Estiva 600

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESTIVA 600 (ESTIVA 600)

Composition:

Active substance: efavirenz;

One tablet contains 600 mg of efavirenz;

Excipients: hydroxypropylcellulose, sodium lauryl sulfate, croscarmellose sodium, microcrystalline cellulose, lactose monohydrate, magnesium stearate, Opadry yellow 03B52155.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: yellow, capsule-shaped film-coated tablets with an engraving "H" on one side and "4" on the other side.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Efavirenz is a non-nucleoside inhibitor of HIV-1 reverse transcriptase. Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase and does not significantly inhibit HIV-2 reverse transcriptase or cellular DNA polymerases (α, β, γ, or δ).

Cardiac electrophysiology. The effect of efavirenz on the QTc interval was evaluated in a controlled study in 58 healthy subjects with CYP2B6 polymorphism. The mean Cmax of efavirenz in subjects with the CYP2B6 *6/*6 genotype after administration of a daily dose of 600 mg for 14 days was 2.25 times higher than the mean Cmax observed in subjects with the CYP2B6 *1/*1 genotype. A positive correlation was observed between efavirenz concentration and QTc interval prolongation. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper 90% confidence interval limit were 8.7 ms and 11.3 ms, respectively, in subjects with the CYP2B6 *6/*6 genotype after administration of a daily dose of 600 mg for 14 days (see section "Interaction with other medicinal products and other forms of interaction").

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 combination with 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 significant 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 cultures 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 exhibited 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 clinical trials of efavirenz who showed signs of treatment failure (viral load rebound) were tested for sensitivity to non-nucleoside reverse transcriptase inhibitors. Thirteen isolates previously characterized as resistant to efavirenz were also found to be 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 were also sensitive 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 clinical trials of efavirenz in patients with advanced HIV infection, specifically those with CD4 cell counts < 50 cells/mm³, or in patients previously treated with protease inhibitors or non-nucleoside reverse transcriptase inhibitors, have not been conducted.

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

Two controlled trials (006 and ACTG 364), each lasting approximately one year, in which efavirenz was used in combination with nucleoside reverse transcriptase inhibitors and/or protease inhibitors, demonstrated a reduction in viral load below the limit of quantification and an increase in CD4 lymphocyte count following 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 trials, 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. Standard doses of nucleoside reverse transcriptase inhibitors every 12 hours were used in each of these trials.

Children. In an uncontrolled trial, ACTG 382, involving 57 children aged 3–16 years who had previously received nucleoside reverse transcriptase inhibitors, 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 were evaluated. The starting dose of efavirenz was equivalent to 600 mg (adjusted 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. The mean number of CD4 cells increased by 63 ± 34.5 cells/mm³ compared to baseline. The duration of treatment response in children was similar to that in adult patients.

Pharmacokinetics.

Absorption: Dose-related increases in Cmax and area under the concentration-time curve (AUC) were observed with doses up to 1600 mg; however, a proportional relationship between the extent of increase and dose was not observed—the result was lower, suggesting reduced absorption at higher doses. The time to reach peak plasma concentrations (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 pharmacokinetics, mean Cmax, Cmin, and AUC values showed linear dependence on daily doses of 200 mg, 400 mg, and 600 mg.

After single-dose administration of 600 mg with a high-fat meal, Cmax and AUC were increased compared to administration of the same dose under fasting conditions.

Distribution: Efavirenz has a high capacity to bind plasma proteins, particularly albumin (approximately 99.5–99.75%). In HIV-infected patients receiving efavirenz at doses of 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 humans and in vitro using human liver microsomes showed that efavirenz is metabolized to hydroxylated derivatives, primarily via the cytochrome P450 system, followed by glucuronidation of the hydroxylated metabolites. 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 cytochrome P450 isoenzymes 2C9, 2C19, and 3A4. In vitro, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations much higher than those achieved under clinical conditions.

Exposure to 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, a potential increase in the frequency and severity of adverse events associated with efavirenz cannot be ruled out. Efavirenz has been shown to induce CYP3A4 and CYP2B6 enzymes, thereby inducing its own metabolism, which may be clinically significant in some patients. Efavirenz has also been shown to induce UGT1A1. Exposure to raltegravir (a UGT1A1 substrate) decreases in the presence of efavirenz.

Although in vitro data suggest that efavirenz inhibits CYP2C9 and CYP2C19, conflicting reports have been observed both in vivo regarding increased and decreased effects of substrates of these enzymes when co-administered with efavirenz. The net effect of co-administration is unclear.

Elimination: Efavirenz has a relatively long elimination half-life of at least 52 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 dose is excreted unchanged in urine.

Hepatic impairment: In a single-dose study, the elimination half-life was doubled in one patient with severe hepatic insufficiency (Child-Pugh class C), indicating a potential for much greater accumulation. Multiple-dose studies showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic insufficiency (Child-Pugh class A) compared to controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh class B or C) affects efavirenz pharmacokinetics.

The pharmacokinetics of efavirenz in children was similar to that in adults. Pharmacokinetic studies have not been conducted in elderly patients.

Gender and race: Pharmacokinetic properties of efavirenz are similar in men and women and among the studied racial groups.

Clinical characteristics.

Indications.

In combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults, adolescents, and children with body weight ≥ 40 kg.

Contraindications.

Efasta 600 is contraindicated in patients with clinically significant hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Severe hepatic impairment (Child-Pugh stage C).

Concomitant administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, due to competition of efavirenz for CYP3A4 (this may lead to inhibition of metabolism of these drugs or potential for serious and/or life-threatening complications – cardiac arrhythmias, prolonged sedative effect, respiratory depression) or with alkaloids of Secale cornutum (e.g., ergotamine, dihydroergotamine, ergonovine, methylergonovine). Concomitant use with herbal products containing St. John’s wort (Hypericum perforatum) due to potential decrease in plasma concentrations and reduced clinical efficacy of efavirenz.

Concomitant use with elbasvir (EBR) and grazoprevir (GZR) due to potential reduction in plasma concentrations of EBR and GZR.

The medicinal product is contraindicated in patients with:

‒ history of sudden cardiac death or congenital prolongation of the QTc interval on electrocardiogram, or any other clinical condition known to prolong the QTc interval in family history;

‒ symptomatic cardiac arrhythmia or clinically significant bradycardia, or congestive heart failure associated with reduced left ventricular ejection fraction in medical history;

‒ severe electrolyte disturbances, such as hypokalemia or hypomagnesemia.

Concomitant use with medicinal products that prolong the QTc interval, such as Class IA and III antiarrhythmics, neuroleptics, antidepressants, certain antibiotics (macrolides, fluoroquinolones, imidazole and triazole antifungals), certain antihistamines (terfenadine, astemizole), cisapride, flecainide, certain antimalarials, and methadone.

Interaction with other medicinal products and other forms of interaction.

Efavirenz is an in vivo inducer of CYP3A4, CYP2B6, and UGT1A1. When efavirenz is administered concomitantly with other medicinal products that are substrates of these enzymes, decreased plasma concentrations of these agents may occur. Efavirenz is also an in vitro inhibitor of CYP3A4. Theoretically, efavirenz may initially increase the effect on 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 coadministration with substrates of these enzymes is not well defined.

The effect of efavirenz may be increased by concomitant administration of medicinal products (e.g., ritonavir) or food (e.g., grapefruit juice) that inhibit the activity of CYP3A4 or CYP2B6. Substances or herbal products (e.g., extracts of Ginkgo biloba and St. John’s wort) that induce these enzymes may lead to reduced plasma concentrations of efavirenz. Concomitant use of efavirenz with St. John’s wort is contraindicated (see section "Contraindications"). Concomitant use of efavirenz with Ginkgo biloba extracts is not recommended (see section "Special warnings and precautions for use").

Medicinal products that prolong the QT interval

Efavirenz is contraindicated with concomitant use of medicinal products (which may cause QTc prolongation and Torsade de Pointes), such as: Class IA and III antiarrhythmics, neuroleptics and antidepressants, certain antibiotics, including agents from the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungals, certain nonsedating antihistamines (terfenadine, astemizole), cisapride, flecainide, certain antimalarials, and methadone (see section "Contraindications").

Pediatric population

Interaction studies have been conducted only in adults.

Contraindications to concomitant use:

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

Elbasvir/grazoprevir

Concomitant use of efavirenz with elbasvir/grazoprevir is contraindicated, as it may result in loss of virological response to elbasvir/grazoprevir. This loss is explained by a significant reduction in plasma concentrations of elbasvir and grazoprevir caused by induction of CYP3A4 (see section "Contraindications").

St. John’s wort (Hypericum perforatum)

Concomitant use of efavirenz and St. John’s wort or products containing St. John’s wort is contraindicated. Decreased plasma concentrations of efavirenz may occur when used concomitantly with St. John’s wort, due to induction of metabolizing enzymes and/or transport 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 checked. Efavirenz levels may increase after discontinuation of St. John’s wort, and dose adjustment of efavirenz may be required. The inducing effect of St. John’s wort may persist for at least 2 weeks after discontinuation.

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 (increase indicated as "↑", decrease as "↓", no change as "↔", and once every 8 or 12 hours as "every 8 hours" or "every 12 hours"). 90% or 95% confidence intervals are given in parentheses if available. Unless otherwise stated, studies were conducted in healthy volunteers.

Interactions between efavirenz and other medicinal products in adults

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

b 95% confidence intervals.

Other interactions: efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid tests have been reported during certain screening assays in both uninfected and HIV-infected subjects receiving efavirenz. In such cases, confirmation testing by a more specific method such as gas chromatography/mass spectrometry is recommended.

Special precautions for use.

There are insufficient clinical data on the use of efavirenz in patients with advanced HIV infection, specifically in 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 used following lack of clinical response to combination therapy containing efavirenz.

Estiva 600 should not be used as a single agent for the treatment of HIV infection, nor should it be added as the sole agent to an ineffective regimen. As with other non-nucleoside reverse transcriptase inhibitors (NNRTIs), resistant virus emerges rapidly when efavirenz is used as monotherapy. When selecting a new antiretroviral agent to be used in combination with efavirenz, the possibility of viral cross-resistance should be considered.

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 efavirenz with sofosbuvir/velpatasvir is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of efavirenz with velpatasvir/sofosbuvir/voxilaprevir is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant administration of glecaprevir/pibrentasvir with efavirenz may significantly reduce plasma concentrations of both glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Concomitant use of glecaprevir/pibrentasvir with efavirenz is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

When prescribing other medicinal products concomitantly with Estiva 600, physicians should refer to the respective product information for those agents.

If any antiretroviral agent within 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 immediately after resolution of intolerance symptoms. Intermittent antiretroviral therapy with repeated cycles of discontinuation and reinitiation is not recommended due to the increased risk of emergence of therapy-resistant mutant viruses.

Skin rash.

During clinical trials with efavirenz, cases of mild to moderate rash were reported, which typically resolved with continued therapy. 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 was reported. Cases of erythema multiforme or Stevens-Johnson syndrome were observed in approximately 0.1% of patients. Efavirenz should be discontinued in cases of severe rash with blistering, desquamation, mucosal involvement, or fever. If treatment with efavirenz is discontinued, a decision should also be made regarding discontinuation of other antiretroviral agents to prevent emergence of therapy-resistant viruses.

Experience with efavirenz use in patients who previously discontinued other NNRTIs 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 NNRTIs.

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 post-marketing reports of severe depression, fatal suicide, delirium, psychosis-like behavior, and catatonia. Patients should be warned that if they develop severe depression, psychosis, or suicidal ideation, they should seek immediate medical evaluation to assess the potential relationship of these symptoms to efavirenz use and, if such a link is established, to determine whether the risks of continuing therapy outweigh its benefits.

Neurological symptoms.

During clinical trials, adverse reactions including, but not limited to, dizziness, insomnia, somnolence, difficulty concentrating, and unusual dreams were reported in patients receiving efavirenz 600 mg once daily. Neurological symptoms typically begin within the first 1–2 days of treatment and usually resolve after the first 2–4 weeks. Patients should be informed that these common neurological symptoms are likely to diminish with continued therapy and are not predictive of less common psychiatric symptoms.

Seizures.

Seizures have been observed in adults and children receiving efavirenz, usually in patients with a history of seizures. In patients receiving concomitant anticonvulsants 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. Efavirenz should be used with caution in patients with a history of seizures.

Liver disease.

There have been 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 pre-existing liver dysfunction or other risk factors.

QT interval prolongation.

Prolongation of the QTc interval has been observed with efavirenz use (see section "Interaction with other medicinal products and other forms of interaction").

Alternative agents to efavirenz should be considered when coadministering with drugs known to carry a risk of Torsade de Pointes, or when treating patients at increased risk of Torsade de Pointes.

Food intake.

Administration of the drug with food may increase the elimination half-life of efavirenz, which in turn may lead to an increased frequency of adverse effects. Estiva 600 is recommended to be taken on an empty stomach, preferably at bedtime.

Immune reconstitution syndrome.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (cART), an inflammatory response 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 of starting cART. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia). Any inflammatory symptoms require evaluation and, if necessary, initiation of appropriate treatment. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported in the setting of immune reconstitution; however, the timing of onset is variable, and these disorders may manifest many months after initiation of treatment.

Body weight and metabolic disturbances.

During antiretroviral therapy, increases in body weight and elevations in blood lipid and glucose levels may occur. These changes may be partly related to improved disease control and lifestyle factors. For lipids, there is some evidence of a treatment effect in certain cases, whereas for weight gain, there is no strong evidence linking it to any specific therapy. Clinical monitoring should include assessment of physical signs of lipodystrophy. 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, and higher body mass index), cases of osteonecrosis have been reported predominantly in patients with advanced HIV infection and/or long-term cART use. Patients should be advised to seek medical attention if they experience joint pain, stiffness, or difficulty walking.

Urolithiasis/Nephrolithiasis.

Serious and non-serious cases of kidney stone formation have been reported in patients receiving efavirenz; these reactions were mostly observed in patients with a history of nephrolithiasis and/or concomitant use of lithogenic agents. Scientific literature has 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 developing malignant neoplasms associated with efavirenz use is not higher than with other antiretroviral agents. No increased risk of malignant neoplasms has been observed in patients receiving efavirenz. Patients receiving antiretroviral drugs do not have an increased risk of developing malignant neoplasms.

Special populations.

Liver disease: Efavirenz is contraindicated in patients with severe hepatic impairment (see section "Contraindications") and is not recommended in patients with moderate hepatic impairment due to insufficient data to determine dose adjustment. Because efavirenz is primarily metabolized by the cytochrome P450 system and clinical experience with efavirenz in patients with chronic liver disease is limited, efavirenz should be used with caution in patients with mild liver disease. Patients should be closely monitored for adverse drug reactions, particularly neurological symptoms. Periodic laboratory tests should be performed to assess liver function.

The safety and efficacy of efavirenz in patients with severe liver dysfunction have not been established. Patients with chronic hepatitis B or C receiving combination antiretroviral therapy are at increased risk of serious and potentially life-threatening hepatic adverse events. The incidence of liver function abnormalities is significantly increased in patients with pre-existing liver disease, including chronic active hepatitis, during combination antiretroviral therapy and should be monitored according to standard practice. If signs of worsening liver disease occur or serum transaminase activity persistently exceeds five times the upper limit of normal, the potential benefit of continuing efavirenz therapy should be weighed against the potential risk of serious hepatotoxicity. Interruption or discontinuation of therapy should be considered for such patients.

Monitoring of liver enzyme activity is also recommended in patients receiving other hepatotoxic drugs. In cases of concomitant antiviral therapy for hepatitis B or C, refer to the respective product information for those agents.

Renal impairment: The pharmacokinetics of efavirenz in patients with renal impairment have not been studied; however, since less than 1% of efavirenz is excreted unchanged in urine, renal impairment is not expected to significantly affect efavirenz elimination. Experience with efavirenz in patients with severe renal impairment is lacking; therefore, careful safety assessment is recommended for such patients.

Elderly patients: It is not possible to determine whether elderly patients respond differently to efavirenz compared to younger patients, as adequate studies including sufficient numbers of elderly subjects have not been conducted.

Paediatric population: Efavirenz has not been studied in children under 3 years of age; therefore, efavirenz should not be administered to this patient group. Efavirenz tablets are not suitable for children weighing less than 40 kg. Rash was reported in 59 of 182 children (32%) receiving efavirenz, with severe rash in six patients. Prophylactic use of appropriate antihistamines may be considered prior to initiating efavirenz therapy in children.

Efavir 600 contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Efavirenz should not be used during pregnancy except when no alternative treatment options are available. Women of childbearing potential should undergo a pregnancy test before starting efavirenz therapy. During treatment, they must always use barrier contraception in combination with other contraceptive methods (e.g., oral or other hormonal contraceptives; see section "Interaction with other medicinal products and other forms of interaction"). Due to the long half-life of efavirenz, adequate contraception is recommended for 12 weeks after discontinuation of efavirenz.

Women taking efavirenz must avoid pregnancy (the drug has shown teratogenic effects in primate studies).

Pregnancy

Seven retrospective reports of neural tube defects, including meningomyelocele, have been reported in fetuses of women treated with efavirenz (excluding any fixed-dose combination tablets containing efavirenz) during the first trimester. Two additional cases (one prospective and one retrospective) of 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 denominator 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 with first-trimester exposure to efavirenz, resulting in 766 live births. One case of neural tube defect was reported, and the frequency and nature of other congenital anomalies were similar to those observed in children exposed to antiretroviral regimens not containing efavirenz. The background rate of neural tube defects in the general population is 0.5–1 per 1000 live births.

Breastfeeding

Efavirenz has been shown to be excreted in human breast milk. However, there is insufficient information on the effects of efavirenz on neonates/infants. Risk to the infant cannot be excluded. Breastfeeding should be discontinued during treatment with efavirenz. To prevent transmission of HIV, women living with HIV are advised not to breastfeed their infants.

Fertility

The effects of efavirenz on fertility in male and female rats were evaluated at systemic exposures equivalent to or lower than those achieved in humans at the recommended doses of efavirenz. In these studies, efavirenz did not impair mating or fertility in male and female rats (doses up to 100 mg/kg twice daily) and did not affect sperm or offspring of male rats (doses up to 200 mg twice daily). The reproductive potential of female rat offspring exposed to efavirenz was not impaired.

Ability to drive and use machines.

Specific studies evaluating the potential effect of efavirenz on the ability to drive or operate complex machinery have not been conducted. Efavirenz may cause dizziness, reduced concentration, and/or somnolence. Patients should be instructed that if they experience such symptoms, they should avoid potentially hazardous activities such as driving a car or operating complex machinery.

Administration and Dosage

Treatment should be conducted only by a physician experienced in HIV therapy.

Efavirenz should be prescribed in combination with other antiretroviral agents.

Estivu 600 is recommended to be taken on an empty stomach. Increased plasma concentrations of efavirenz have been observed when efavirenz is taken with food, which may lead to an increased incidence of adverse effects.

To improve tolerability of nervous system-related adverse events, it is recommended to take the medicinal product before bedtime.

Adults and adolescents with body weight greater than 40 kg.

The recommended dosage of efavirenz in combination with nucleoside reverse transcriptase inhibitors (NRTIs), with or without a protease inhibitor, is 600 mg orally once daily.

Estiva 600 is not suitable for children with body weight less than 40 kg.

Dose adjustment.

If ESTIVA 600 is coadministered with voriconazole, the maintenance dose of the latter should be increased to 400 mg every 12 hours; the dose of ESTIVA 600 should be reduced by 50%, e.g. to 300 mg once daily. When voriconazole therapy is discontinued, the initial dosage of ESTIVA 600 should be restored.

When ESTIVA 600 is coadministered with rifampicin in patients with body weight of 50 kg or more, it is recommended to increase the dose of ESTIVA 600 to 800 mg once daily.

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

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

Children.

The use of efavirenz has not been studied in children under 3 years of age; therefore, efavirenz should not be prescribed to this patient population. Estiva 600 tablets are not suitable for children with body weight less than 40 kg.

Overdose.

In patients who accidentally took 600 mg of efavirenz twice daily, symptoms of nervous system disturbances occurred (one patient experienced involuntary muscle contractions).

Treatment: includes monitoring of vital signs and general supportive measures. There is no specific antidote for efavirenz. Activated charcoal may be used to eliminate unabsorbed drug. Since efavirenz is highly protein-bound, dialysis is unlikely to remove a significant amount of the drug from the blood.

Adverse reactions.

Studies have been conducted in 9000 patients receiving efavirenz. In a subgroup of 1008 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 common 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 efavirenz use are skin rashes and central nervous system (CNS) symptoms. CNS symptoms usually occur soon after initiation of therapy and generally resolve after the first 2–4 weeks. Serious skin-related adverse reactions such as Stevens-Johnson syndrome and erythema multiforme, as well as psychiatric adverse reactions including severe depression, suicide, psychosis, and seizures, have also been reported in patients receiving efavirenz. Administration of efavirenz with food may increase drug exposure and lead to an increased frequency of adverse reactions (see section "Special precautions").

The long-term safety of efavirenz-containing regimens was evaluated in a controlled trial 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.

Moderate or severe adverse events considered possibly related to the treatment regimen and reported in clinical trials of efavirenz at the recommended dose as part of combination therapy are listed below. Also listed in italics are adverse reactions observed under post-marketing conditions associated with antiretroviral treatment regimens containing efavirenz. The frequency of events is defined as: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000).

*,†,‡ For more detailed information, see section "Description of selected adverse reactions"

Description of selected adverse reactions

Information from post-marketing surveillance

† Adverse reactions were identified through post-marketing surveillance; however, frequency data were derived from 16 clinical trials (n = 3969).

‡ Adverse reactions were identified through post-marketing surveillance but were not observed in the 16 clinical trials. The frequency category "rare" was determined based on the defined upper limit of the 95% confidence interval at 0 cases among patients treated with efavirenz in these clinical trials (n = 3969).

Rash

In clinical trials, skin rash was observed in 26% of patients receiving 600 mg efavirenz compared to 17% of patients in control groups. Rash was considered treatment-related in 18% of patients receiving efavirenz. Severe rash 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.

Maculopapular rashes of mild to moderate severity are commonly observed, typically emerging within the first two weeks after initiating efavirenz therapy. In most patients, the rash resolves within one month while continuing efavirenz treatment. Reinitiation of efavirenz may be considered in patients who discontinued the drug due to rash. When reinitiating efavirenz, concomitant administration of appropriate antihistamines and/or corticosteroids is recommended.

Experience with efavirenz use in patients who discontinued other antiretroviral agents of the non-nucleoside reverse transcriptase inhibitor (NNRTI) class is limited.

Recurrent rash following switch from nevirapine to efavirenz has been reported in 13–18% of cases, compared to rates observed in patients receiving efavirenz in clinical trials (see section "Special warnings and precautions for use").

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 increased risk of developing these serious psychiatric adverse reactions, with the incidence of each of the above-mentioned events ranging from 0.3% for manic reactions to 2% for severe depression and suicidal ideation. There have also been post-marketing reports of fatal outcomes due to suicide, delirium, psychosis-like behavior, and catatonia.

Nervous system

In clinical controlled trials, adverse reactions frequently reported included, but were not limited to, dizziness, insomnia, somnolence, difficulty concentrating, and abnormal dreams. Neurological symptoms of moderate to severe intensity were observed in 19% of patients (severe cases 2%) compared to 9% of patients (severe cases 1%) receiving the control regimen. In clinical studies, 2% of patients receiving efavirenz discontinued therapy due to the emergence of such symptoms.

Neurological symptoms usually occur on the first or second day of therapy and resolve in most cases after the first 2–4 weeks. In studies of uninfected volunteers, typical neurological symptoms appeared on average 1 hour after dose administration 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 emerging neurological symptoms among patients receiving efavirenz was generally similar to that observed in the control group of patients.

Hepatic failure

Some post-marketing reports of hepatic failure, including in patients without prior history of liver disease or other defined risk factors, described acute onset and rapidly progressive disease, in some cases leading to the need for transplantation or resulting in death.

Immune Reconstitution Syndrome

In HIV-infected patients with severe immune deficiency, initiation of combination antiretroviral therapy (cART) may result in inflammatory reactions to asymptomatic or residual opportunistic pathogens. In HIV-infected patients with severe immune deficiency, inflammatory reactions to asymptomatic or residual opportunistic infections may occur upon initiation of combination antiretroviral therapy. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the time to onset of these conditions is variable, and such disorders may present many months after the start of treatment (see section "Special warnings and precautions for use").

Osteonecrosis

Cases of osteonecrosis have been reported in clinical studies, particularly in patients with well-known risk factors, advanced HIV disease stage, or those on long-term cART. The frequency of occurrence is unknown (see section "Special warnings and precautions for use").

Laboratory abnormalities

Liver enzymes: Elevations in AST and ALT levels greater than 5 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 a clinical study). Similar elevations occurred in patients receiving the control regimen (5% after long-term treatment). Elevations in GGT levels greater than 5 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 patients receiving the control regimen after long-term treatment). Isolated elevations in GGT in patients receiving efavirenz may indicate enzyme induction. During long-term study, 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 study, asymptomatic elevations in serum amylase concentration greater than 1.5 times ULN were observed in 10% of patients receiving efavirenz and in 6% of patients receiving the control regimen. The clinical significance of asymptomatic elevations in serum amylase is unknown.

Lipodystrophy and metabolic disturbances

During antiretroviral therapy, increases in body weight and levels of lipids and glucose in the blood may occur (see section "Special warnings and precautions for use").

Children

Adverse events in children are mostly similar to those in adults. Rash occurs more frequently in children (32% of 59 out of 182 patients treated with efavirenz) than in adults and tends to be more severe [severe rash cases observed in 6 out of 182 children (3.3%)]. Prophylactic administration of appropriate antihistamines to children prior to initiation of efavirenz therapy may be beneficial in preventing rash.

Other special populations

Liver enzymes in patients co-infected with hepatitis B or C: In a long-term study of 137 patients treated with efavirenz (mean duration of therapy 68 weeks) and 84 patients receiving the control regimen (mean duration 56 weeks), patients were seropositive at screening for hepatitis B (surface antigen positive) and/or hepatitis C (hepatitis C antibodies positive). Among co-infected patients in this study, elevations in AST levels greater than 5 times ULN occurred in 13% of patients receiving efavirenz and in 7% of patients receiving the control regimen, and elevations in ALT levels greater than 5 times ULN occurred 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 warnings and precautions for use").

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging. 30 tablets in a container; 1 container in a cardboard box.

Prescription status. Prescription only.

Manufacturer. HETERO LABS LIMITED.

Manufacturer's address and place of business.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.