/or C, 13% developed AST and 20% developed ALT concentrations greater than 5-times the ULN. Elevations of GGT to 5-times the ULN were observed in 5% to 8% of adult patients. Isolated elevation of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity. There have been postmarketing reports of hepatic failure, requiring transplantation or resulting in death, in patients with no pre-existing hepatic disease or other identifiable risk factors; therefore, liver enzyme monitoring is recommended before and during efavirenz treatment in all patients. Hypercholesterolemia consisting of increases in total cholesterol of 10% to 20% have been observed in non-HIV infected volunteers receiving efavirenz. In adult patients treated with efavirenz in combination with other antiretrovirals, increases in non-fasting cholesterol of 20% to 54%, increases in HDL of 4% to 35%, and increases in triglycerides of 6% to 11% were observed. The significance of the hypercholesterolemia and hypertriglyceridemia in patients treated with efavirenz is unknown. Other serious hepatotoxic reactions include hepatic failure and hepatitis.

In general, adverse reactions observed in pediatric patients were similar to those reported in adults. Asymptomatic hyperamylasemia (serum amylase > 1.5-times the upper limit of normal) was seen in 4% to 6% of adult patients treated with efavirenz as part of combination therapy. The clinical significance of asymptomatic increases in serum amylase is unknown. Pancreatitis has been reported, although a causal relationship with efavirenz has not been established.

In general, adverse reactions observed in pediatric patients were similar to those reported in adults. Gastrointestinal adverse reactions in adults reported during efavirenz therapy include nausea (2% to 10%), vomiting (3% to 6%), diarrhea (3% to 14%), dyspepsia (4%), and abdominal pain (2% to 3%). Constipation and malabsorption have been noted in postmarketing reports.

While more commonly associated with protease inhibitor therapy, a lipodystrophy syndrome consisting of redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, accumulation of facial fat, lipomas, gynecomastia, and other Cushingoid features has been reported in patients receiving long-term highly active antiretroviral therapy (HAART) that includes efavirenz. The mechanism by which nucleoside analogues may cause body fat changes is not known. It has been suggested that nucleoside analogs may damage the mitochondria of adipocytes. An increased incidence of body fat changes is noted in those patients receiving long-term nucleoside therapy and in female patients.

In general, adverse reactions observed in pediatric patients were similar to those reported in adults. Fatigue (2% to 8%) and pain (1% to 13%) were reported with efavirenz as part of adult combination antiretroviral therapy. Adverse reactions reported during postmarketing experience with efavirenz include asthenia, arthralgia, dyspnea, flushing, myalgia, myopathy, and palpitations.

Efavirenz may cause teratogenesis when administered to a pregnant woman. Birth defects have occurred with exposure during all trimesters, including neural tube defect (first trimester exposure). Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz. Due to the long half-life, the manufacturer recommends the use of contraceptive measures for 12 weeks after discontinuation of efavirenz.

In general, adverse reactions observed in pediatric patients were similar to those reported in adults. Neutropenia has been reported in 2% to 10% of adult patients receiving efavirenz as part of combination therapy in clinical trials.

In general, adverse reactions observed in pediatric patients were similar to those reported in adults. Hyperglycemia has been reported in 2% to 5% of adult patients receiving efavirenz as part of combination therapy in clinical trials.

QT prolongation has been reported with the use of efavirenz.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), or drug non-availability. If short-term treatment interruption is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in patients receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific assay is recommended.

Efavirenz is not recommended in patients with moderate or severe hepatic impairment. Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported with efavirenz. Reports have included patients with underlying hepatic disease, including those with hepatitis B or C, and patients without preexisting hepatic disease or other identifiable risk factors. Monitoring of liver enzymes prior to and during treatment with efavirenz is recommended in all patients, particularly in patients with mild hepatic impairment. Consider treatment discontinuation in patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of normal. Discontinue efavirenz if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation. Perform hepatitis B virus (HBV) screening in any patient who presents with HIV infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression.

Fat redistribution and hyperlipidemia have become increasingly recognized side effects with the use of antiretroviral agents. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during antiretroviral treatment, possible interventions include dietary modification, use of lipid lowering agents, or modification of treatment regimen. Monitoring of serum cholesterol and triglycerides is recommended during efavirenz therapy.

A majority of patients receiving efavirenz during clinical trials experienced CNS side effects, including dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, hallucinations, euphoria, confusion, agitation, amnesia, stupor, and depersonalization. In most cases, these symptoms were mild to moderate in severity and began during the first or second day of therapy. Inform drug recipients that these common symptoms will likely improve with continued use of the drug (generally after the first 2 to 4 weeks of therapy) and are not predictive of subsequent onset of less frequent psychiatric symptoms. Use of ethanol or other psychoactive drugs may worsen these symptoms, while dosing at bedtime may improve the tolerability. Advise patients to avoid activities requiring coordination and concentration (e.g., riding a bicycle, driving) until they know how efavirenz may affect them. Some patients may experience late-onset neurotoxicity, including ataxia and encephalopathy (i.e., impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), that develops months to years after starting efavirenz therapy. Of note, some cases of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz concentrations despite standard dosing. Serious psychiatric adverse events (i.e., severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, catatonic reactions, manic reactions) have also been associated with efavirenz therapy. Promptly evaluate any patient who presents with signs or symptoms of a serious neurologic adverse reaction. Patients with a history of mental illness (e.g., bipolar disorder, depression, mania, schizophrenia, or psychosis), alcoholism, or substance abuse, may be at increased risk for CNS adverse events, including psychiatric adverse events.

Daily efavirenz doses of 600 mg PO administered for 14 days to healthy subjects with CYP2B6 polymorphisms, specifically the CYP2B6 *6/*6 genotype, have resulted in a mean QTc prolongation of 8.7 milliseconds. Health care providers are advised to consider alternatives to efavirenz in patients receiving medications that have the potential to cause Torsade de Pointes (TdP). Use efavirenz with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Rash is a common adverse reaction associated with efavirenz therapy. In most patients, it is a self-limiting mild-to-moderate maculopapular eruption that develops within the first 2 weeks of treatment. However, in rare cases, serious rash (e.g., erythema multiforme, Stevens-Johnson syndrome) has been observed. Discontinue efavirenz in patients who develop a rash associated with blistering, desquamation (e.g., exfoliative dermatitis), mucosal involvement, or fever. It can be restarted following interruptions due to rash; however, for those patients experiencing a life-threatening cutaneous reaction (Stevens-Johnson syndrome), an alternative treatment is recommended. Use of appropriate antihistamines and/or corticosteroids may be considered when efavirenz is restarted; these agents may improve the tolerability and hasten the resolution of the rash. Compared with adults, children tend to have more frequent and severe rashes. Consider prophylaxis with antihistamines prior to initiating therapy with efavirenz in pediatric patients.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, antimicrobial resistance can develop when efavirenz is used either alone or in combination with other agents. Monotherapy with efavirenz is not recommended. Cross-resistance between reverse transcriptase inhibitors and protease inhibitors is unlikely because different enzyme targets are involved. In patients whom a planned discontinuation or interruption of efavirenz therapy is planned, there is an increased risk of NNRTI-resistant mutations. Pharmacokinetic data demonstrate the persistence of detectable drug levels for at least 21 days after discontinuation of efavirenz; simultaneously stopping all drugs in a regimen containing efavirenz may result in functional efavirenz monotherapy due to its long half-life. This is further complicated by evidence that certain genetic polymorphisms, more common among some ethnic groups (such as African patients, Asian patients, and Hispanic patients), may result in a slower rate of clearance. Some experts recommend stopping efavirenz before the other antiretroviral drugs, although the optimal interval between stopping efavirenz and other antiretroviral drugs is not known. An alternative strategy is to substitute the efavirenz with a protease inhibitor (PI) prior to interruption of all antiretroviral drugs; if this strategy is used, the goal is to ensure that the PI used also achieves complete viral suppression during this interval. Further research to determine the best approach to temporarily discontinuing efavirenz is needed.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to efavirenz therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, autoimmune hepatitis, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Use efavirenz with caution in patients with a history of seizures. Although infrequent, seizures have been observed in patients receiving efavirenz and these events have typically occurred in the presence of a known medical history of seizure disorder. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin, carbamazepine, and phenobarbital, may require periodic monitoring of anticonvulsant plasma concentrations.

Counsel adolescent females about the reproductive risk and contraception requirements during treatment; barrier contraception must always be used in combination with other methods of contraception during therapy and for 12 weeks after efavirenz therapy has been discontinued. Efavirenz can cause serious fetal harm when administered during the first trimester of pregnancy. Females of childbearing age should undergo pregnancy testing prior to initiating efavirenz therapy.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and in all HIV-infected adolescents. Treatment of HCV infection in children less than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older and in adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts more than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Description: Efavirenz is an oral, non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. Advantages of efavirenz include once daily dosing and penetration into cerebrospinal fluid (CSF). Conversely, disadvantages include an association with serous psychiatric adverse events and the potential for birth defects with first trimester exposure. Rash was more common in pediatric patients than in adults. Efavirenz is FDA-approved for use in pediatric patients as young as 3 months of age.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Efavirenz plus a 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option is an alternative NNRTI-based regimen for initial therapy for treatment-naive children 3 years and older. Although efavirenz is FDA-approved for use in children 3 months and older, the HIV guidelines state that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype.
-Efavirenz plus a 2-NRTI backbone option is a preferred NNRTI-based regimen for initial therapy for treatment-naive adolescents in certain clinical situations.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage:
Infants 3 months and older weighing 3.5 to 4 kg: 100 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. Although efavirenz is FDA-approved for use in infants and children 3 months and older, the HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype. If efavirenz use is unavoidable in this population, CYP2B6 genotyping should be performed, and therapeutic drug monitoring should be considered (efavirenz concentration obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment). Investigational dosing recommendations based on CYP2B6 genotype are available in guidelines for children younger than 3 years.
Infants 3 months and older weighing 5 to 7.4 kg: 150 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. Although efavirenz is FDA-approved for use in infants and children 3 months and older, the HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype. If efavirenz use is unavoidable in this population, CYP2B6 genotyping should be performed, and therapeutic drug monitoring should be considered (efavirenz concentration obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment). Investigational dosing recommendations based on CYP2B6 genotype are available in guidelines for children younger than 3 years.
Infants and Children 3 months and older weighing 7.5 to 14 kg: 200 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. Although efavirenz is FDA-approved for use in infants and children 3 months and older, the HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype. If efavirenz use is unavoidable in this population, CYP2B6 genotyping should be performed, and therapeutic drug monitoring should be considered (efavirenz concentration obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment). Investigational dosing recommendations based on CYP2B6 genotype are available in guidelines for children younger than 3 years.
Children weighing 15 to 19 kg: 250 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. Although efavirenz is FDA-approved for use in infants and children 3 months and older, the HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype. If efavirenz use is unavoidable in this population, CYP2B6 genotyping should be performed, and therapeutic drug monitoring should be considered (efavirenz concentration obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment). Investigational dosing recommendations based on CYP2B6 genotype are available in guidelines for children younger than 3 years.
Children weighing 20 to 24 kg: 300 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations.
Children weighing 25 to 32.4 kg: 350 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations.
Children and Adolescents weighing 32.5 to 39 kg: 400 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. The HIV guidelines recommend that adolescents in late puberty (i.e., Sexual Maturity Rating (SMR) Stage 4 or 5) should follow the adult dosing schedule (i.e., 600 mg once daily at bedtime).
Children and Adolescents weighing 40 kg or more: 600 mg PO once daily at bedtime.
-Investigational Dosing for patients with CYP2B6 516 GG and GT Genotypes (Extensive Metabolizers)*:
Oral dosage:
Infants 3 to 11 months weighing 3 to 4 kg: 200 mg PO once daily based on IMPAACT study P1070, an ongoing study in HIV-infected children younger than 3 years. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.
Infants and Children 3 months to 2 years weighing 5 to 6 kg: 300 mg PO once daily based on IMPAACT study P1070, an ongoing study in HIV-infected children younger than 3 years. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.
Infants and Children 3 months to 2 years weighing 7 to 13 kg: 400 mg PO once daily based on IMPAACT study P1070, an ongoing study in HIV-infected children younger than 3 years. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.
Children 1 to 2 years weighing 14 to 16 kg: 500 mg PO once daily based on IMPAACT study P1070, an ongoing study in HIV-infected children younger than 3 years. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.
Children 1 to 2 years weighing 17 kg or greater: 600 mg PO once daily based on IMPAACT study P1070, an ongoing study in HIV-infected children younger than 3 years. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.
-Investigational Dosing for patients with CYP2B6 516 TT Genotype (Slow Metabolizers)*:
Oral dosage:
Infants and Children 3 months to 2 years weighing 3 to 6 kg: 50 mg PO once daily based on IMPAACT study P1070, an ongoing study in HIV-infected children younger than 3 years. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.
Infants and Children 3 months to 2 years weighing 7 to 13 kg: 100 mg PO once daily based on IMPAACT study P1070, an ongoing study in HIV-infected children younger than 3 years. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.
Infants and Children 3 months to 2 years weighing 14 kg or greater: 150 mg PO once daily based on IMPAACT study P1070, an ongoing study in HIV-infected children younger than 3 years. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

Therapeutic Drug Monitoring:
Suggested target trough concentration: 1,700 ng/mL
-Routine monitoring of plasma concentrations of antiretroviral (ARV) drugs is generally not recommended in HIV-infected children. However, therapeutic drug monitoring may be considered in the following situations :-use of drugs with limited pharmacokinetic data and/or therapeutic experience in children
-use of drugs with significant food and/or drug interactions
-suboptimal treatment response
-suspected suboptimal absorption, distribution, metabolism, or elimination of the drug
-suspected concentration-dependent drug-associated toxicity
-use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials
-heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs

-Due to CYP2B6 G516T polymorphism in young children, efavirenz therapeutic drug monitoring is recommended in this population. If efavirenz is used in children younger than 3 years, plasma trough concentrations should be obtained 2 weeks after therapy initiation. If investigational dosing is used, trough concentrations should also be obtained at age 3 years for potential dose adjustments.
-Adverse central nervous system (CNS) effects (i.e., CNS depression, dizziness, insomnia, hallucinations) have been shown to correlate with efavirenz plasma trough concentrations more than 4 mcg/mL in adult and pediatric studies.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
1 to 2 months or weighing less than 3.5 kg: Safety and efficacy have not been established.
3 to 11 months weighing 3.5 to 4 kg: 100 mg/day PO.
3 to 11 months weighing 5 to 7.4 kg: 150 mg/day PO.
3 to 11 months weighing 7.5 to 14 kg: 200 mg/day PO.
-Children
5 to 7.4 kg: 150 mg/day PO.
7.5 to 14 kg: 200 mg/day PO.
15 to 19 kg: 250 mg/day PO.
20 to 24 kg: 300 mg/day PO.
25 to 32.4 kg: 350 mg/day PO.
32.5 to 39 kg: 400 mg/day PO.
40 kg or more: 600 mg/day PO.
-Adolescents
25 to 32.4 kg: 350 mg/day PO.
32.5 to 39 kg: 400 mg/day PO.
40 kg or more: 600 mg/day PO.

Patients with Hepatic Impairment Dosing
Mild impairment (Child-Pugh class A, total score of 5 or 6): No dosage adjustment needed.
Moderate impairment (Child-Pugh class B, total score of 7 to 9): Not recommended.
Severe impairment (Child-Pugh class C, total score more than 10): Not recommended.

Patients with Renal Impairment Dosing
Efavirenz has not been studied in patients with renal impairment; however, since less than 1% is excreted into the urine unchanged, no dosage adjustment is required.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Efavirenz is a non-nucleoside reverse transcriptase inhibitor of HIV-1. It binds directly to a site on reverse transcriptase that is near but distinct from where nucleoside reverse transcriptase inhibitors (NRTIs) bind. This binding causes disruption of the enzyme's active site thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. Unlike NRTIs, efavirenz does not compete with template or nucleoside triphosphates nor does it require phosphorylation to be active. HIV-2 reverse transcriptase is not inhibited by efavirenz. The 90-95% inhibitory concentrations range from 1.7 to 25 nM.

Pharmacokinetics: Efavirenz is administered orally. It is highly protein bound (99%), predominantly to albumin. In HIV-infected adults (n = 9) receiving 200-600 mg once daily for at least one month, CSF concentrations ranged from 0.26-1.19% (mean 0.69%) of the corresponding plasma concentration. This is approximately 3-times higher than the non-protein bound fraction of efavirenz in plasma.

Efavirenz is metabolized by cytochrome P450 (CYP) 3A and CYP2B6 to hydroxylated metabolites with subsequent glucuronidation of these metabolites. A mass balance/excretion study showed approximately 14-34% of radiolabeled efavirenz and/or metabolites was excreted in urine and 16-61% in feces. Nearly all of the urinary excretion was in the form of metabolites, while efavirenz accounted for the majority of the total radioactivity measured in the feces.

Affected cytochrome P450 isoenzymes: CYP2C9, CYP2C19, CYP2B6, and CYP3A
Efavirenz has been shown in vivo to induce CYP3A and CYP2B6, which is its most prominent effect, thus increasing the biotransformation of drugs metabolized by these enzymes, including itself. In vitro studies have shown efavirenz inhibits CYP2C9 and CYP2C19 enzymes with Ki values (8.5-17 micro-M) in the range of observed plasma concentrations. Efavirenz inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically (Ki values 82-160 micro-M). Coadministration with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isoenzymes may result in altered plasma concentrations of the coadministered drug. Drugs that induce CYP3A or CYP2B6 activity would be expected to increase the clearance of efavirenz.


-Route-Specific Pharmacokinetics
Oral Route
Peak efavirenz plasma concentrations were seen 3-5 hours after administrating single doses of 200, 400, and 600 mg . Steady state plasma concentrations were reached in 6-10 days. For the capsules, a high-fat/high-caloric meal (e.g., 894 kcal, 54% of total calories from fat) increased the AUC and Cmax by 22% and 39%, respectively; a reduced-fat/normal-caloric meal (e.g., 440 kcal, 4% calories from fat) increased the AUC and Cmax by 17% and 51%, respectively, as compared to fasting conditions. For the tablets, a high-fat/high-caloric meal (e.g., 1000 kcal, 50-60% calories from fat) increased the AUC by 28% and increased the Cmax by 79% compared to fasting conditions. Administration of the capsule contents with 2 teaspoons of applesauce, grape jelly, yogurt, or infant formula resulted in an AUC that was bioequivalent to administration of the intact capsule under fasting conditions.


-Special Populations
Pediatrics
Infants >= 3 months, Children, and Adolescents
Steady-state pharmacokinetic parameters of efavirenz in pediatric patients receiving the FDA-labeled weight-based dosing via the capsule sprinkle method of administration were predicted by a population pharmacokinetic model to be as follows: AUC (range, 220.52-284.28 micromolar x hr); Cmax (range, 5.81-7.75 mcg/ml); Cmin (range, 2.3-2.87 mcg/ml). These were predicted to be similar to parameters noted in adults. Some data (n = 43) suggest that clearance may be higher in younger patients as compared to older pediatric populations and adults. The half-life in patients less than 3 years (n = 6) was 11.4 hours as compared to a half-life of 17 hours in patients 3-12 years (n = 17) and 23.5 hours in patients 13-21 years (n = 13).

Hepatic Impairment
The pharmacokinetics of efavirenz are not significantly altered in patients with mild hepatic impairment (Child-Pugh Class A). Pharmacokinetic data are insufficient to recommend use in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C).

Renal Impairment
The pharmacokinetics of efavirenz have not been studied in patient with renal impairment. However, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on elimination should be minimal.

Ethnic Differences
According to the manufacturer, the pharmacokinetics of efavirenz appear to be similar among different racial groups. However, published literature in adult patients have reported higher plasma concentrations in patients of African and Asian descent, as well as Latino patients, compared to White patients. Studies evaluating these racial differences attribute the elevated concentrations to single nucleotide polymorphisms (SNP) in CYP2B6, the enzyme primarily responsible for efavirenz metabolism. Patients with the SNP experience reduced CYP2B6 activity resulting in impaired efavirenz metabolism and elevated plasma concentrations. In a study evaluating the pharmacokinetics of efavirenz in 58 healthy subjects with CYP2B6 polymorphisms, the mean Cmax was found to be 2.25-fold higher in subjects with the CYP2B6 *6/*6 genotype than in those with the CYP2B6 *1/*1 genotype. The implication in pediatric patients is unknown.