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Product
Antiretroviral products (Efavir)
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Antiretroviral products (Efavir)
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Efavir
Efavirenz 200 mg capsules / Efavirenz 600 mg tablets
COMPOSITION
EFAVIR - 200
Each hard gelatin capsule contains
Efavirenz 200 mg
EFAVIR - 600
Each film-coated tablet contains
Efavirenz 600 mg
DOSAGE FORM
EFAVIR – 200 : Oral, hard gelatin capsules
EFAVIR – 600 : Oral, film-coated tablets
PHARMACOLOGY
Pharmacodynamics
Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma and delta are not inhibited by efavirenz.
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Pharmocokinetics
Absorption: Peak efavirenz plasma concentrations of 1.6-9.1 µM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose related increase in C max , AUC were less than proportional suggesting diminished absorption at higher 78 doses.
In HIV-infected patients at steady state, mean C max , mean C min , and mean AUC were 80 dose proportional following 200-mg, 400-mg, and 600-mg daily doses. Time-to-peak 81 plasma concentrations were approximately 3-5 hours and steady-state plasma 82 concentrations were reached in 6-10 days. In 35 patients receiving efavirenz 600 mg 83 once daily, steady-state C max was 12.9 ± 3.7 µM (mean ± SD), steady-state C min was 84 5.6 ± 3.2 µM, and AUC was 184 ± 73 µM•h.
Effect of Food on Oral Absorption:
Capsules --Administration of a single 600-mg dose of efavirenz capsules with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC (infinity) and a mean increase of 39% and 51% in efavirenz C max , respectively, relative to the exposures achieved when given under fasted conditions (see DosAGE and Administration)
Tablets --Administration of a single 600-mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC (infinity) of efavirenz and a 79% increase in mean C max of efavirenz relative to the exposures achieved under fasted conditions (see Dose and Administration)
Distribution: Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.
Metabolism: Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism.
Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours).
Elimination: Efavirenz has a terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14 C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.
Special Populations
Hepatic Impairment: The pharmacokinetics of efavirenz have not been adequately 123 studied in patients with hepatic impairment (see WARNINGS AND PRECAUTIONS).
Renal Impairment: The pharmacokinetics of efavirenz have not been studied in 125 patients with renal insufficiency; however, less than 1% of efavirenz is excreted 126 unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Gender and Race: The pharmacokinetics of efavirenz in patients appear to be similar 129 between men and women and among the racial groups studied.
INDICATIONS
EFAVIR (efavirenz) in combination with other antiretroviral agents is indicated for HIV-1 infection. This indication is based on two clinical trials of at least one year duration that demonstrated prolonged suppression of HIV RNA.
DOSAGE AND ADMINISTRATION
Adults : The recommended dose of EFAVIR is 600 mg orally, once daily in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs).
It is recommended that EFAVIR be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of EFAVIR with food may lead to an increase in frequency of adverse events (see CLINICAL PHARMACOLOGY: Effect of Food on Oral Absorption). Dosing at bedtime may improve the tolerability of nervous system symptoms (see WARNINGS AND PRECAUTIONS : Nervous System Symptoms and UNDESIRABLE EFFECTS) .
Concomitant Antiretroviral Therapy: EFAVIR must be given in combination with 659 other antiretroviral medications (see WARNINGS AND PRECAUTIONS: DRUG INTERACTIONS AND INDICATIONS ).
Dosage Adjustment: If EFAVIR is co-administered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the EFAVIR dose should be decreased to 300 mg once daily using the capsule formulation (three 100-mg capsules or one 200-mg and one 100-mg capsule).
Pediatric use
It is recommended that EFAVIR be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of EFAVIR for pediatric patients 3 years of age or older and weighing between 10 and 40 kg. The recommended dose of efavirenz for pediatric patients weighing greater than 40 kg is 600 mg once daily.
Table 1: Pediatric dose to be administered once daily
| Body Weight |
SUSTIVA Dose (mg) |
| kg |
lbs |
| 10 to <15 |
22 to <33 |
200 |
| 15 to <20 |
33 to <44 |
250 |
| 20 to <25 |
44 to <55 |
300 |
| 25 to <32.5 |
55 to <71.5 |
350 |
| 32.5 to <40 |
71.5 to <88 |
400 |
| ≥40 |
≥88 |
600 |
CONTRAINDICATIONS
EFAVIR is contraindicated in patients with clinically significant hypersensitivity to any of its components.
Efavirenz must not be administered concurrently with astemizole, bepridil, cisapride, midazolam, pimozide, triazolam, or ergot derivatives because competition for the CYP3A4 enzyme by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening adverse events (for e.g., cardiac arrhythmias, prolonged sedation or respiratory depression). Efavirenz should not be administered concurrently with standard doses of voriconazole because efavirenz significantly decreases voriconazole plasma concentrations. Adjusted doses of voriconazole and efavirenz may be administered concomitantly ( see WARNINGS AND PRECAUTIONS , Tables 2, 4 and 5; and DOSAGE AND ADMINISTRATION ).
WARNINGS AND PRECAUTIONS
ALERT: Find out about medicines that should NOT be taken with efavirenz.
Efavirenz must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agent(s) to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance.
Coadministration of EFAVIR with (efavirenz/emtricitabine/ and tenofovir disoproxil fumarate) is not recommended, since efavirenz is one of its active ingredients.
Psychiatric Symptoms
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 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.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 outweighs the benefits. (see UNDESIRABLE EFFECTS).
Nervous System Symptoms
Fifty-three percent of patients receiving efavirenz in controlled trials reported central nervous system symptoms compared to 25% of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%) and hallucinations (1.2%). These symptoms were severe in 2.0% of patients, and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve the tolerability of these nervous system symptoms (see UNDESIRABLE EFFECTS and DOSAGE AND ADMINISTRATION).
Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks and 76 weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm.
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.
Skin Rash
In controlled clinical trials, 26% of patients treated with 600 mg efavirenz experienced new-onset rash compared with 17% of patients treated in control groups. Rash associated with blistering, moist desquamation or ulceration occurred in 0.9% of patients treated with efavirenz. The incidence of Grade 4 rash (e.g, erythema multiforme or Stevens-Johnson Syndrome) was approximately 0.1%.The median time to onset of rash in adults was 11 days and the median duration 16 days. The discontinuation rate for rash in clinical trials was 1.7 %. Efavirenz must 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.
Rash was reported in 26 of 57 pediatric patients (46%) treated with efavirenz capsules. One pediatric patient experienced Grade 3 rash (confluent rash with fever), and two patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 8 days. Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in pediatric patients should be considered (see UNDESIRABLE EFFECTS ).
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Liver Enzymes
In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended. In patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of normal range, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity (see UNDESIRABLE EFFECTS: Laboratory Abnormalities ).
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.
Convulsions
Convulsions have been observed infrequently in patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution must be observed in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. (see DRUG INTERACTIONS )
Cholesterol
Monitoring of cholesterol and triglycerides should be considered in patients treated with efavirenz (see UNDESIRABLE EFFECTS).
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.
Immune Reconstitution Syndrome
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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Drug Interactions
Efavirenz has been shown in vivo to induce CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co administered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Co administration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the co-administered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.
Psychiatric symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials, the frequency of specific serious psychiatric symptoms 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%). Additional psychiatric symptoms observed at a frequency of > 2% among patients treated with efavirenz or control groups, respectively in controlled clinical trials were depression (19%, 16%), anxiety (13%, 9%) and nervousness (7%, 2%).
Skin rash
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz. In most patients, rash resolves with continuing efavirenz therapy within one month. 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. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever.
Packing information
Efavir 200 – pack of 30capsules
Efavir 600_ pack of 30 tablets
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