Efamat

Efavirenz.

Each Efamat and Efamat-200 tablet contains efavirenz 200 mg and 600 mg respectively.
Efamat also contains the following excipients: Cellulose microcrystalline, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, lactose monohydrate, magnesium stearate. Film-Coating: Hypromellose, titanium dioxide, macrogol/PEG 400, yellow iron oxide, red iron oxide.

Pharmacotherapeutic Group: HIV-1 specific NNRTI.. ATC Code: J05A G03.
Pharmacology: Pharmacodynamics: Mechanism of Action: Efavirenz is a NNRTI of HIV-1. Efavirenz is a noncompetitive inhibitor of HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (α, β, γ or δ).
Antiviral Activity: The free concentration of efavirenz required for 90-95% inhibition of wild type or zidovudine resistant laboratory and clinical isolates in vitro ranged from 0.46-6.8 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures.
Resistance: The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to that observed against wild type viral strains. The single substitutions which led to the highest resistance to efavirenz in cell culture correspond to a leucine to isoleucine change at position 100 (L100I, 17-22 fold resistance) and a lysine to asparagine at position 103 (K103N, 18-33 fold resistance). Greater than 100 fold loss of susceptibility was observed against HIV variants expressing K103N in addition to other amino acid substitutions in RT.
K103N was the most frequently observed RT substitution in viral isolates from patients who experienced a significant rebound in viral load during clinical studies of efavirenz in combination with indinavir or zidovudine + lamivudine. This mutation was observed in 90% of patients receiving efavirenz with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N. The pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of the other antiviral medications used in combination with efavirenz.
Cross Resistance: Cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the K103N substitution confers loss of susceptibility to all 3 NNRTIs. Two of 3 delavirdine resistant clinical isolates examined were cross resistant to efavirenz and contained the K103N substitution. A 3rd isolate which carried a substitution at position 236 of RT was not cross resistant to efavirenz.
Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showed evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen isolates previously characterised as efavirenz resistant were also resistant to nevirapine and delavirdine. Five of these NNRTI resistant isolates were found to have K103N or a valine-to-isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment failure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive to nevirapine and delavirdine.
The potential for cross resistance between efavirenz and PIs is low because of the different enzyme targets involved. The potential for cross resistance between efavirenz and NRTIs is low because of the different binding sites on the target and mechanism of action.
Pharmacodynamic Effects: Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namely with CD4 counts <50 cells/mm³, or in PI or NNRTI experienced patients. Clinical experience in controlled studies with combinations including didanosine or zalcitabine is limited.
Two controlled studies (006 and ACTG 364) of approximately 1 yr duration with efavirenz in combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy naive and NRTI experienced HIV infected patients. Study 020 showed similar activity in NRTI experienced patients over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose of indinavir was 1000 mg every 8 hrs when used with efavirenz and 800 mg every 8 hrs when used without efavirenz. The dose of nelfinavir was 750 mg given 3 times a day. The standard doses of NRTIs given every 12 hrs were used in each of these studies.
Study 006, a randomized, open-label trial, compared efavirenz + zidovudine + lamivudine or efavirenz + indinavir with indinavir + zidovudine + lamivudine in 1266 patients who were required to be efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell count was 341 cells/mm³ and the mean baseline HIV-RNA level was 60,250 copies/mL. Efficacy results for study 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 1. In the analysis of responder rates (the non-completer equals failure analysis [NC=F]), patients who terminated the study early for any reason, or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA >50 or >400 copies/mL at the missing time points. (See Table 1.)

Click on icon to see table/diagram/image

Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with EFV+IDV, 196 patients with EFV+ZDV+3TC and 127 patients with IDV+ZDV+3TC, respectively), suggest durability of response in terms of proportions of patients with HIV-RNA <400 copies/mL, HIV-RNA <50 copies/mL and in terms of mean change from baseline CD4 cell count.
Efficacy results for studies ACTG 364 and 020 are found in Table 2. Study ACTG 364 enrolled 196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled 327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed to change their patient's NRTI regimen upon entry into the study. Responder rates were highest in patients who switched NRTIs. (See Table 2.)

Click on icon to see table/diagram/image

Paediatric Trial: ACTG 382 is an ongoing uncontrolled study of 57 NRTI-experienced paediatric patients (3-16 yrs) which characterises the pharmacokinetics, antiviral activity and safety of efavirenz in combination with nelfinavir (20-30 mg/kg given 3 times a day) and ≥1 NRTIs. The starting dose of efavirenz was the equivalent of a 600 mg dose (adjusted from calculated body size based on weight). The response rate, based on the NC=F analysis of the percentage of patients with plasma HIV-RNA <400 copies/mL at 48 weeks was 60% (95%, CI 47, 72), and 53% (CI 40, 66) based on percentage of patients with plasma HIV-RNA <50 copies/mL. The mean CD4 cell counts were increased by 63 ±34.5 cells/mm³ from baseline. The durability of the response was similar to that seen in adult patients.
Pharmacokinetics: Absorption: Peak efavirenz plasma concentrations (C_max) of 1.6-9.1 μM were attained by 5 hrs following single oral doses of 100-1600 mg administered to uninfected volunteers. Dose related increases in C_max and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3-5 hrs) did not change following multiple dosing and steady state plasma concentrations were reached in 6-7 days.
In HIV infected patients at steady state, mean C_max, mean C_min, and mean AUC were linear with 200, 400, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steady state C_max was 12.9 ±3.7 μM (29%) [Mean ±SD (% CV)], steady state C_min was 5.6 ±3.2 μM (57%), and AUC was 184 ±73 μM·h (40%).
Effect of Food: The AUC and C_max of a single 600 mg dose of efavirenz film coated tablets in uninfected volunteers was increased by 28% (90% CI: 22-33%) and 79% (90% CI: 58-102%), respectively, when given with a high fat meal, relative to when given under fasted conditions.
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 200-600 mg once daily for at least 1 month, cerebrospinal fluid concentrations ranged from 0.26-1.19% (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.
Biotransformation: Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolised 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 and that it inhibited P450 isozymes 2C9, 2C19, and 3A4. In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.
Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variant of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be excluded.
Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism. In uninfected volunteers, multiple doses of 200-400 mg/day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half life compared with single dose administration (see below).
Elimination: Efavirenz has a relatively long terminal half life of 52-76 hrs after single doses and 40-55 hrs after multiple doses. Approximately 14-34% of a radiolabelled dose of efavirenz was recovered in the urine and <1% of the dose was excreted in urine as unchanged efavirenz.
In the single patient studied with severe hepatic impairment (Child Pugh Grade C), half life was doubled indicating a potential for a much greater degree of accumulation.
Paediatric Pharmacokinetics: In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted from calculated body size based on weight), steady state C_max was 14.1 μM, steady state C_min was 5.6 μM, and AUC was 216 μM·h. The pharmacokinetics of efavirenz in paediatric patients were similar to adults.
Gender, Race, Elderly: Pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied. Although limited data suggest that Asian and Pacific Island patients may have higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz. Pharmacokinetic studies have not been performed in the elderly.
Toxicology: Preclinical Safety Data: Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays.
Efavirenz induced foetal resorptions in rats. Malformations were observed in 3 of 20 foetuses/newborns from efavirenz treated cynomolgus monkeys given doses resulting in plasma efavirenz concentrations similar to those seen in humans. Anencephaly and unilateral anophthalmia with secondary enlargement of the tongue were observed in 1 foetus, microophthalmia was observed in another foetus, and cleft palate was observed in a 3rd foetus. No malformations were observed in foetuses from efavirenz treated rats and rabbits.
Biliary hyperplasia was observed in cynomolgus monkeys given efavirenz for 1 yr at a dose resulting in mean AUC values approximately 2 fold greater than those in humans given the recommended dose. The biliary hyperplasia regressed upon cessation of dosing. Biliary fibrosis has been observed in rats. Non-sustained convulsions were observed in some monkeys receiving efavirenz for 1 yr, at doses yielding plasma AUC values 4-13 fold greater than those in humans given the recommended dose.
Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female mice, but not in male mice. The mechanism of tumour formation and the potential relevance for humans are not known.
Carcinogenicity studies in male mice, male and female rats were negative. While the carcinogenic potential in humans is unknown, these data suggest that the clinical benefit of efavirenz outweighs the potential carcinogenic risk to humans.

Efavirenz is indicated in antiviral combination treatment of HIV-1 infected adults, adolescents and children ≥3 yrs.
Efavirenz has not been adequately studied in patients with advanced HIV disease, namely in patients with CD4 counts <50 cells/mm³ or after failure of protease inhibitor (PI) containing regimens.
Although cross-resistance of efavirenz with PIs has not been documented, there are at present insufficient data on the efficacy of subsequent use of PI based combination therapy after failure of regimens containing efavirenz.
For a summary of clinical and pharmacodynamic information, see Pharmacology: Pharmacodynamics under Actions.

The therapy should be initiated by a physician experienced in the management of HIV infection.
Concomitant Antiretroviral Therapy: Efavirenz must be given in combination with other antiretroviral medications.
It is recommended that Efamat be taken on an empty stomach. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse events. In order to improve the tolerability of nervous system undesirable effects, bedtime dosing is recommended.
Adults: The recommended dosage of efavirenz in combination with nucleoside analogue reverse transcriptase inhibitors (NRTIs) with or without a PI is 600 mg orally, once daily.
Adolescents and Children (3-17 yrs): The recommended dose of efavirenz in combination with a PI and/or NRTIs for patients between 3-17 yrs is described in Table 3. Efavirenz is not recommended for use in patients <3 yrs or weighing <13 kg due to a lack of data on safety and efficacy in that age group. (See Table 3.)

Click on icon to see table/diagram/image

Dosage Adjustment: If efavirenz is co-administered with voriconazole, the voriconazole maintenance dose must be increased to 400 mg every 12 hrs and the Efavirenz dose must be reduced by 50%, ie, to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
If efavirenz is co-administered with rifampicin, an increase in the dose of efavirenz to 800 mg/day may be considered.
Renal Insufficiency: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, <1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Liver Disease: Patients with mild to moderate liver disease may be treated with their normally recommended dose of efavirenz. Patients should be monitored carefully for dose related adverse events, especially nervous system symptoms.

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
Treatment of overdose with efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to remove significant quantities of it from blood.

Hypersensitivity to efavirenz or to any of the excipients of Efamat.
Efavirenz must not be used in patients with severe hepatic impairment (Child Pugh Grade C).
Efavirenz must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (eg, ergotamine, dihydroergotamine,ergonovine, and methylergonovine) because competition for CYP3A4 by efavirenz could result in inhibition of metabolism and create the potential for serious and/or life-threatening undesirable effects (eg, cardiac arrhythmias, prolonged sedation or respiratory depression).
Herbal preparations containing St. John's wort (Hypericum perforatum) must not be used while taking efavirenz due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz.

Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors (NNRTIs), 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.
Co-administration of efavirenz the fixed combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate, is not recommended.
When prescribing medicinal products concomitantly with efavirenz, physicians should refer to the corresponding summary of product characteristics.
Patients should be advised that current antiretroviral therapy, including efavirenz, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.
If any antiretroviral medicinal product in a combination regimen is interrupted because of suspected intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral medicinal products. The antiretroviral medicinal products should be restarted at the same time upon resolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction of antiretroviral agents is not advisable because of the increased potential for selection of resistant virus.
Rash: Mild to moderate rash has been reported in clinical studies with efavirenz and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration has been reported in <1% of patients treated with efavirenz. The incidence of erythema multiforme or Stevens Johnson syndrome was approximately 0.1%. Efavirenz must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with efavirenz is discontinued, consideration should also be given to interrupting therapy with other antiretroviral agents to avoid development of resistant virus.
Rash was reported in 26 of 57 children (46%) treated with efavirenz during a 48-week period and was severe in 3 patients. Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered.
Patients who discontinued treatment with other NNRTIs due to rash may be at higher risk of developing rash during treatment with efavirenz.
Psychiatric Symptoms: Psychiatric adverse experiences have been reported in patients treated with efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences. In particular, severe depression was more common in those with a history of depression. There have also been post marketing reports of severe depression, death by suicide, delusions and psychosis like behaviour. Patients should be advised that if they experience symptoms eg, severe depression, psychosis or suicidal ideation, they should contact their doctor immediately 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.
Nervous System Symptoms: Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported undesirable effects in patients receiving efavirenz 600 mg daily in clinical studies. Nervous system symptoms usually begin during the first 1 or 2 days of therapy and generally resolve after the first 2-4 weeks. Patients should be informed that if they do occur, these common symptoms are likely to improve with continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric symptoms.
Seizures: Convulsions have been observed rarely in patients receiving efavirenz, generally in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal products primarily metabolised by the liver eg, phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with efavirenz. Caution must be taken in any patient with a history of seizures.
Effect of Food: The administration of efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of undesirable effects. This effect may be more evident for the film-coated tablets than for the hard capsules. It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime.
Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the 1st few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Lipodystrophy and Metabolic Abnormalities: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors eg, longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Lactose: This medicinal product contains 21.30 mg, 42.60 mg, 85.20 mg and 256 mg of lactose in 50 mg, 100 mg, 200 mg and 600 mg in each daily dose respectively. This quantity is not likely to induce symptoms of lactose intolerance.
Efavirenz film coated tablets are unsuitable for individuals with the rare hereditary disorders of galactosaemia or glucose/galactose malabsorption syndrome. Individuals with these conditions may take efavirenz oral solution, which is free from lactose.
Special Populations: Liver Disease: Because of the extensive cytochrome P450 mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution must be exercised in administering efavirenz to patients with mild to moderate liver disease. Patients should be monitored carefully for dose related adverse events, especially nervous system symptoms. Laboratory tests should be performed to evaluate their liver disease at periodic intervals.
The safety and efficacy of efavirenz has not been established in patients with significant underlying liver disorders. Efavirenz is contraindicated in patients with severe hepatic impairment. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. Patients with preexisting liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease or persistent elevations of serum transaminases to >5 times the upper limit of the normal range, the benefit of continued therapy with efavirenz needs to be weighed against the potential risks of significant liver toxicity. In such patients, interruption or discontinuation of treatment must be considered.
In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.
Renal Insufficiency: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, <1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. There is no experience in patients with severe renal failure and close safety monitoring is recommended in this population.
Effects on the Ability to Drive or Operate Machinery: Efavirenz has not been specifically evaluated for possible effects on the ability to drive a car or operate machinery. Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.
Use in pregnancy & lactation: Efavirenz should not be used during pregnancy unless there are no other appropriate treatment options.
Women of Childbearing Potential: Pregnancy should be avoided in women treated with efavirenz. Barrier contraception should always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz.
Pregnancy: There are no adequate and well-controlled studies of efavirenz in pregnant women. In postmarketing experience through an antiretroviral pregnancy registry, >200 pregnancies with 1st-trimester exposure to efavirenz as part of a combination antiretroviral regimen have been reported with no specific malformation pattern. Retrospectively in this registry, a small number of cases of neural tube defects, including meningomyelocele, have been reported but causality has not been established. Studies in animals have shown reproductive toxicity including marked teratogenic effects.
Lactation: Studies in rats have demonstrated that efavirenz is excreted in milk reaching concentrations much higher than those in maternal plasma. It is not known whether efavirenz is excreted in human milk. Since animal data suggest that the substance may be passed into breast milk, it is recommended that mothers taking efavirenz do not breast feed their infants. It is recommended that HIV infected women do not breast feed their infants under any circumstances in order to avoid transmission of HIV.
Use in children: Efavirenz has not been evaluated in children <3 yrs or who weigh <13 kg.
Use in elderly: Insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether they respond differently than younger patients.

Use in pregnancy & lactation: Efavirenz should not be used during pregnancy unless there are no other appropriate treatment options.
Women of Childbearing Potential: Pregnancy should be avoided in women treated with efavirenz. Barrier contraception should always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz.
Pregnancy: There are no adequate and well-controlled studies of efavirenz in pregnant women. In postmarketing experience through an antiretroviral pregnancy registry, >200 pregnancies with 1st-trimester exposure to efavirenz as part of a combination antiretroviral regimen have been reported with no specific malformation pattern. Retrospectively in this registry, a small number of cases of neural tube defects, including meningomyelocele, have been reported but causality has not been established. Studies in animals have shown reproductive toxicity including marked teratogenic effects.
Lactation: Studies in rats have demonstrated that efavirenz is excreted in milk reaching concentrations much higher than those in maternal plasma. It is not known whether efavirenz is excreted in human milk. Since animal data suggest that the substance may be passed into breast milk, it is recommended that mothers taking efavirenz do not breast feed their infants. It is recommended that HIV infected women do not breast feed their infants under any circumstances in order to avoid transmission of HIV.

Efavirenz has been studied in over 9000 patients. In a subset of 1008 adult patients who received 600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the most frequently reported treatment related undesirable effects of at least moderate severity reported in at least 5% of patients were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%). The most notable undesirable effects associated with efavirenz are rash and nervous system symptoms. The administration of efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of undesirable effects.
The long-term safety profile of efavirenz containing regimens was evaluated in a controlled trial (006) in which patients received efavirenz + zidovudine + lamivudine (n=412, median duration 180 weeks), efavirenz + indinavir (n=415, median duration 102 weeks), or indinavir + zidovudine + lamivudine (n=401, median duration 76 weeks). Long-term use of efavirenz in this study was not associated with any new safety concerns.
Rash: In clinical studies, 26% of patients treated with 600 mg of efavirenz experienced skin rash compared with 17% of patients treated in control groups. Skin rash was considered treatment related in 18% of patients treated with efavirenz. Severe rash occurred in <1% of patients treated with efavirenz, and 1.7% discontinued therapy because of rash. The incidence of erythema multiforme or Stevens Johnson syndrome was approximately 0.1%.
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 therapy with efavirenz within 1 month. Efavirenz can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is restarted.
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 2 discontinued because of rash. 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 an average of 1.6 yrs and 635 patients treated with control regimens for an average of 1.3 yrs, the frequency of specific serious psychiatric events are detailed in Table 4: See Table 4.

Click on icon to see table/diagram/image

Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences with the frequency of each of the above events ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation. There have also been post marketing reports of death by suicide, delusions and psychosis like behaviour.
Nervous System Symptoms: In clinical controlled trials, frequently reported undesirable effects in patients receiving 600 mg efavirenz with other antiretroviral agents included, but were not limited to: dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous system symptoms of moderate to severe intensity were experienced by 19.4% of patients compared to 9.0% of patients receiving control regimens. These symptoms were severe in 2.0% of patients receiving efavirenz 600 mg daily and in 1.3% of patients receiving control regimens. In clinical studies 2.1% of patients treated with 600 mg of efavirenz discontinued therapy because of nervous system symptoms.
Nervous system symptoms usually begin during the first 1 or 2 days of therapy and generally resolve after the first 2-4 weeks. In 1 clinical study, the monthly prevalence of nervous system symptoms of at least moderate severity between weeks 4 and 48, ranged from 5-9% in patients treated with regimens containing efavirenz and 3-5% in patients treated with the control regimen. In a study of uninfected volunteers, a representative nervous system symptom had a median time to onset of 1 hr post dose and a median duration of 3 hrs. Nervous system symptoms may occur more frequently when efavirenz is taken concomitantly with meals possibly due to increased efavirenz plasma levels. Dosing at bedtime seems to improve the tolerability of these symptoms and can be recommended during the first weeks of therapy and in patients who continue to experience these symptoms. Dose reduction or splitting the daily dose has not been shown to provide benefit.
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 control arm.
Adverse reactions of moderate or greater severity with at least possible relationship to treatment regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended dose in combination therapy (n=1008) are listed below. Frequency is defined using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000) including isolated reports.
Immune System Disorders: Uncommon: Hypersensitivity.
Psychiatric Disorders: Common: Anxiety, depression. Uncommon: Affect lability, aggression, euphoric mood, hallucination, mania, paranoia, suicide attempt, suicide ideation.
Nervous System Disorders: Common: Abnormal dreams, disturbance in attention, dizziness, headache, insomnia, somnolence. Uncommon: Agitation, amnesia, ataxia, abnormal coordination and thinking, confusional state, convulsions.
Eye Disorders: Uncommon: Blurred vision.
Ear and Labyrinth Disorders: Uncommon: Vertigo.
Gastrointestinal Disorders: Common: Abdominal pain, diarrhoea, nausea, vomiting. Uncommon: Acute pancreatitis.
Hepatobiliary Disorders: Uncommon: Acute hepatitis.
Skin and Subcutaneous Tissue Disorders: Very Common: Rash. Common: Pruritus. Uncommon: Erythema multiforme, Stevens-Johnson syndrome.
General Disorders and Administration Site Conditions: Common: Fatigue.
Reproductive System and Breast Disorders: Uncommon: Gynaecomastia.
Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.
Lipodystrophy and Metabolic Abnormalities: Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.
Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.
Laboratory Test Abnormalities: Liver Enzymes: Elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to >5 times the upper limit of the normal range (ULN) were seen in 3% of 1008 patients treated with 600 mg of efavirenz (5-8% after long-term treatment in study 006). Similar elevations were seen in patients treated with control regimens (5% after long-term treatment). Elevations of gamma glutamyltransferase (GGT) to >5 times ULN were observed in 4% of all patients treated with 600 mg of efavirenz and 1.5-2% of patients treated with control regimens (7% of efavirenz-treated patients and 3% of control-treated patients after long-term treatment). Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction. In the long-term study (006), 1% of patients in each treatment arm discontinued because of liver or biliary system disorders.
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 co infected patients, elevations in AST to >5 times ULN developed in 13% of patients in the efavirenz arms and 7% of those in the control arm, and elevations in ALT to >5 times ULN developed in 20% of patients in the efavirenz arms and 7% of the patients in the control arm. Among co-infected 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. Reasons for discontinuation among co infected recipients of efavirenz included abnormalities in hepatic enzymes; there were no discontinuations reported in this study for cholestatic hepatitis, hepatic failure, or fatty liver.
Amylase: In the clinical trial subset of 1008 patients, asymptomatic increases in serum amylase levels >1.5 times the upper limit of normal were seen in 10% of patients treated with efavirenz and 6% of patients treated with control regimens. The clinical significance of asymptomatic increases in serum amylase is unknown.
Lipids: Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz. In clinical trials of various efavirenz-containing regimens in treatment naive patients, total cholesterol, HDL-cholesterol, and triglycerides increased over 48 weeks of treatment (21-31%, 23-34%, and 23-49%, respectively). The proportion of patients with a total cholesterol/HDL-cholesterol ratio >5 was unchanged. The magnitude of changes in lipid levels may be influenced by factors such as duration of therapy and other components of the antiretroviral regimen.
Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers who received efavirenz. False positive test results have only been observed with the CEDIA DAU Multi-Level THC assay, which is used for screening, and have not been observed with other cannabinoid assays tested including tests used for confirmation of positive results.
Post marketing experience with efavirenz has shown the following additional adverse events to occur in association with efavirenz-containing antiretroviral treatment regimens: delusion, gynaecomastia, hepatic failure, neurosis, photoallergic dermatitis, psychosis and completed suicide.
Adolescents and Children: Undesirable effects in children were generally similar to those of adult patients. Rash was reported more frequently in children (in a clinical study including 57 children who received efavirenz during a 48-week period, rash was reported in 46%) and was more often of higher grade than in adults (severe rash was reported in 5.3% of children). Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered. Although nervous system symptoms are difficult for young children to report, they appear to be less frequent in children and were generally mild. In the study of 57 children, 3.5% of patients experienced nervous system symptoms of moderate intensity, predominantly dizziness. No child had severe symptoms or had to discontinue because of nervous system symptoms.

Efavirenz is an inducer of CYP3A4 and an inhibitor of some CYP isozymes including CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with efavirenz. Efavirenz exposure may also be altered when given with medicinal products or food (eg, grapefruit juice) which affect CYP3A4 activity.
Contraindications of Concomitant Use: Efavirenz must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (eg, ergotamine, dihydroergotamine, ergonovine, and methylergonovine) since inhibition of their metabolism may lead to serious, life-threatening events.
St. John's Wort (Hypericum perforatum): Co-administration of efavirenz and St. John's wort or herbal preparations containing St. John's wort is contraindicated. Plasma levels of efavirenz can be reduced by concomitant use of St. John's wort due to induction of drug metabolising enzymes and/or transport proteins by St. John's wort. If a patient is already taking St. John's wort, stop St. John's wort, check viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John's wort and the dose of efavirenz may need adjusting. The inducing effect of St. John's wort may persist for at least 2 weeks after cessation of treatment. Other Interactions: Interactions between efavirenz and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in Table 5 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, and once every 8 or 12 hrs as “q8h” or “q12h”). If available, 90% or 95% confidence intervals are shown in parentheses. Studies were conducted in healthy subjects unless otherwise noted.

Do not store above 30°C. Store in the original container.
Shelf-Life: 36 Months.

Antivirals

J05AG03 - efavirenz ; Belongs to the class of non-nucleoside reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

S

FC tab 200 mg (peach colored, debossed with 3X on one side and M on other side) x 30's. 600 mg (peach colored, debossed with M 109 on one side) x 30's.