Efavirenz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EFAVIRENZ (Efavirenz)

Composition:

Active substance: efavirenz;

One film-coated tablet contains 200 mg or 600 mg of efavirenz;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, sodium lauryl sulfate, hydroxypropylcellulose, magnesium stearate; Opadry Brown film-coating mixture (hypromellose, polyethylene glycol, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for the 200 mg dosage: round, biconvex tablets with two scored lines on one side, film-coated, color ranging from almost white to white with a light brownish hue;

for the 600 mg dosage: capsule-shaped, biconvex tablets, film-coated, color ranging from almost white to white with a light brownish hue.

Pharmacotherapeutic group.

Direct-acting antiviral agents. Non-nucleoside reverse transcriptase inhibitors. Efavirenz. ATC code J05AG03.

Pharmacological properties.

Pharmacodynamics.

Efavirenz is an antiviral agent, a non-nucleoside inhibitor of reverse transcriptase, active against human immunodeficiency virus type 1 (HIV-1). The drug's action is related to competitive effects on nucleosides and nucleoside triphosphates.

Antiviral activity. The free concentration of efavirenz required for 90–95% inhibition of wild-type or zidovudine-resistant laboratory and clinical isolates in vitro ranges from 0.46 to 6.8 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures.

Resistance. The efficacy of efavirenz in cell culture against viral variants with amino acid substitutions in reverse transcriptase at positions 48, 108, 179, 181, or 236, as well as against variants with amino acid substitutions in protease, was similar to that observed against wild-type viral strains. The only substitutions leading to the highest level of resistance to efavirenz in cell culture were leucine to isoleucine at position 100 (L100I, 17- to 22-fold resistance) and lysine to asparagine at position 103 (K103N, 18- to 33-fold resistance). Loss of susceptibility exceeding 100-fold was observed against HIV variants expressing K103N in addition to other amino acid substitutions in reverse transcriptase.

K103N is the most commonly observed substitution in reverse transcriptase in viral isolates obtained from patients who experienced significant viral load rebound during clinical trials of efavirenz in combination with indinavir or zidovudine + lamivudine. This mutation was observed in 90% of patients receiving efavirenz who did not achieve a marked virological response. Substitutions in reverse transcriptase at positions 98, 100, 101, 108, 138, 188, 190, or 225 were also observed, but less frequently and often only in combination with K103N. The pattern of amino acid substitutions in reverse transcriptase associated with resistance to efavirenz was independent of other antiviral agents used in combination with efavirenz.

Cross-resistance. Cross-resistance profiles of efavirenz, nevirapine, and delavirdine in cell culture showed that the K103N substitution leads to loss of susceptibility to all three non-nucleoside reverse transcriptase inhibitors. Two of the three delavirdine-resistant clinical isolates tested showed cross-resistance with efavirenz and contained the K103N substitution. The third isolate, with a substitution in reverse transcriptase at position 236, did not show cross-resistance with efavirenz.

Viral isolates obtained from peripheral blood mononuclear cells of patients enrolled in efavirenz clinical trials who showed signs of treatment failure (viral load rebound) were tested for susceptibility to non-nucleoside reverse transcriptase inhibitors. Thirteen isolates previously characterized as resistant to efavirenz were also resistant to nevirapine and delavirdine. Five of these non-nucleoside reverse transcriptase inhibitor-resistant isolates were found to contain either the K103N substitution or valine to isoleucine substitution at position 108 (V108I) in reverse transcriptase. Among isolates tested after efavirenz treatment failure, three isolates remained sensitive to efavirenz in cell culture and also showed sensitivity to nevirapine and delavirdine.

Cross-resistance between efavirenz and protease inhibitors is unlikely due to different target enzymes. Cross-resistance between efavirenz and NRTIs is also unlikely due to different binding sites on the target and different mechanisms of action.

Pharmacodynamic effects

Controlled studies of efavirenz use in patients with advanced HIV infection, specifically those with CD4 cell counts < 50 cells/mm³, as well as patients previously treated with protease inhibitors or non-nucleoside reverse transcriptase inhibitors, have not been conducted.

Clinical experience with combinations including didanosine or zalcitabine during controlled trials is limited.

Two controlled studies (006 and ACTG 364), lasting approximately 1 year, in which efavirenz was used in combination with nucleoside reverse transcriptase inhibitors and/or protease inhibitors, demonstrated reduction in viral load below the limit of quantification and an increase in CD4 lymphocyte count after initial antiretroviral therapy and in HIV-infected patients previously treated with nucleoside reverse transcriptase inhibitors. Study 020 showed a similar effect in patients previously treated with nucleoside reverse transcriptase inhibitors at 24 weeks. In these studies, the dose of efavirenz was 600 mg once daily; the dose of indinavir was 1000 mg every 8 hours when used in combination with efavirenz and 800 mg every 8 hours when used without efavirenz. The dose of nelfinavir was 750 mg three times daily. In each of these studies, standard doses of nucleoside reverse transcriptase inhibitors were administered every 12 hours.

Children. An ongoing uncontrolled study, ACTG 382, includes 57 children aged 3–16 years who previously received nucleoside reverse transcriptase inhibitors. This study evaluates the pharmacokinetics, antiviral activity, and safety of efavirenz in combination with nelfinavir (20–30 mg/kg three times daily) and one or more nucleoside reverse transcriptase inhibitors. The starting dose of efavirenz was equivalent to 600 mg (calculated according to age and body weight). The treatment response rate, defined by NC = F analysis of the percentage of patients with HIV-RNA concentration < 400 copies/mL in plasma after 48 weeks, was 60% (95% CI: 47, 72) and 53% (CI: 40, 66) based on the percentage of patients with HIV-RNA concentration < 50 copies/mL in plasma. Mean CD4 cell count increased compared to baseline. The duration of treatment response in children was similar to that in adult patients.

Pharmacokinetics.

Absorption. In healthy volunteers, peak plasma concentrations of efavirenz ranging from 1.6 to 9.1 µM were achieved within 5 hours after single oral doses of 100 mg to 1600 mg. A dose-related increase in Cmax and area under the concentration-time curve (AUC) was observed up to 1600 mg; however, a proportional relationship between the degree of increase and dose was not observed—the increase was less than expected, suggesting reduced absorption at higher doses. Time to peak plasma concentration (3–5 hours) did not change after multiple dosing, and steady-state plasma concentrations were achieved within 6–7 days.

In HIV-infected patients at steady state, pharmacokinetic parameters Cmax, Cmin, and AUC showed linear dependence on daily doses of 200 mg, 400 mg, and 600 mg. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 µM (29%) [mean ± standard deviation (% coefficient of variation (C.V.))], steady-state Cmin was 5.6 ± 3.2 µM (57%), and AUC was 184 ± 73 µM·h (40%).

Effect of food. AUC and Cmax after a single 600 mg dose of efavirenz in film-coated tablets increased by 28% (90% CI: 22–33%) and 79% (90% CI: 58–102%), respectively, in healthy volunteers when tablets were taken with a high-fat meal compared to fasting.

Distribution. Efavirenz has a high capacity to bind plasma proteins, particularly albumin (approximately 99.5–99.75%). In HIV-infected patients (N=9) who received efavirenz 200–600 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 value is approximately 3 times higher than the concentration of unbound (free) fractions of efavirenz in plasma.

Biological transformation. Studies in patients and in vitro studies using human liver microsomes showed that efavirenz is metabolized to hydroxylated derivatives formed via hydroxylation, primarily mediated by the cytochrome P450 system, followed by glucuronidation. These metabolites are inactive against HIV-1. In vitro studies suggest that CYP3A4 and CYP2B6 are the main isoenzymes responsible for efavirenz metabolism, and that efavirenz inhibits the CYP2C9, 2C19, and 3A4 isoenzymes of the cytochrome P450 system. In vitro, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations much higher than those achieved clinically.

Metabolism of efavirenz in plasma may increase in patients homozygous for the G516T variant of the CYP2B6 isoenzyme. The clinical significance of this effect is unknown; however, at least an increased frequency and severity of adverse events associated with efavirenz cannot be ruled out.

Efavirenz has been shown to induce cytochrome P450 enzymes, thus leading to induction of its own metabolism. In healthy volunteers receiving multiple doses of 200–400 mg daily for 10 days, a lower degree of drug accumulation (22–42% lower) and a shorter terminal half-life of 40–55 hours (single-dose half-life is 52–76 hours) were observed.

Elimination. Efavirenz has a relatively long terminal half-life of 52–76 hours after a single dose and 40–55 hours after multiple doses. Approximately 14–34% of the radiolabeled dose of efavirenz is recovered in urine, and less than 1% of the efavirenz dose is excreted unchanged in urine.

In one patient with severe hepatic impairment (Child-Pugh class C), a two-fold increase in half-life was observed, indicating the potential for significantly greater accumulation.

Pharmacokinetics in children. In 49 children receiving a dose equivalent to 600 mg of efavirenz (dose calculated according to age and body weight), steady-state Cmax was 14.1 µM, steady-state Cmin was 5.6 µM, and AUC was 216 µM·h. The pharmacokinetics of efavirenz in children were similar to those in adults.

Sex, race, and age. Similar pharmacokinetics of efavirenz were observed in men and women, as well as in patients of different racial backgrounds. Limited data suggest that individuals of Asian and Pacific Islander origin may have increased sensitivity to efavirenz, although no reduced tolerability of efavirenz has been observed in these patients. Pharmacokinetic studies have not been conducted in elderly patients.

Clinical characteristics.

Indications.

In combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children aged 3 years and older.

Contraindications.

Hypersensitivity to the active substance or any of the excipients.

Severe hepatic impairment (Child-Pugh class C).

Concomitant use with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, and methylergonovine), as competition by efavirenz for CYP3A4 may lead to inhibition of metabolism of these drugs and create conditions for the development of serious and/or life-threatening adverse events (e.g., cardiac arrhythmias, prolonged sedative effects, or respiratory depression).

Concomitant use with herbal products containing St. John’s wort (Hypericum perforatum), due to the potential for decreased plasma concentrations and reduced clinical efficacy of efavirenz.

Interaction with other medicinal products and other forms of interaction.

Efavirenz is an inducer in vivo of CYP3A4, CYP2B6, and UGT1A1. When efavirenz is used concomitantly with other medicinal products that are substrates of these enzymes, reduced plasma concentrations of these agents may occur. Efavirenz is an inhibitor of CYP3A4 in vitro. Theoretically, efavirenz may initially increase the effect on cytochrome CYP3A4 substrates; therefore, substrates with a narrow therapeutic index should be monitored (see section "Contraindications").

Efavirenz may be an inducer of CYP2C19 and CYP2C9; however, inhibition has been observed in vitro, and the overall effect of co-administration with substrates of these enzymes is not fully defined.

The effect of efavirenz may be enhanced when used concomitantly with medicinal products (e.g., ritonavir) or food (e.g., grapefruit juice, which inhibits CYP3A4 and CYP2B6 activity). Constituents or herbal products (e.g., Ginkgo biloba extracts and St. John’s wort) that induce these enzymes may lead to decreased plasma concentrations of efavirenz. Concomitant use of efavirenz with Ginkgo biloba extracts is not recommended (see section "Special precautions for use").

Pediatric population

Interaction studies have been conducted only in adults.

Contraindications for concomitant use

Efavirenz should not be used concomitantly with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, and methylergonovine), because inhibition of their metabolism may lead to serious, life-threatening consequences.

St. John’s wort (Hypericum perforatum)

Concomitant use of efavirenz and St. John’s wort or products containing St. John’s wort is contraindicated. Concomitant use with St. John’s wort may reduce efavirenz plasma concentrations due to induction of efavirenz-metabolizing enzymes and/or transporter proteins by St. John’s wort. If a patient is already taking St. John’s wort, its use should be discontinued, viral load should be monitored, and, if possible, efavirenz levels should be assessed. Efavirenz levels may increase after discontinuation of St. John’s wort, and dose adjustment of efavirenz may be required.

The inductive effect of St. John’s wort may persist for at least 2 weeks after discontinuation of its use.

Other interactions

Interactions of efavirenz with protease inhibitors, with other antiretroviral agents different from protease inhibitors, and with other non-antiretroviral medicinal products are presented in the table (enhancement is indicated as "↑", reduction as "↓", and no change as "↔"). 90% or 95% confidence intervals are provided in parentheses where available. Unless otherwise stated, studies were conducted in healthy volunteers.

Interaction between efavirenz and other medicinal products in adults

a Unless otherwise specified, 90 % confidence intervals are provided.

b 95 % confidence intervals.

Special precautions.

There are insufficient clinical data on the use of efavirenz in patients with advanced HIV infection, specifically: patients with CD4 cell counts < 50 cells/mm³, as well as in cases of failure of protease inhibitor therapy. Cross-resistance between efavirenz and protease inhibitors has not been observed; however, there are currently insufficient data on the efficacy of protease inhibitor-based combination therapy when prior combination therapy containing efavirenz has failed clinically.

Efavirenz must not be used as a single agent for the treatment of HIV infection, nor should it be added as a single agent to an ineffective regimen. As with other non-nucleoside reverse transcriptase inhibitors, resistant virus emerges rapidly when efavirenz is used as monotherapy. When selecting a new antiretroviral agent to be used in combination with efavirenz, potential for cross-resistance should be considered.

When prescribing other medicinal products concomitantly with efavirenz, physicians should refer to the prescribing information for those products.

Concomitant use of efavirenz with the fixed-dose combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate is not recommended, except in cases requiring dose adjustment (e.g., with rifampicin).

Concomitant use of Ginkgo biloba extracts is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Patients should be informed that their antiretroviral therapy, including efavirenz, does not eliminate the risk of HIV transmission through sexual contact or blood. Patients should continue to take appropriate preventive measures.

When any antiretroviral agent in a combination regimen is discontinued due to suspected intolerance, careful consideration should be given to discontinuing all antiretroviral agents simultaneously. All discontinued antiretroviral agents should be restarted promptly after resolution of intolerance symptoms. Intermittent antiretroviral therapy with subsequent reinitiation increases the risk of emergence of drug-resistant mutant viruses and is not recommended.

Skin rash. Mild to moderate rash, which usually resolves with continued therapy, has been reported. Appropriate antihistamines and/or corticosteroids may improve tolerability and hasten resolution of rash. In less than 1% of patients receiving efavirenz, severe rash with blistering, moist desquamation, or ulceration has been reported. Cases of erythema multiforme or Stevens-Johnson syndrome have occurred in approximately 0.1% of patients. Efavirenz should be discontinued in the event of severe rash with blistering, desquamation, mucosal involvement, or accompanied by fever. If treatment with efavirenz is discontinued, consideration should also be given to discontinuing other antiretroviral agents to prevent emergence of drug-resistant virus.

Experience with efavirenz use in patients who previously discontinued other non-nucleoside reverse transcriptase inhibitors is limited. Efavirenz is not recommended for patients who previously experienced a life-threatening skin reaction (e.g., Stevens-Johnson syndrome) during treatment with other non-nucleoside reverse transcriptase inhibitors.

Psychiatric symptoms.

Psychiatric adverse effects have been observed in patients receiving efavirenz. Patients with a history of psychiatric disorders are more likely to experience these serious psychiatric adverse events.

In particular, severe depression occurred more frequently in patients with a history of depression.

There have also been isolated reports of severe depression, suicidal ideation, delirium, and psychosis-like behavior. Patients should be advised that if severe depression, psychosis, or suicidal thoughts occur, they should seek immediate medical evaluation to assess the possible relationship of these symptoms to efavirenz use and, if such a relationship is established, to determine whether the risks of continuing therapy outweigh its benefits.

Central nervous system symptoms.

Adverse reactions including, but not limited to, dizziness, insomnia, somnolence, difficulty concentrating, and abnormal dreams have been reported in patients receiving 600 mg of efavirenz daily. Central nervous system symptoms usually begin within the first 1–2 days of therapy and generally resolve after the first 2–4 weeks. Patients should be informed that these symptoms are likely to diminish with continued therapy and are not harbingers of the less common psychiatric symptoms.

Seizures. Seizures have been reported rarely in patients receiving efavirenz, mostly in those with a history of seizures. In patients receiving concomitant anticonvulsants that are primarily metabolized in the liver, such as phenytoin, carbamazepine, and phenobarbital, periodic monitoring of plasma concentrations is recommended. In a drug interaction study, plasma concentrations of carbamazepine were reduced when coadministered with efavirenz. Caution should be exercised when prescribing efavirenz to patients with a history of seizures.

Food intake. Administration of efavirenz with food may increase the elimination half-life of the drug, which may in turn increase the frequency of adverse effects. It is recommended to take efavirenz on an empty stomach, preferably at bedtime.

Liver disease. There are a small number of reports of liver failure in patients without prior liver disease or other identified risk factors. Monitoring of liver enzymes may also be advisable in patients without prior liver dysfunction or other risk factors.

Since efavirenz is primarily metabolized by the cytochrome P450 system and clinical experience with efavirenz in patients with chronic liver disease is limited, caution should be exercised when prescribing efavirenz to patients with mild to moderate hepatic impairment. Patients should be closely monitored for adverse reactions related to the drug, particularly central nervous system symptoms. Liver function tests should be performed periodically.

The safety and efficacy of efavirenz in patients with severe hepatic impairment have not been established. Efavirenz is contraindicated in patients with severe hepatic impairment. Patients with chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of serious and potentially life-threatening hepatic adverse events. In patients with a history of liver dysfunction, including chronic active hepatitis, the frequency of liver function abnormalities during combination antiretroviral therapy is significantly increased, and monitoring should be performed according to standard practice. If signs of worsening liver disease occur or serum transaminase levels persistently exceed the upper limit of normal by more than five times, the potential benefit of continuing efavirenz therapy versus the risk of serious hepatotoxicity should be carefully weighed. Interruption or discontinuation of therapy should be considered for such patients.

In patients receiving other hepatotoxic drugs, monitoring of liver enzyme activity is also recommended. In cases of concomitant antiviral therapy for hepatitis B or C, appropriate information on these drugs should be consulted.

Immune reconstitution syndrome.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (cART), an inflammatory reaction to indolent or residual opportunistic pathogens may occur, leading to serious clinical conditions or exacerbation of symptoms. These reactions typically occur within the first few weeks or months after starting cART. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia (commonly known as Pneumocystis carinii pneumonia). Any inflammatory symptoms require evaluation; treatment should be initiated if necessary. Autoimmune disorders (such as Graves' disease) have also been reported in the context of immune reconstitution; however, the time to onset is variable, and these disorders may occur many months after initiation of therapy.

Lipodystrophy and metabolic disturbances.

Combination antiretroviral therapy (cART) is associated with redistribution of body fat (lipodystrophy) in HIV-infected patients. The long-term consequences of these events are unknown. The mechanism is not fully understood.

The association with visceral lipomatosis and lipoatrophy is hypothetical.

Increased risk of lipodystrophy is associated with individual factors such as older age, as well as drug-related factors such as longer duration of antiretroviral therapy and associated metabolic disturbances.

Clinical examination should include assessment of physical signs of fat redistribution.

Weight gain and increased levels of lipids and glucose in the blood may occur during antiretroviral therapy. Such changes may be partly related to disease control and lifestyle. In some cases, treatment efficacy has been reported for lipid levels, while information on weight gain related to any specific treatment regimen is lacking.

Decisions should be based on measurements of serum lipids and blood glucose levels. Lipid abnormalities should be managed appropriately.

Osteonecrosis.

Although the etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been observed predominantly in patients with longstanding HIV infection and/or prolonged cART use. Patients should be informed to seek medical attention if they experience joint pain, joint stiffness, or difficulty walking.

Renal impairment. The pharmacokinetics of efavirenz in patients with renal impairment have not been studied. However, since less than 1% of the drug is excreted unchanged in urine, renal impairment is not expected to significantly affect efavirenz elimination. There is no experience with efavirenz use in patients with severe renal impairment; therefore, careful safety assessment is recommended in such patients.

Nephrolithiasis/uroliithiasis. Reports of serious and non-serious kidney stone formation have been recorded in patients receiving efavirenz; in most cases, these events occurred in patients with a history of nephrolithiasis and/or concomitant use of lithogenic drugs. Literature reports have identified kidney stones containing efavirenz metabolites.

Fatal cases have not been reported.

Cases of nephrolithiasis have been reported during post-marketing surveillance of HIV-infected patients receiving efavirenz therapy. As these cases were reported in clinical practice, their frequency cannot be estimated.

Malignant neoplasms. The potential risk of malignant neoplasms associated with efavirenz use is not higher than with other antiretroviral drugs. Additionally, no signals indicating increased risk of malignancies in patients using efavirenz have been identified. Patients using these medicinal products do not have an increased risk of developing malignant neoplasms.

Exacerbation of efavirenz-mediated adverse reactions upon switching from oral solution to solid dosage forms of efavirenz (tablets or capsules). The solid dosage form provides more stable bioavailability across all age groups, including children. However, due to increased bioavailability and inter-patient variability, an increased drug effect may be observed when switching from oral solution to solid dosage form.

Therefore, patients should be carefully monitored for signs of efavirenz toxicity during the transition period from oral solution to solid dosage form. Although no new manifestations of drug toxicity have been identified in patients taking the solid dosage form, there is a potential for increased frequency of known adverse reactions, particularly during the first few weeks of therapy. Since young children may not be able to report such toxicity, clinical monitoring is justified.

Development of neurocognitive changes in HIV-infected children. In most studies, neurocognitive deficit is more common in HIV-infected patients than in HIV-negative individuals, regardless of ART status or disease stage. HIV-associated neurocognitive disorders (HAND) are primarily characterized by subcortical dysfunction along with memory and psychomotor impairments, depressive symptoms, and motor disorders; pathologically, HIV predominantly affects subcortical and deep gray matter structures. Neurocognitive deficit associated with HAND may improve over time, unlike progressive neurological disorders seen in other neurodegenerative diseases such as Alzheimer's disease. Selection of ART regimens for patients suspected of HAND should be optimized based on viral resistance profile in plasma and minimizing therapy toxicity or intolerance; additional benefit may be achieved by selecting a regimen optimized for CNS penetration.

There is insufficient information regarding potential observation of HAND symptoms in children that were previously considered typical only in adults. In children receiving efavirenz, no signals related to HAND-associated neurocognitive adverse reactions or increased risk of potentially irreversible central nervous system changes have been recorded. Efavirenz can be safely used in children, provided all psychoneurological precautions indicated in the instructions are followed.

CYP2B6 isoenzyme polymorphism. Efavirenz metabolism in plasma may be increased in patients homozygous for the G516T variant of the CYP2B6 isoenzyme. Post-marketing surveillance data indicate reduced efavirenz clearance in patients with CYP2B6 genetic polymorphism. The clinical significance of this effect is unknown; however, an increased frequency and severity of adverse events associated with efavirenz use cannot be ruled out.

Geriatric patients. It is not possible to determine whether geriatric patients respond differently to the drug compared to younger patients, as adequate studies involving sufficient numbers of elderly patients have not been conducted.

Efavirenz film-coated tablets must not be administered to patients with rare hereditary conditions: galactose intolerance or glucose-galactose malabsorption (Lapp syndrome). Patients with these conditions may take the lactose-free efavirenz oral solution.

Use during pregnancy or breastfeeding.

Use during pregnancy

Women of reproductive potential should undergo a pregnancy test before starting efavirenz. Efavirenz must not be prescribed during pregnancy except when no alternative treatment options are available.

Women taking efavirenz must avoid pregnancy. Barrier contraception should always be used in combination with other contraceptive methods (e.g., oral or hormonal contraceptives; see section "Interaction with other medicinal products and other forms of interaction"). Due to the long elimination half-life of efavirenz, effective contraception is recommended for 12 weeks after discontinuation of efavirenz.

Seven retrospective reports of neural tube defects, including meningomyelocele, have been received in mothers treated with regimens containing efavirenz (excluding any fixed-dose combination tablets containing efavirenz) during the first trimester. Additionally, two cases (one prospective and one retrospective), including events related to neural tube defects, have been reported with the use of fixed-dose combination tablets containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate. A causal relationship between these events and efavirenz use has not been established, and the dominant active ingredient is unknown. Since neural tube defects occur within the first 4 weeks of fetal development (when neural tubes are closing), this potential risk applies to women using efavirenz during the first trimester of pregnancy.

As of July 2013, the Antiretroviral Pregnancy Registry (APR) had received prospective reports of 904 pregnancies exposed to efavirenz-containing regimens during the first trimester, resulting in 766 live births. One infant was reported to have a neural tube defect. The frequency and pattern of other congenital anomalies were similar to those observed in infants exposed to regimens not containing efavirenz, including HIV-negative controls. The background rate of neural tube defects in the general population ranges from 0.5 to 1 case per 1000 live births.

Use during breastfeeding

Efavirenz is excreted in human milk. However, there is insufficient information on the effects of efavirenz on newborns/infants. Risk to infants cannot be excluded. Women taking efavirenz during lactation are advised to discontinue breastfeeding. Some experts believe that HIV-infected mothers should never breastfeed to avoid HIV transmission.

Fertility

The effect of efavirenz on fertility in male and female rats was evaluated at doses achieving systemic drug exposure equivalent to or lower than that achieved in humans at recommended efavirenz doses. In these studies, efavirenz did not impair mating or fertility in male or female rats (doses up to 100 mg/kg twice daily), nor did it affect sperm or offspring of male rats (doses up to 200 mg twice daily). Reproductive potential of offspring born to female rats treated with efavirenz was not impaired.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted to evaluate the potential effect of efavirenz on the ability to drive or operate complex machinery. Efavirenz may cause dizziness, reduced concentration, and/or somnolence. Patients should be aware that if such symptoms occur, they should avoid potentially hazardous activities such as driving or operating complex machinery.

Dosage and Administration.

Treatment should be administered by a physician experienced in managing HIV infection.

Concomitant antiretroviral therapy. Efavirenz should be used in combination with other antiretroviral agents.

Efavirenz is recommended to be taken on an empty stomach. Administration of efavirenz with food has been shown to increase plasma concentrations of efavirenz, which may lead to an increased incidence of adverse effects.

To improve tolerability of nervous system side effects, it is recommended to take the medication at bedtime.

Adults. The recommended dose of efavirenz, in combination with nucleoside reverse transcriptase inhibitors and with or without a protease inhibitor, is 600 mg orally once daily.

Children (aged 3 to 17 years). Recommended doses of efavirenz in combination with a protease inhibitor and/or nucleoside reverse transcriptase inhibitors for patients aged 3 to 17 years are listed in the table below. Efavirenz tablets should be prescribed only to children who are able to swallow tablets. Efavirenz is not recommended for use in children under 3 years of age or weighing less than 13 kg, due to insufficient data on safety and efficacy in this patient population.

Dosing for pediatric use (once daily)

To achieve the required dosage in children, use tablets containing the appropriate amount of active substance.

Dosage adjustment. If efavirenz is coadministered with voriconazole, the maintenance dose of the latter should be increased to 400 mg every 12 hours; the dose of efavirenz should be reduced by 50%, e.g. to 300 mg once daily. When voriconazole therapy is discontinued, the initial efavirenz dosage should be restored.

Rifampicin. When efavirenz is coadministered with rifampicin in patients with body weight of 50 kg or more, an increase of efavirenz dose to 800 mg once daily is recommended.

Renal impairment. The pharmacokinetics of efavirenz in patients with renal impairment has not been studied. However, since less than 1% of the drug is excreted unchanged in urine, renal dysfunction is not expected to significantly affect efavirenz elimination.

Hepatic disease. Patients with mild to moderate hepatic impairment may receive the standard recommended dose of efavirenz. Patients should be carefully monitored for adverse drug reactions, particularly symptoms related to the nervous system.

Children.

The use of efavirenz in children under 3 years of age or weighing less than 13 kg has not been studied. Therefore, efavirenz should not be administered to children under 3 years of age.

Overdose.

In some patients who accidentally took 600 mg twice daily, an increased incidence of nervous system symptoms was observed. In one patient, involuntary muscle contractions occurred.

In case of efavirenz overdose, treatment consists of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Activated charcoal may be used to eliminate unabsorbed drug. There is no specific antidote. Because efavirenz is highly protein-bound, dialysis is unlikely to remove a significant amount of the drug from the blood.

Adverse reactions.

Summary of safety studies

Studies have been conducted in 9,000 patients receiving efavirenz. In a subgroup of 1,008 adult patients who received 600 mg of efavirenz daily in combination with protease inhibitors and/or nucleoside reverse transcriptase inhibitors in controlled clinical trials, the most frequently reported adverse reactions of at least moderate severity occurring 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 adverse reactions associated with the use of Efavirenz are skin rash and central nervous system (CNS) symptoms. CNS symptoms usually begin soon after initiation of therapy and generally resolve within the first 2–4 weeks. Serious skin reactions, such as Stevens-Johnson syndrome and erythema multiforme, have been reported in patients receiving efavirenz. Psychiatric adverse reactions including severe depression, suicide, psychosis, and seizures have also been reported. Administration of efavirenz with food may increase drug exposure and lead to an increased frequency of adverse reactions (see section "Posology and method of administration").

The long-term safety of efavirenz-containing regimens was evaluated in a controlled trial (006), in which patients received efavirenz + zidovudine + lamivudine (n = 412, mean duration 180 weeks), efavirenz + indinavir (n = 415, mean duration 102 weeks), or indinavir + zidovudine + lamivudine (n = 401, mean duration 76 weeks). Long-term use of efavirenz in this study was not associated with any new safety concerns.

List of adverse reactions

The moderate or severe adverse reactions associated with efavirenz at the recommended dose in combination therapy (n = 1,008) observed in clinical trials are listed below. Adverse reactions identified from post-marketing experience with efavirenz-containing products and antiretroviral drugs are also listed in italics. Frequency categories are defined as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); or very rare (< 1/10,000).

Immune system disorders

uncommon: hypersensitivity.

Metabolism and nutrition disorders

common: hypertriglyceridaemia*;

uncommon: hypercholesterolaemia*.

Psychiatric disorders

common: sleep disorders, anxiety, depression, insomnia*;

uncommon: affect lability, aggression, confusion, euphoria, hallucinations, mania, paranoia, psychosis+, suicide attempts, suicidal ideation*;

rare: delirium±, neurosis±, completed suicide±*.

Nervous system disorders

common: coordination disorders and confusion+, abnormal dreams, attention disorders (3.6%), dizziness (8.5%), headache (5.7%), insomnia, somnolence (2.0%)*;

uncommon: feeling anxious, amnesia, ataxia, convulsions, disordered thinking, tremor±.

Eye disorders

uncommon: blurred vision.

Ear and labyrinth disorders

uncommon: tinnitus+, dizziness.

Vascular disorders

uncommon: flushing+.

Gastrointestinal disorders

common: abdominal pain, diarrhoea, nausea, vomiting;

uncommon: acute pancreatitis.

Hepatobiliary disorders

common: increased aspartate aminotransferase (AST)*, increased alanine aminotransferase (ALT)*, increased gamma-glutamyltransferase (GGT)*;

uncommon: acute hepatitis;

rare: hepatic failure±,+.

Skin and subcutaneous tissue disorders

very common: rash (11.6%)*;

common: pruritus;

uncommon: exudative multiform erythema, Stevens-Johnson syndrome*;

rare: photoallergic dermatitis+.

Reproductive system and breast disorders

uncommon: gynaecomastia.

General disorders and administration site conditions

common: increased fatigue.

*, ±, + for detailed information see below.

Description of selected adverse reactions

Information regarding post-marketing surveillance

• adverse reactions identified by post-marketing surveillance; however, frequency data were derived from 16 clinical trials (n = 3,969).

± adverse reactions identified by post-marketing surveillance but not reported as cases associated with efavirenz use in 16 clinical trials. The frequency category "rare" was determined using guidance A of the Summary of Product Characteristics (revised 2 September 2009), based on the defined upper limit of the 95% confidence interval at 0 cases among patients treated with efavirenz in these clinical trials (n = 3,969).

Rash

In clinical trials, skin rash was observed in 26% of patients receiving 600 mg of efavirenz compared to 17% of patients in control groups. Rash was considered treatment-related in 18% of patients receiving efavirenz. Severe rashes occurred in less than 1% of patients receiving efavirenz, and 1.7% of patients discontinued treatment due to rash. Cases of erythema multiforme or Stevens-Johnson syndrome occurred in approximately 0.1% of patients.

Typically, mild to moderate maculopapular skin rashes occur within the first two weeks after initiating efavirenz therapy. In most patients, the rash resolves with continued efavirenz treatment within one month. Reintroduction of efavirenz may be considered in patients who discontinued it due to rash. When reinitiating efavirenz, concomitant administration of appropriate antihistamines and/or corticosteroids is recommended.

Experience with efavirenz in patients who discontinued other NNRTI-class antiretroviral drugs is limited.

Reported rates of recurrent rash after switching from nevirapine to efavirenz are primarily based on retrospective data from published literature, ranging from 13% to 18%, compared to rates observed in patients receiving efavirenz in clinical trials (see section "Posology and method of administration").

Psychiatric symptoms

Serious psychiatric adverse reactions have been observed in patients receiving efavirenz. In controlled trials, the frequency of specific serious psychiatric disorders was:

Patients with a history of psychiatric disorders are at an increased risk of developing such serious psychiatric adverse reactions, with an incidence ranging from 0.3% for manic reactions to 2% for severe depression and suicidal ideation. There are also post-marketing reports of suicides, delusions, and psychosis-like behavior.

Nervous system side effects

Neurological symptoms of moderate to severe intensity were observed in 19% of patients (2% severe cases) treated with efavirenz, compared to 9% of patients (1% severe cases) receiving the control treatment regimen. In clinical trials, 2% of patients receiving efavirenz discontinued therapy due to these neurological symptoms.

Neurological symptoms usually occur during the first or second day of therapy and resolve in most cases within the first 2–4 weeks. In studies conducted in uninfected volunteers, typical neurological symptoms appeared on average 1 hour after dosing and lasted approximately 3 hours. Neurological symptoms may occur more frequently when efavirenz is taken with food, possibly due to increased plasma concentrations of efavirenz. To improve tolerability of these symptoms, it is recommended to take the medication at bedtime during the first weeks of therapy. This dosing schedule is also recommended for patients in whom these symptoms persist. Dose reduction or splitting the daily dose generally does not provide a beneficial effect.

Analysis of long-term data showed that, over 24 weeks of therapy, the incidence of newly occurring neurological symptoms among patients taking efavirenz was generally similar to that observed in the control group.

Hepatic failure

Some post-marketing reports of hepatic failure, including cases in patients without prior liver disease or other defined risk factors, have been described as sudden and rapidly progressive illness, which in some cases led to liver transplantation or death.

Immune Reconstitution Syndrome

In HIV-infected patients with severe immune deficiency at the initiation of combination antiretroviral therapy (CART), inflammatory reactions to asymptomatic or residual opportunistic pathogens may occur. Autoimmune disorders (such as Graves’ disease) have also been reported; however, the time to onset of these conditions is variable, and such disorders may manifest many months after initiation of treatment (see section "Special precautions for use").

Osteonecrosis: There have been reports of osteonecrosis, particularly in patients with generally recognized risk factors, advanced HIV disease (AIDS), or those on long-term CART. The frequency of occurrence is unknown.

Laboratory abnormalities

Liver enzymes: Elevations in AST and ALT, and increased gamma-glutamyl transferase (GGT).

Elevations in AST and ALT levels more than five times the upper limit of normal (ULN) were observed in 3% of 1008 patients receiving 600 mg of efavirenz (5–8% after long-term treatment in Study 006). Similar elevations were observed in patients receiving the control treatment regimen (5% after long-term treatment). Elevations in GGT more than five times ULN were observed in 4% of all patients receiving 600 mg of efavirenz and in 1.5–2% of patients receiving the control regimen (7% of patients receiving efavirenz and 3% of control patients after long-term treatment). Isolated increases in GGT in patients taking efavirenz may indicate enzyme induction. In the long-term study (006), 1% of patients in each treatment group discontinued therapy due to hepatic or biliary disorders.

Amylase: In a subgroup of 1008 patients in a clinical trial, asymptomatic elevations in serum amylase concentration greater than 1.5 times the upper normal limit were observed in 10% of patients receiving efavirenz and in 6% of patients receiving the control treatment regimen. The clinical significance of asymptomatic elevations in serum amylase is unknown.

Lipodystrophy and metabolic disturbances: Combination antiretroviral therapy is considered to cause redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast enlargement, and fat accumulation in the dorsocervical region (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic disturbances such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia.

Lipids: Increased levels of total cholesterol, HDL cholesterol, and triglycerides. Lipid level changes may depend on factors such as duration of treatment and other components of antiretroviral regimens.

Cannabinoid testing: Efavirenz does not bind to cannabinoid receptors; however, there have been reports of false-positive urine cannabinoid tests in uninfected volunteers receiving efavirenz. False-positive test results were observed only with the CEDIA DAU Multi-Level THC assay used for screening and were not observed with other cannabinoid tests, including confirmatory tests.

Children. Adverse events in children are generally similar to those in adults. Rash occurs more frequently in children (59 out of 182 patients (32%) treated with efavirenz) than in adults and is often of higher severity (severe rash observed in 6 out of 182 children (3.3%)). Prophylactic administration of appropriate antihistamines to children prior to starting efavirenz therapy may be beneficial. Although young children may have difficulty describing neurological symptoms, such symptoms occur less frequently in children and are mostly mild to moderate in intensity. The most commonly observed neurological symptoms are of moderate intensity, primarily dizziness. Severe neurological symptoms were not reported in any child, and no patient discontinued the drug due to neurological symptoms.

Other special populations

Liver enzymes in patients co-infected with hepatitis B or C: In data from the long-term Study 006, 137 patients treated with regimens containing efavirenz (mean duration of therapy 68 weeks) and 84 patients receiving the control regimen (mean duration 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or hepatitis C (hepatitis C antibodies positive). Among co-infected patients in Study 006, elevations in AST levels more than five times ULN were observed in 13% of patients receiving efavirenz and 7% of those receiving the control regimen, and elevations in ALT more than five times ULN in 20% and 7%, respectively. Among co-infected patients, 3% in the efavirenz group and 2% in the control group discontinued treatment due to hepatic function abnormalities (see section "Special precautions for use").

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

200 mg dosage: 90 tablets in a high-density polyethylene container with a plastic cap equipped with a first-opening control system, labeled in Ukrainian.

600 mg dosage: 30 tablets in a high-density polyethylene container with a plastic cap equipped with a first-opening control system, labeled in Ukrainian.

One container per cardboard box, labeled in Ukrainian.

Prescription category. Prescription only.

Manufacturer.

STRIDES PHARMA SCIENCE LIMITED.

Manufacturer’s address.

No. 36/7, Suragadrajakanahalli, Indlavadi Cross, Anekal Taluk, Bangalore, Karnataka 562106, India.

Marketing authorization holder.

Strides Cis Limited.

Address of the marketing authorization holder.

Julia House, 3 Themistocles Dervis Street, CY-1066, Nicosia, Cyprus.