Eltvir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELTVIR (ELTVIR)

Composition:

Active substances: efavirenz, lamivudine, tenofovir disoproxil fumarate;

One tablet contains 400 mg of efavirenz, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate.

Excipients: microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; hydroxypropyl cellulose; magnesium stearate; sodium lauryl sulfate; yellow iron oxide (E 172); Opadry II White 85F18422 (polyvinyl alcohol (E 1203); polyethylene glycol (E 1521); titanium dioxide (E 171); talc (E 553b)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white to almost white in color, oval-shaped, biconvex with beveled edges, marked with "Н" on one side and "Е 66" on the other.

Pharmacotherapeutic group. Antiviral agents for treatment of HIV infection, combinations.

ATC code J05AR11.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Efavirenz is a non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI). Efavirenz binds directly to reverse transcriptase and blocks RNA-dependent and RNA-independent DNA polymerase activity by inducing a conformational change that disrupts the enzyme's catalytic site. Efavirenz activity is non-competitive with either template or nucleoside triphosphates. Efavirenz does not inhibit HIV-2 reverse transcriptase or eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, and δ). Lamivudine, the negative enantiomer of 2′-deoxy-3′-thiacytidine, is a dideoxynucleoside analogue. Tenofovir disoproxil is converted in vivo to tenofovir, an analogue of nucleotide adenosine monophosphate. Lamivudine and tenofovir are phosphorylated by cellular enzymes to form lamivudine triphosphate and tenofovir diphosphate, respectively. Lamivudine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in chain termination of viral DNA. Both compounds are active against HIV-1 and HIV-2, as well as hepatitis B virus.

Antiviral activity. The antiviral activity of lamivudine against HIV-1 was evaluated using various cell lines, including monocytes and peripheral blood mononuclear cells (PBMCs), by standard susceptibility assays. EC50 values ranged from 0.003 to 15 μM against HIV-1 subtypes A–G and group O viruses. The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed using T-lymphoblastoid cell lines, primary monocytes/macrophages, and PBMCs. Tenofovir EC50 values ranged from 0.04 to 8.5 μM. Antiviral activity has been demonstrated in cell culture against HIV-1 subtypes A, B, C, D, E, F, G, and O (EC50 values ranging from 0.5 to 2.2 μM).

Resistance. A high proportion of patients experiencing virological failure on efavirenz-based regimens develop resistance to efavirenz. Primary mutations occur at K103N, G190S/A/E, and Y188L; each of these mutations alone is sufficient to confer high-level resistance. Cross-resistance between efavirenz and nevirapine or delavirdine is substantial; therefore, patients who have experienced virological failure on any of these agents are highly likely to harbor virus resistant to efavirenz, and vice versa. As the number of NNRTI-associated mutations increases, susceptibility to etravirine also decreases. Due to the long elimination half-life of efavirenz, after discontinuation of an effective antiretroviral regimen containing efavirenz, a period of functional monotherapy with efavirenz persists. This may lead to significant resistance development and reduced future efficacy of efavirenz, nevirapine, and delavirdine (see section "Special precautions").

In many cases of treatment failure with regimens containing lamivudine, the M184V mutation emerges early. The M184V mutation confers high-level resistance to lamivudine (reduced susceptibility >300-fold). Viruses with the M184V mutation replicate less efficiently than wild-type viruses. In vitro data suggest that continued antiretroviral therapy with lamivudine despite the presence of the M184V mutation may retain residual antiretroviral activity (likely due to reduced viral replicative capacity). The clinical significance of these findings is unknown.

Cross-resistance due to the M184V mutation is limited to nucleoside/nucleotide reverse transcriptase inhibitors. The M184V mutation confers complete cross-resistance to emtricitabine. Antiretroviral activity of zidovudine and stavudine against lamivudine-resistant HIV-1 is preserved. Abacavir retains antiretroviral activity against HIV-1 with only the M184V mutation. The M184V mutation causes less than a 4-fold reduction in susceptibility to didanosine; the clinical significance of this is unknown.

The K65R mutation occurs in vitro when HIV-1 is cultured in the presence of increasing concentrations of tenofovir. It may also emerge in vivo during virological failure on tenofovir-containing regimens. The K65R mutation reduces in vitro susceptibility to tenofovir by approximately two-fold and is associated with lack of response to tenofovir-containing regimens. K65R may also be selected by abacavir or didanosine and leads to reduced susceptibility to these agents as well as to lamivudine, emtricitabine, and tenofovir. Viruses with the K65R mutation retain full susceptibility to efavirenz. Additionally, under the influence of tenofovir, the K70E substitution in HIV-1 reverse transcriptase may occur, leading to a slight reduction in susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.

In HIV-infected patients harboring three or more thymidine analogue mutations (TAMs), including M41L or L210W, reduced susceptibility to tenofovir has been observed.

Clinical trial results. The efficacy of the individual components of this fixed-dose combination product has been established in several clinical trials. Efavirenz, lamivudine, and tenofovir disoproxil have been used as individual agents in various combination therapy regimens. Clinical trials of the combination of efavirenz, lamivudine, and tenofovir disoproxil have not been conducted.

When tenofovir disoproxil and lamivudine were used in combination with efavirenz in treatment-naive patients with HIV-1, the proportion of patients with HIV RNA < 50 copies/mL was 79% at week 48 and 68% at week 144.

Specific studies on the use of the combination of efavirenz, lamivudine, and tenofovir disoproxil in adolescent patients have not been conducted.

Pharmacokinetics.

The effect of food on efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets has not been evaluated.

Efavirenz. In patients infected with HIV-1, the time to reach maximum plasma concentration was approximately 3–5 hours, and steady-state plasma concentrations were achieved within 6–10 days. Efavirenz is almost completely (approximately 99.5–99.75%) bound to plasma proteins, primarily albumin. After administration of 14C-labeled efavirenz, 14–34% of the administered dose was excreted in urine (mainly as metabolites) and 16–61% in feces (mainly as unchanged drug). In vitro studies indicate that CYP3A and CYP2B6 are the main isoenzymes responsible for the metabolic transformation of efavirenz. Efavirenz has been shown to induce CYP enzyme systems, leading to autoinduction of its own metabolism. The terminal elimination half-life of efavirenz is 52–76 hours after a single dose and 40–55 hours with multiple dosing.

Lamivudine. After oral administration of lamivudine at a dose of 2 mg/kg twice daily in nine HIV-1-infected adults, the maximum serum concentration (Cmax) of lamivudine was 1.5 ± 0.5 μg/mL (mean ± SD). The area under the plasma concentration–time curve (AUC) and Cmax increased proportionally with oral dose over the range of 0.25–10 mg/kg, and absolute bioavailability was 86% ± 16% (mean ± SD) in 12 adult patients receiving 150 mg tablets, and 87% ± 13% when administered as an oral solution. Lamivudine protein binding in plasma is low (< 36%). Twelve hours after a single oral dose of lamivudine in six HIV-1-infected adults, 5.2% ± 1.4% (mean ± SD) of the administered dose was excreted in urine as trans-sulfoxide metabolites. Most lamivudine is excreted unchanged in urine via organic cation transporter proteins. The observed elimination half-life (t1/2) was 5–7 hours in most single-dose studies where serum samples were collected over 24 hours post-dose.

Tenofovir disoproxil fumarate. After a single 300 mg oral dose of tenofovir disoproxil fumarate administered to HIV-1-infected volunteers under fasting conditions, maximum serum concentration (Cmax) was reached at 1.0 ± 0.4 hours (mean ± SD), and Cmax and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•h/mL, respectively. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate under fasting conditions is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding level is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70–80% of intravenously administered tenofovir is excreted unchanged in urine. Tenofovir elimination is achieved via glomerular filtration and active tubular secretion; renal clearance in adults with normal renal function is 243 ± 33 mL/min (mean ± SD). After a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.

Special populations

Age and sex

Exposure parameters of tenofovir in adolescent patients receiving daily oral tenofovir disoproxil 245 mg were similar to those in adults receiving daily tenofovir disoproxil 245 mg.

Pharmacokinetic studies involving children and elderly individuals (aged 65 years and older) have not been conducted.

No significant or clinically important sex-related differences in the pharmacokinetics of lamivudine and tenofovir have been identified. Limited data suggest that efavirenz exposure may be higher in women; however, tolerability of efavirenz in women is not reduced.

Race

There is no evidence to suggest the need for dose adjustment of efavirenz, lamivudine, or tenofovir disoproxil fumarate due to ethnic differences affecting pharmacokinetic parameters.

Renal impairment

The pharmacokinetics of efavirenz have not been evaluated in patients with renal impairment. However, less than 1% of the administered dose of efavirenz is excreted unchanged in urine; therefore, the impact of renal impairment on efavirenz exposure is likely minimal.

Pharmacokinetic parameters were determined after single-dose administration of lamivudine 300 mg and tenofovir disoproxil 245 mg as individual formulations in non-HIV-infected patients with varying degrees of renal impairment.

Eltrivr (Efavirenz/Lamivudine/Tenofovir disoproxil fumarate) is not recommended for patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min). Dose adjustment of lamivudine and tenofovir disoproxil fumarate is required in patients with moderate to severe renal impairment, which is not feasible with the fixed-dose combination product (see sections "Dosage and administration", "Special precautions").

Hepatic impairment

Caution is advised when using Eltrivr in patients with mild hepatic impairment (see sections "Contraindications", "Special precautions").

Eltrivr should not be used in patients with severe hepatic impairment (see section "Contraindications"), and its use is not recommended in patients with moderate hepatic impairment. In a single-dose study, the elimination half-life of efavirenz doubled in the only patient with severe hepatic impairment (Child-Pugh class C), suggesting the potential for significantly greater accumulation. In a multiple-dose study, no significant effect on efavirenz pharmacokinetics was observed in patients with mild hepatic impairment (Child-Pugh class A) compared to controls. Data are insufficient to assess the impact of moderate or severe hepatic impairment (Child-Pugh class B or C) on efavirenz pharmacokinetics.

Lamivudine pharmacokinetic parameters are not altered by impaired hepatic function. The safety and efficacy of lamivudine in patients with decompensated liver disease have not been evaluated.

Tenofovir pharmacokinetic parameters were evaluated after a single 245 mg dose of tenofovir disoproxil in non-HIV-infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C). No significant differences in tenofovir pharmacokinetics were observed between patients with hepatic impairment and those without liver disease.

Clinical characteristics.

Indications.

As a complete treatment regimen for human immunodeficiency virus type 1 (HIV-1) infection in adults and children with body weight of at least 35 kg.

Contraindications.

Hypersensitivity to efavirenz, lamivudine, tenofovir disoproxil fumarate, or any excipient of the medicinal product.

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). Competition of efavirenz for cytochrome P450 (CYP) 3A4 may lead to inhibition of metabolism and potentiate the development of life-threatening adverse reactions (e.g., cardiac arrhythmias, prolonged sedative effect, or respiratory depression) (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with elbasvir/grazoprevir due to expected significant decrease in plasma concentrations of elbasvir and grazoprevir (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with voriconazole, since efavirenz significantly reduces voriconazole plasma concentrations, while voriconazole significantly increases efavirenz plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction"). Dose adjustment of efavirenz in the fixed-dose combination product is not feasible (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with dasabuvir + ombitasvir/paritaprevir/ritonavir. Concomitant use may lead to increased ALT levels, and reduced therapeutic effect of dasabuvir + ombitasvir/paritaprevir/ritonavir is expected (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with herbal products containing St. John's wort (Hypericum perforatum), due to the risk of reduced plasma concentrations and diminished clinical effect of efavirenz.

Use in patients with:

• family history of sudden fatal outcome or congenital prolongation of the QTc interval on electrocardiograms, or any other clinical condition known to prolong the QTc interval;
• history of symptomatic cardiac arrhythmias or with clinically significant bradycardia or with congestive heart failure associated with reduced left ventricular ejection fraction;
• serious disturbances of electrolyte balance, such as hypokalemia or hypomagnesemia.

Concomitant use with medicinal products known to prolong the QTc interval (antiarrhythmic agents).

These include:

• Class IA and III antiarrhythmic agents;
• neuroleptics, antidepressants;
• some antibiotics, including certain agents from the following classes: macrolides, fluoroquinolones, imidazoles, and triazole antifungals;
• some non-sedating antihistamines (terfenadine, astemizole);
• cisapride;
• flecainide;
• some antimalarial agents;
• methadone.

Interaction with other medicinal products and other forms of interaction.

Interaction studies of Eltvir with other drugs have not been conducted. Since Eltvir contains efavirenz, lamivudine, and tenofovir disoproxil fumarate, interactions observed when these drugs are used separately may occur. Interaction studies for these components were conducted in adult patients.

Since Eltvir is a fixed-dose combination product, it should not be used concomitantly with other medicinal products containing the same active substances—lamivudine or tenofovir disoproxil fumarate. Eltvir should not be used with medicinal products containing efavirenz. Due to structural similarity to lamivudine, this medicinal product should not be used concomitantly with other cytidine analogues such as emtricitabine. Also, the product should not be used concomitantly with adefovir dipivoxil or medicinal products containing tenofovir alafenamide.

Efavirenz in vivo induces CYP3A4, CYP2B6, and UGT1A1. Drugs that are substrates of these enzymes may reduce efavirenz plasma concentrations when used concomitantly. Efavirenz may be an inducer of CYP2C19 and CYP2C9; in vitro inhibition has also been observed, and the net effect of concomitant use of substrates of these enzymes is not established.

Exposure to efavirenz may be increased when used concomitantly with drugs (e.g., ritonavir) or food (e.g., grapefruit juice) that inhibit the activity of CYP3A4 or CYP2B6. Drugs that inhibit these enzymes may lead to reduced efavirenz plasma concentrations.

Herbal products (e.g., Ginkgo biloba or St. John's wort extracts) that induce these enzymes may lead to reduced plasma concentrations when used concomitantly with efavirenz. Concomitant use of St. John's wort is contraindicated. Concomitant use of Ginkgo biloba extract is not recommended.

When used concomitantly with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, and methylergonovine), competition with efavirenz for the CYP3A4 isoenzyme may lead to inhibition of metabolism and potential development of serious and/or life-threatening adverse reactions (such as cardiac arrhythmias, prolonged sedative effect, or respiratory depression).

Elbasvir/grazoprevir

Concomitant use of Eltvir with elbasvir/grazoprevir is contraindicated due to the potential for virological response failure to elbasvir/grazoprevir.

Dasabuvir + ombitasvir/paritaprevir/ritonavir

Concomitant use of Eltvir with dasabuvir + ombitasvir/paritaprevir/ritonavir is contraindicated, as it may lead to increased ALT levels, and reduced therapeutic effect of dasabuvir + ombitasvir/paritaprevir/ritonavir is expected.

Voriconazole

Concomitant use of standard-dose efavirenz and voriconazole is contraindicated. Since Eltvir is a fixed-dose combination product, the dose of efavirenz cannot be adjusted; therefore, concomitant use of voriconazole and Eltvir is not possible.

In vitro studies and clinical pharmacokinetic interaction studies indicate that the likelihood of CYP isoenzyme-mediated interactions of lamivudine and tenofovir disoproxil with other medicinal products is low.

Trimethoprim/sulfamethoxazole

Trimethoprim/sulfamethoxazole increases lamivudine plasma concentrations, but clinically significant effects are not expected; monitoring of patients with significant renal impairment or when high-dose trimethoprim/sulfamethoxazole is used (e.g., for Pneumocystis jirovecii pneumonia) is necessary to detect signs of lamivudine toxicity promptly.

Atazanavir/ritonavir

Data to support dosing recommendations for atazanavir/ritonavir in combination with the fixed-dose combination of efavirenz/lamivudine/tenofovir disoproxil fumarate are insufficient. Therefore, concomitant use of atazanavir/ritonavir and Eltvir is not recommended.

Posaconazole

Concomitant use of posaconazole and Eltvir should be avoided, as it leads to reduced posaconazole plasma concentrations.

Didanosine

Concomitant use of Eltvir and didanosine is not recommended (see section "Special precautions for use").

Cladribine

Lamivudine in vitro inhibits intracellular phosphorylation of cladribine, potentially reducing cladribine efficacy in clinical settings when used in combination. Clinical data also suggest possible interaction between lamivudine and cladribine. Therefore, concomitant use of lamivudine and cladribine is not recommended (see section "Special precautions for use").

Concomitant use of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg oral dose of lamivudine led to dose-dependent reductions in lamivudine exposure of 14%, 32%, and 36% (AUC∞) and 28%, 52%, and 55% in Cmax in adults. Prolonged concomitant use of lamivudine with medicinal products containing sorbitol or other osmotically active polyols or sugar alcohols (e.g., xylitol, mannitol, lactitol, maltitol) should be avoided if possible. More frequent monitoring of HIV-1 viral load should be considered when prolonged concomitant use cannot be avoided.

Medicinal products eliminated by kidneys

Since lamivudine and tenofovir are primarily eliminated by the kidneys, concomitant use of Eltvir with medicinal products capable of impairing renal function or competing for active tubular secretion may lead to increased serum concentrations of lamivudine, tenofovir, and/or concomitantly administered medicinal products.

Concomitant use of Eltvir with nephrotoxic medicinal products should be avoided. Examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2 (see section "Special precautions for use").

Given that tacrolimus may affect renal function, careful monitoring is recommended when used concomitantly with tenofovir.

Interaction with cannabinoid testing. Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with certain screening assays in both uninfected and HIV-infected subjects receiving efavirenz. In such cases, confirmatory testing using a more specific instrumental method is recommended.

Other interactions. Interactions between components of Eltvir and protease inhibitors, antiretroviral agents (other than protease inhibitors), and non-antiretroviral medicinal products are presented below.

ANTIMICROBIAL AGENTS

Antiretroviral agents

(In principle, this product provides a complete antiretroviral therapy regimen; however, interactions with other antiretroviral agents are described below for completeness).

Nucleoside analogues

Emtricitabine/lamivudine. Emtricitabine and Eltvir should not be used concomitantly due to similarity between emtricitabine and lamivudine and expected lack of additive effects (see section "Special precautions for use").

Didanosine (400 mg)/tenofovir. Increased AUC of didanosine by 40–60%. Risk of didanosine-related adverse effects (e.g., pancreatitis, lactic acidosis) appears increased, and CD4 cells may significantly decrease with concomitant use. Also, didanosine 250 mg used concomitantly with tenofovir in various combination antiretroviral regimens has been associated with a high rate of virological failure. Concomitant use of Eltvir and didanosine is not recommended (see section "Special precautions for use").

Non-nucleoside reverse transcriptase inhibitors

Nevirapine, etravirine. Concomitant use is not recommended due to additive toxicity and lack of benefit in terms of efficacy.

Protease inhibitors

Fosamprenavir/ritonavir (700/100 mg)/efavirenz. No clinically significant interaction at steady state with twice-daily dosing. Dose adjustment is not required.

Fosamprenavir/ritonavir (1400/200 mg)/efavirenz. 36% reduction in steady-state Cmin of amprenavir. Concomitant use of Eltvir and once-daily fosamprenavir should be avoided.

Saquinavir/ritonavir (1000/100 mg)/efavirenz. No clinically significant interaction observed. Data to support dosing recommendations for saquinavir, with or without ritonavir, in combination with Eltvir are insufficient. Concomitant use of saquinavir with or without ritonavir is not recommended.

Indinavir (800 mg)/efavirenz (200 mg). Concomitant use of unboosted indinavir is not recommended.

Indinavir/ritonavir (800/100 mg)/efavirenz. Concomitant use with boosted indinavir is recommended only if plasma indinavir concentration monitoring is possible.

Ritonavir (500 mg)/efavirenz (600 mg). Interaction studies show moderate increases in AUC of both ritonavir and efavirenz. Concomitant use with full-dose ritonavir should be avoided due to low tolerability.

Lopinavir/ritonavir. Data to support dosing recommendations for lopinavir/ritonavir in combination with Eltvir are insufficient. Concomitant use is not recommended.

Atazanavir (400 mg). Concomitant use of Eltvir and unboosted atazanavir is not recommended.

Atazanavir/ritonavir (300/100 mg). Concomitant use with tenofovir leads to increased tenofovir exposure. Higher tenofovir concentrations may lead to adverse reactions, including renal impairment. Concomitant use with efavirenz is not recommended. Concomitant use of atazanavir/ritonavir and Eltvir is not recommended.

Tipranavir/ritonavir. No adequate data on interaction of tipranavir at the approved dosing regimen with efavirenz. Use of Eltvir in combination with tipranavir/ritonavir should be avoided.

Darunavir/ritonavir (300/100 mg). Interaction with efavirenz and tenofovir: Eltvir in combination with darunavir/ritonavir 800/100 mg once daily may lead to suboptimal Cmin levels of darunavir. If Eltvir is used in combination with darunavir/ritonavir, the darunavir/ritonavir combination should be administered at 600/100 mg twice daily. Darunavir/ritonavir should be used with caution in combination with Eltvir (see ritonavir below). Monitoring of renal function may be necessary, especially in patients with underlying systemic disease or kidney disease, and in patients receiving nephrotoxic drugs.

CCR5 antagonists

Maraviroc. Efavirenz and tenofovir concentrations were not determined; no effect is expected. Refer to the maraviroc product information.

Integrase strand transfer inhibitor

Raltegravir (400 mg). Eltvir and raltegravir can be used concomitantly without dose adjustment.

HEPATITIS B VIRUS AGENTS

Adefovir dipivoxil. Eltvir should not be used concomitantly with adefovir dipivoxil due to expected lack of additive effect (see section "Special precautions for use").

Entecavir. Clinically significant pharmacokinetic interactions with Eltvir are not expected.

HEPATITIS C VIRUS AGENTS

Boceprevir (800 mg). Boceprevir plasma concentrations decrease when used concomitantly with efavirenz. The clinical significance of the observed reduction in boceprevir minimum concentration has not been directly evaluated.

Telaprevir. If Eltvir and telaprevir are used concomitantly, the telaprevir dose should be 1,125 mg every 8 hours.

Simeprevir (150 mg). When used concomitantly with efavirenz, simeprevir plasma concentrations are significantly reduced due to CYP3A induction by efavirenz, potentially leading to loss of simeprevir therapeutic effect. Concomitant use of simeprevir and Eltvir is not recommended.

Elbasvir/grazoprevir (50/200 mg). Concomitant use of Eltvir with elbasvir/grazoprevir is contraindicated, as it may lead to loss of virological response to elbasvir/grazoprevir. This loss is due to significant reduction in elbasvir/grazoprevir plasma concentrations caused by CYP3A4 or P-gp induction. For additional information, refer to the elbasvir/grazoprevir product information.

Daclatasvir (60 mg). The daclatasvir dose should be increased to 90 mg once daily when used concomitantly with Eltvir.

Dasabuvir + ombitasvir/paritaprevir/ritonavir. A regimen combining efavirenz (enzyme inducer) and dasabuvir + paritaprevir/ritonavir leads to increased ALT levels, likely due to efavirenz induction. Concomitant use of dasabuvir + ombitasvir/paritaprevir/ritonavir with Eltvir is contraindicated.

Sofosbuvir. No clinically significant pharmacokinetic interaction between sofosbuvir and efavirenz or tenofovir. Eltvir and sofosbuvir can be used concomitantly without dose adjustment.

Sofosbuvir/velpatasvir. Concomitant use of sofosbuvir/velpatasvir and efavirenz leads to approximately 50% reduction in systemic exposure to velpatasvir. Concomitant use with regimens containing efavirenz is not recommended (see section "Special precautions for use").

Sofosbuvir/velpatasvir/voxilaprevir. Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and efavirenz is not recommended, as loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir is possible.

Ledipasvir/sofosbuvir. Dose adjustment is not required. Increased tenofovir exposure may enhance adverse reactions associated with tenofovir disoproxil, including renal impairment. Careful monitoring of renal function is required (see section "Special precautions for use").

ANTIMYCOTIC AND ANTIBIOTIC AGENTS

Clarithromycin (500 mg). Clinical significance of changes in clarithromycin exposure, if any, is unknown. Skin rashes were frequent when used concomitantly in healthy volunteers. Consider replacing clarithromycin with azithromycin if possible.

Azithromycin (600 mg). No clinically significant pharmacokinetic interactions. Dose adjustment of either drug is not required.

Rifampicin (600 mg). Insufficient data to support dosing recommendations for rifampicin in combination with Eltvir tablets; therefore, concomitant use is not recommended.

Rifabutin (300 mg). Rifabutin dose should be increased by 50% when used concomitantly with Eltvir.

ANTIFUNGAL AGENTS

Fluconazole (200 mg). No clinically significant interaction. Dose adjustment of either drug is not required.

Itraconazole (200 mg). Reduced itraconazole concentrations occur with efavirenz. Consider using an alternative antifungal agent.

Posaconazole (400 mg). Significant reduction in AUC and Cmax occurs with efavirenz (400 mg once daily). Concomitant use of posaconazole and Eltvir should be avoided.

Voriconazole (200 mg). Concomitant use of standard doses of efavirenz and voriconazole is contraindicated. Since Eltvir is a fixed-dose combination product, the efavirenz dose cannot be adjusted; therefore, concomitant use of Eltvir and voriconazole is not possible.

ANTIMALARIAL AGENTS

Chloroquine, mefloquine, proguanil, sulfadoxine, pyrimethamine. No official interaction studies. Drug interaction and safety with efavirenz have not been systematically evaluated. Clinically significant interaction with efavirenz is unlikely on theoretical grounds.

Amodiaquine/artesunate. An interaction study (efavirenz at steady state) was discontinued after the first two participants developed asymptomatic but significant increases in liver enzymes after a three-day course of amodiaquine. Potential for increased hepatotoxicity. Concomitant use of amodiaquine and Eltvir should be avoided.

Quinine. No official interaction studies. Quinine metabolism involves CYP3A isoenzyme. Reduced quinine exposure and diminished antimalarial effect are possible with concomitant use of efavirenz. An alternative agent to quinine should be considered for patients receiving Eltvir, if possible.

Lumefantrine/halofantrine. No official interaction studies. Metabolism of these agents involves CYP3A isoenzyme; therefore, reduced exposure is possible with concomitant use of efavirenz. Reduced antimalarial efficacy is possible with concomitant use of Eltvir. Caution is required.

Artemether/lumefantrine. Reduced antimalarial efficacy is possible with concomitant use of Eltvir. Caution is required.

Artemisinin and its derivatives. No official interaction studies. Metabolism of artemisinin and its derivatives involves CYP3A isoenzyme; therefore, reduced exposure is possible with concomitant use of efavirenz. Empirical data are lacking; clinical consequences are unknown.

Atovaquone and proguanil hydrochloride. Concomitant use of atovaquone/proguanil with Eltvir should be avoided if possible.

ANTICONVULSANTS

Carbamazepine. Reduced carbamazepine concentrations (CYP3A4 induction) and reduced efavirenz concentrations (CYP3A4 and CYP2B6 induction) occur with interaction. Concomitant use with Eltvir should be avoided if plasma monitoring of carbamazepine and efavirenz is not possible.

Phenytoin, phenobarbital, and other anticonvulsants that are substrates of CYP450 isoenzymes. Interaction studies not conducted. Reduced or increased concentrations of phenytoin, phenobarbital, and other anticonvulsants that are CYP isoenzyme substrates are possible with efavirenz. Concomitant use should be avoided if plasma monitoring of anticonvulsants and efavirenz is not possible.

Valproic acid. No clinically significant effect on efavirenz pharmacokinetics. Limited data indicate no clinically significant effect on valproic acid pharmacokinetics. Eltvir and valproic acid can be used concomitantly without dose adjustment. Patients should be monitored for seizure control.

Vigabatrin, gabapentin. Interactions not studied. Clinically significant interactions are not expected, as vigabatrin and gabapentin are excreted unchanged in urine, making competition with efavirenz for the same metabolic enzymes and elimination pathways unlikely. Eltvir and vigabatrin can be used concomitantly without dose adjustment.

ANTICOAGULANTS

Warfarin, acenocoumarol. Interactions not studied. Plasma concentrations and effects of warfarin or acenocoumarol may be increased or decreased by efavirenz. Dose adjustment of warfarin or acenocoumarol may be required with concomitant use of Eltvir.

ANTIDEPRESSANTS

Selective serotonin reuptake inhibitors (SSRIs)

Sertraline. Sertraline dose should be increased based on clinical response when used concomitantly with Eltvir.

Paroxetine. Eltvir and paroxetine can be used concomitantly without dose adjustment.

Fluoxetine. Interaction studies not conducted. Since fluoxetine's metabolic profile is similar to paroxetine (significant inhibition of CYP2D6 isoenzyme), absence of interaction with fluoxetine can be expected. Eltvir and fluoxetine can be used without dose adjustment.

Noradrenaline and dopamine reuptake inhibitors

Bupropion. Bupropion dose should be increased based on clinical response, but the maximum recommended bupropion dose should not be exceeded. No efavirenz dose adjustment is required.

CARDIOVASCULAR AGENTS

Calcium channel blockers

Diltiazem. Increased efavirenz pharmacokinetic parameters are not considered clinically significant. Diltiazem dose should be adjusted based on clinical response when used concomitantly with Eltvir (see diltiazem product information).

Verapamil, felodipine, nifedipine, nicardipine. Interaction studies not conducted. Reduced exposure to calcium channel blockers that are CYP3A4 substrates is possible with efavirenz. Clinical effect should be monitored, and calcium channel blocker dose increased if necessary.

AGENTS LOWERING LIPID LEVELS

HMG-CoA reductase inhibitors

Atorvastatin. Regular cholesterol monitoring is required; atorvastatin dose should be increased if efficacy is insufficient.

Pravastatin. Regular cholesterol monitoring is required; pravastatin dose should be increased if efficacy is insufficient.

Simvastatin. Regular cholesterol monitoring is required; simvastatin dose should be increased if efficacy is insufficient.

Rosuvastatin. Interaction studies not conducted. Rosuvastatin is primarily excreted unchanged in feces; therefore, metabolic interaction with efavirenz is not expected. Eltvir can be used concomitantly with rosuvastatin without dose adjustment.

HORMONAL CONTRACEPTIVES

Ethinylestradiol + norgestimate/efavirenz. No change in ethinylestradiol exposure. Levonorgestrel: AUC ↓ 83%, Cmax ↓ 80%, Cmin ↓ 86% (inhibition of metabolic conversion). Norelgestromin: AUC ↓ 64%, Cmax ↓ 46%, Cmin ↓ 82%. Efavirenz: no clinically significant interaction. In addition to hormonal contraceptives, a reliable barrier method of contraception should be used.

Depot medroxyprogesterone acetate (DMPA). Pharmacokinetic characteristics and efficacy of DMPA were not altered with concomitant use of efavirenz. Since available information is very limited, a reliable barrier method of contraception should be used in addition to hormonal contraceptives.

Levonorgestrel (implant). In a randomized parallel-group study, HIV-infected women with LNG implant receiving EFV as part of ART had 57% lower LNG levels at 48 weeks. Additionally, contraceptive failure was observed in 15% (3/20) of patients in this group. In addition to hormonal contraceptives, a reliable barrier method of contraception should be used.

Etonogestrel (implant). Interaction studies not conducted. Reduced etonogestrel exposure due to CYP3A isoenzyme inhibition by efavirenz is expected. Post-marketing reports include isolated cases of contraceptive failure with etonogestrel in patients receiving efavirenz. In addition to hormonal contraceptives, a reliable barrier method of contraception should be used.

IMMUNOSUPPRESSANTS

Immunosuppressants metabolized by CYP3A4 (e.g., cyclosporine, tacrolimus, sirolimus). Interactions with efavirenz not studied. Reduced exposure to immunosuppressants (CYP3A) is expected. Immunosuppressants are not expected to affect efavirenz exposure. Dose adjustment of immunosuppressants may be necessary. Careful monitoring of immunosuppressant concentrations is recommended for at least two weeks (until steady state is reached) after initiation or discontinuation of Eltvir therapy.

OPIOIDS

Methadone. Concomitant use of methadone with Eltvir should be avoided due to risk of QTc interval prolongation. In a study of HIV-infected injecting drug users, concomitant use of efavirenz and methadone led to reduced methadone plasma levels and opioid withdrawal symptoms. Methadone dose was increased by an average of 22% to alleviate withdrawal symptoms. Monitoring for withdrawal symptoms is required; methadone dose should be increased if necessary.

Buprenorphine. No clinically significant pharmacokinetic interaction with efavirenz. Although buprenorphine exposure decreases, withdrawal symptoms were not observed. Dose adjustment of buprenorphine may not be necessary with concomitant use of Eltvir.

Studies conducted with other drugs. No clinically significant interactions were observed when efavirenz was used with azithromycin, cetirizine, fosamprenavir/ritonavir, lorazepam, zidovudine, antacids containing magnesium/aluminum hydroxide, famotidine, or fluconazole. Potential interaction of efavirenz with other azole antifungals (e.g., ketoconazole) has not been studied.

Clinically significant pharmacokinetic interactions were absent when lamivudine was used concomitantly with stavudine, zidovudine, or famciclovir.

Clinically significant pharmacokinetic interactions were absent when tenofovir disoproxil was used concomitantly with emtricitabine or ribavirin.

Special precautions for use.

General information

Testing for hepatitis B virus (HBV) antibodies should be offered to all patients prior to initiating therapy with lamivudine and tenofovir disoproxil (see below "Patients co-infected with HIV and hepatitis B (HBV) or hepatitis C (HCV)").

Concomitant use with other medicinal products.

Since Eltvir is a fixed-dose combination product, it should not be administered concurrently with other medicinal products containing the same active substances – efavirenz, lamivudine or tenofovir disoproxil fumarate.

Due to similarity to lamivudine, Eltvir should not be used concomitantly with medicinal products containing other cytidine analogues such as emtricitabine. Eltvir should not be used concomitantly with medicinal products containing adefovir dipivoxil or tenofovir alafenamide.

Concomitant use of Eltvir and didanosine is not recommended, as exposure to didanosine is significantly increased when co-administered with tenofovir (see section "Interaction with other medicinal products and other types of interactions"). There have been reports of rare cases of pancreatitis and lactic acidosis, sometimes fatal.

There are no data on the safety and efficacy of concomitant use of efavirenz, lamivudine and tenofovir disoproxil in combination with other antiretroviral agents.

Combination of lamivudine with cladribine is not recommended (see section "Interaction with other medicinal products and other types of interactions").

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

Concomitant use with amodiaquine is not recommended, as exposure to amodiaquine is significantly increased when co-administered with efavirenz. Cases of hepatotoxicity have been observed (see section "Interaction with other medicinal products and other types of interactions").

Concomitant use with bedaquiline is not recommended, as plasma concentrations of bedaquiline are significantly reduced due to induction of CYP3A isoenzymes by efavirenz, potentially resulting in loss of bedaquiline's therapeutic effect (see section "Interaction with other medicinal products and other types of interactions").

The safety and efficacy of Eltvir in the treatment of HIV/tuberculosis co-infected patients receiving rifampicin have not been evaluated. Data to support recommendations for dosing of rifampicin in combination with Eltvir are insufficient. Therefore, concomitant use of rifampicin and Eltvir is not recommended.

Antiviral agents against HCV

Concomitant use with simeprevir is not recommended, as plasma concentrations of simeprevir are significantly reduced due to induction of CYP3A isoenzymes by efavirenz, potentially resulting in loss of simeprevir's therapeutic effect (see section "Interaction with other medicinal products and other types of interactions").

Concomitant use with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended, as plasma concentrations of velpatasvir are significantly reduced due to induction of CYP3A isoenzymes by efavirenz, potentially resulting in loss of velpatasvir's therapeutic effect. When tenofovir disoproxil is co-administered with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir, increased plasma concentrations of tenofovir have been demonstrated. Monitoring of patients for tenofovir-related adverse reactions is required in patients receiving ledipasvir/sofosbuvir and Eltvir.

Concomitant use of glecaprevir/pibrentasvir and efavirenz may result in a significant reduction in plasma concentrations of glecaprevir/pibrentasvir, leading to reduced therapeutic effect. Concomitant use of glecaprevir/pibrentasvir and efavirenz is not recommended.

Switching from an antiretroviral regimen containing a protease inhibitor.

Available data suggest that patients switching from an antiretroviral regimen containing a protease inhibitor to Eltvir may experience reduced response to therapy. These patients should be closely monitored for increases in viral load and (since the safety profiles of efavirenz and protease inhibitors differ) for adverse reactions.

Liver disease.

The pharmacokinetics, safety and efficacy of Eltvir in patients with severe concomitant liver disease have not been established. Eltvir is contraindicated in patients with severe hepatic impairment and not recommended in patients with moderate hepatic impairment. Since efavirenz is primarily metabolized by the cytochrome P450 (CYP450) system, Eltvir should be used with caution in patients with mild hepatic impairment. Such patients should be closely monitored for adverse effects of efavirenz, particularly neurological symptoms. Periodic laboratory tests should be performed to assess the course of liver disease.

In patients with pre-existing liver function abnormalities, including chronic active hepatitis, the frequency of pathological changes in liver function is increased during combination antiretroviral therapy; these patients should be monitored according to standard practice. If signs of liver disease exacerbation are detected in such patients, consideration should be given to interrupting or discontinuing further therapy.

Hepatic reactions.

There have been reports of liver failure in patients without a history of liver disease or other known risk factors receiving efavirenz (see section "Adverse reactions"). Monitoring of liver enzyme levels should be considered in patients without pre-existing liver dysfunction and other risk factors.

Patients with HIV and concomitant hepatitis B (HBV) or C (HCV) infection

Patients with chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse reactions.

The physician should follow current HIV treatment guidelines for optimal management of HIV-infected patients with HBV co-infection.

In case of concomitant antiviral therapy for hepatitis B or C, the respective product information for the drugs used should be consulted.

Elevations in transaminase levels may occur months after initiation of therapy with efavirenz; such cases are more frequent in patients with concomitant HBV and/or HCV infection.

Lamivudine and tenofovir disoproxil are also active against HBV. Therefore, discontinuation of therapy with Eltvir in patients co-infected with HIV and HBV may be associated with severe acute exacerbation of hepatitis. Patients co-infected with HIV and HBV require careful monitoring, including clinical and laboratory assessments, for at least four months after discontinuation of therapy. Resumption of specific anti-hepatitis B therapy may be indicated if necessary. Specific anti-hepatitis B therapy should be continued without interruption in patients with liver disease or advanced cirrhosis.

Exacerbation of hepatitis

Exacerbation during therapy. Spontaneous exacerbations of chronic hepatitis B are relatively common and are characterized by transient increases in serum ALT levels. After initiation of antiviral therapy, serum ALT levels may increase in some patients (see section "Adverse reactions"). In patients with compensated liver disease, such ALT elevations are usually not associated with increases in serum bilirubin or hepatic decompensation. For patients with cirrhosis, the risk of hepatic decompensation following hepatitis exacerbation is higher; therefore, careful monitoring of these patients during therapy is required.

Exacerbation after therapy discontinuation. There have also been reports of sudden hepatitis exacerbations in patients after discontinuation of therapy for hepatitis B. Exacerbations after therapy discontinuation are usually associated with increased HBV DNA levels; intervention is usually not required. However, there have been reports of severe exacerbations, including fatal outcomes. Regular monitoring of liver function, including clinical and laboratory assessments, is required for at least six months after discontinuation of therapy for hepatitis B. Resumption of specific anti-hepatitis B therapy may be indicated if necessary. Therapy interruption is not recommended in patients with liver disease or advanced cirrhosis, as hepatitis exacerbation after therapy discontinuation may lead to hepatic decompensation. Hepatitis exacerbation is a serious condition and may be fatal in patients with decompensated liver disease.

QTc interval prolongation

Prolongation of the QTc interval has been observed with efavirenz. Patients at increased risk of Torsade de Pointes or those receiving drugs with a known risk of Torsade de Pointes should consider alternative therapies to Eltvir.

Psychiatric symptoms.

Adverse psychiatric reactions have been reported in patients receiving efavirenz. Patients with a history of psychiatric disorders have a higher risk of developing serious psychiatric adverse reactions. In particular, severe depression occurred more frequently in patients with a history of depression. In the post-marketing period, severe depression, fatal suicide, delirium, and psychosis-like behavior have been reported. Patients should be informed that if symptoms of severe depression, psychosis, or suicidal thoughts occur, they should seek immediate medical attention to determine whether these symptoms are related to efavirenz use, and if so, whether the benefits of continuing therapy outweigh the risks.

Neurological symptoms.

Symptoms including (but not limited to) dizziness, insomnia, somnolence, difficulty concentrating, and abnormal dreams have frequently been reported in patients receiving efavirenz 600 mg in clinical trials. Dizziness was frequently reported in clinical trials of lamivudine and tenofovir disoproxil fumarate. Headache has been reported in lamivudine trials. Neurological symptoms associated with efavirenz usually occur within the first 1–2 days and typically resolve within 2–4 weeks of treatment. Patients should be informed that these common symptoms are likely to resolve with continued treatment and do not predict the development of less frequent psychiatric symptoms.

Seizures.

Seizures have been observed with efavirenz in patients with a history of seizures. Patients receiving concomitant anticonvulsants that are primarily metabolized in the liver (such as phenytoin, carbamazepine, and phenobarbital) may require periodic monitoring of plasma levels. In a drug interaction study, plasma concentrations of carbamazepine were reduced when co-administered with efavirenz. Precautions should be taken for all patients with a history of seizures.

Renal function.

Lamivudine and tenofovir disoproxil are primarily eliminated by the kidneys via glomerular filtration and active tubular secretion. Eltvir is not recommended for patients with moderate to severe renal impairment (creatinine clearance <50 ml/min). In patients with such conditions, the dose of lamivudine and tenofovir disoproxil fumarate cannot be adjusted when using fixed-dose combination tablets.

Cases of renal failure, renal dysfunction, elevated creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir disoproxil in clinical practice (see section "Adverse reactions").

Creatinine clearance/estimated glomerular filtration rate should be assessed in all patients prior to initiating therapy and as clinically indicated during Eltvir therapy. If regular creatinine monitoring is feasible, estimated glomerular filtration rate should be determined prior to initiating tenofovir disoproxil fumarate therapy. If regular creatinine monitoring is not feasible, a urine dipstick test may be useful to detect glucosuria or severe nephrotoxic effects of tenofovir disoproxil fumarate in patients without risk factors. Regular creatinine monitoring is strongly recommended for patients at high risk (elderly patients, those with concomitant kidney disease, advanced diabetes, uncontrolled hypertension, or concomitant use of protease inhibitors or other nephrotoxic drugs) to detect and prevent further progression of renal impairment. Careful benefit-risk assessment is required. In such patients, serum phosphorus levels should also be monitored if possible. If serum phosphorus levels fall below 1.5 mg/dl (0.48 mmol/l) or creatinine clearance decreases to <50 ml/min in any patient receiving the drug, renal function should be re-evaluated within one week, including assessment of blood glucose, blood potassium, and urine glucose (see section "Adverse reactions", proximal tubulopathy). Since Eltvir is a fixed-dose combination product and the dosing intervals of individual components cannot be modified, further use of this product should be discontinued in patients with confirmed creatinine clearance <50 ml/min or serum phosphorus levels below 1.0 mg/dl (0.32 mmol/l).

Therapy interruption should also be considered in cases of progressive worsening of renal function if no other causes are identified. If discontinuation of one of the components or dose modification is required, efavirenz, lamivudine, and tenofovir disoproxil may be used as separate agents.

Use of this medicinal product should be avoided in patients who are concomitantly receiving or have recently received nephrotoxic agents (e.g., high-dose or multiple-dose non-steroidal anti-inflammatory drugs, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2). If concomitant use of Eltvir and nephrotoxic agents cannot be avoided, renal function should be monitored weekly (see section "Interaction with other medicinal products and other types of interactions").

There is no clinical evaluation of outcomes with tenofovir disoproxil in patients receiving medicinal products eliminated via the same renal pathways, including human organic anion transporters (hOAT) 1 and 3 or multidrug resistance-associated proteins (MRP4) (e.g., cidofovir, a known nephrotoxic medicinal product). These renal transport proteins may be responsible for tubular secretion and partially for renal elimination of tenofovir and cidofovir. Therefore, pharmacokinetic characteristics of these medicinal products eliminated via the same renal pathways, including hOAT 1 and 3 or MRP4 transporters, may be altered when used concomitantly. Concomitant use of medicinal products eliminated via the same renal pathways is not recommended unless absolutely necessary; if concomitant use cannot be avoided, renal function should be monitored weekly (see section "Interaction with other medicinal products and other types of interactions").

Elderly patients

Reduced renal function is more likely in elderly patients; therefore, caution is required when using tenofovir disoproxil in elderly patients.

Skin reactions.

Mild to moderate skin rash has been reported with individual components of Eltvir. Rash associated with efavirenz usually resolves with continued treatment. Appropriate antihistamines and/or corticosteroids may improve tolerability and hasten resolution of rash. Severe rash, associated with blistering, moist desquamation, or ulceration, has been observed in over 1% of patients treated with efavirenz. Multiform erythema or Stevens-Johnson syndrome occurred at a frequency of 0.1%. Eltvir should be discontinued in patients with severe rash characterized by blisters, desquamation, mucosal involvement, or fever. Experience with efavirenz in patients who discontinued another NNRTI due to adverse reactions is limited. Eltvir is not recommended for patients with life-threatening skin reactions (such as Stevens-Johnson syndrome) that occurred during NNRTI therapy.

Effects on bone.

In a controlled clinical trial, decreased bone mineral density in the spine and changes in bone biomarkers compared to baseline were observed in adult patients in both groups, but such changes were significantly greater in the tenofovir disoproxil group than in the comparator group (stavudine, both in combination with lamivudine and efavirenz) at 144 weeks. Decreased bone mineral density in the femur of patients in this group was significantly greater over 96 weeks. However, over

144 weeks, there was no increase in fracture risk or evidence of clinically significant bone abnormalities.

In HIV-infected adolescents aged 12 years and older, the average rate of bone mass gain in the tenofovir disoproxil group was lower than in the placebo group. The effect on skeletal growth (height) appears to be absent. Bone turnover markers in the tenofovir disoproxil group indicate increased bone turnover, consistent with effects observed in adults. Given the potential impact of tenofovir disoproxil on bone metabolism, Eltvir should be used in patients under 18 years of age only when benefits outweigh risks (see section "Adverse reactions").

Bone abnormalities (which may often lead to fractures) may be associated with proximal tubulopathy (see section "Adverse reactions"). In case of suspected bone abnormalities, consultation with a specialist is recommended.

Osteonecrosis.

Although etiology is considered multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, high body mass index), cases of osteonecrosis have been observed predominantly in patients with advanced HIV infection and/or long-term cART. Patients should be informed to seek medical attention if they experience joint pain, stiffness, or difficulty moving joints.

Body weight and metabolic parameters

Weight gain and increased blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partially related to disease control and lifestyle. Regarding lipids, there is some evidence of a treatment effect, whereas for weight gain, there is no strong evidence linking it to any specific treatment. Monitoring of blood lipids and glucose should follow established HIV treatment guidelines. Lipid disorders should be managed according to clinical circumstances.

Mitochondrial dysfunction.

Nucleoside and nucleotide analogues have been shown in vitro and in vivo to cause mitochondrial dysfunction of varying severity. There have been reports of mitochondrial dysfunction in HIV-negative children exposed to nucleoside analogues during intrauterine development and/or after birth. According to reports, the main adverse events include hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transient. There have also been reports of delayed neurological disorders (hypertonia, seizures, behavioral abnormalities). Whether neurological disorders are transient or permanent is currently unknown. Any child exposed to nucleosides and nucleotide analogues in utero, even if HIV-negative, should be followed up with clinical and laboratory assessments and comprehensive evaluation for possible mitochondrial dysfunction if signs or symptoms are present. These data do not alter current national recommendations for prescribing antiretroviral therapy to pregnant women to prevent vertical HIV transmission.

Immune reconstitution syndrome.

In HIV-infected patients with severe immunodeficiency at the time of initiation of combination antiretroviral therapy (cART), inflammatory reactions to asymptomatic or residual opportunistic pathogens may occur more frequently and may lead to serious clinical conditions or exacerbation of symptoms. These reactions are mainly observed during the first weeks or months of cART. Important examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis pneumonia. Any inflammatory symptoms should be evaluated as necessary and appropriate treatment initiated.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution; however, the time to onset of the disorder varied, and such reactions may occur many months after initiation of treatment.

Pancreatitis

Continued use of Eltvir should be discontinued immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis develop (see section "Adverse reactions").

Effect of food intake.

Administration of Eltvir with food may increase exposure to efavirenz and lead to increased frequency of adverse reactions. The product is recommended to be taken on an empty stomach, preferably at bedtime.

Transmission of HIV.

Patients should be informed that antiretroviral agents, including Eltvir, do not protect against the risk of HIV transmission to others through sexual contact or blood. Appropriate safety measures should continue to be observed.

Opportunistic infections.

Opportunistic infections or other complications of HIV infection may develop in patients receiving antiretroviral therapy. Therefore, the physician should conduct careful clinical monitoring of patients with HIV-associated diseases.

Excipients.

This medicinal product contains lactose monohydrate. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This product contains 1 mmol (23.6 mg) of sodium per dose, which should be considered by patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy

Efavirenz

There have been reports of neural tube defects in infants born to women who received the drug during the first trimester of pregnancy. Systematic review and meta-analysis of data from cohort observational studies indicate no increased overall risk of congenital malformations; this conclusion is based on results from over 2000 cases of efavirenz use during pregnancy compared to other antiretroviral agents. However, risks to the fetus cannot be excluded. Animal studies with efavirenz indicate reproductive toxicity, including marked teratogenic effects.

Tenofovir disoproxil and lamivudine

Animal studies do not indicate direct or indirect harmful effects of tenofovir disoproxil and lamivudine on reproductive toxicity parameters. The safety of tenofovir disoproxil for women during pregnancy has not been fully established. However, a sufficient number of first-trimester exposures have been monitored to detect at least a twofold increase in overall risk of congenital malformations. No increase in congenital malformations has been observed in women receiving tenofovir disoproxil and lamivudine (www.apregistry.com).

Eltvir should not be used during pregnancy except in cases where the woman's clinical condition requires treatment with efavirenz/lamivudine/tenofovir disoproxil fumarate.

Breastfeeding.

It has been demonstrated that efavirenz, lamivudine, and tenofovir pass into breast milk. Information on the effects of efavirenz, lamivudine, and tenofovir on newborns/infants is insufficient. Risk to the newborn cannot be excluded; therefore, Eltvir should not be used during breastfeeding.

According to general guidelines, HIV-infected women should not breastfeed to prevent transmission of HIV to the child.

Fertility.

There are no data on the effect of Eltvir in humans. Animal studies did not show harmful effects of efavirenz, lamivudine, or tenofovir disoproxil fumarate on fertility.

Ability to drive and use machines.

Studies on the effect of the medicinal product on the ability to drive and use machines have not been conducted. However, cases of dizziness have been reported during treatment with efavirenz and tenofovir disoproxil fumarate. Efavirenz may also cause impaired concentration and/or somnolence. Patients should be aware that if these symptoms occur, they should avoid potentially hazardous activities such as driving or operating machinery.

Method of Administration and Dosage

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

Method of Administration

Elvir should be taken once daily.

The tablets should be swallowed whole with water. The tablets should be taken on an empty stomach.

Elvir is preferably taken at bedtime to improve efavirenz tolerability, considering the nervous system-related adverse reactions (see section "Adverse Reactions").

Dosage

Adults and Adolescents

The recommended dose of Elvir is 1 tablet (orally) once daily.

Special Patient Groups

Elderly Patients
Elvir should be used with caution in elderly patients.

Dose Adjustment
In cases where discontinuation of further therapy with one of the components contained in Elvir or dose modification is indicated, separate formulations containing efavirenz, lamivudine, or tenofovir disoproxil fumarate are available. (See Brief Characteristics of these medicinal products.)

Renal Impairment

Elvir is not recommended for patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min). Dose adjustment of lamivudine and tenofovir disoproxil fumarate is required in patients with moderate to severe renal impairment, which cannot be achieved when using a fixed-dose combination product (see section "Special Precautions").

Hepatic Impairment

Elvir is not recommended for patients with moderate to severe hepatic impairment due to insufficient data regarding the need for dose adjustment. Patients with mild hepatic impairment (Child-Pugh Class A) may be prescribed the standard recommended dose (see sections "Contraindications", "Special Precautions"). Close monitoring of these patients is required to detect adverse reactions promptly, particularly nervous system symptoms associated with efavirenz.

When discontinuing further treatment with Elvir in patients co-infected with HIV and HBV, careful monitoring of such patients is necessary to detect timely hepatitis exacerbation (see section "Special Precautions").

When discontinuing further use of Elvir, the long elimination half-life of efavirenz, as well as the prolonged intracellular half-life of tenofovir and lamivudine, should be taken into account. Considering the variability of these parameters among different patients and concerns about resistance development, guidance from HIV treatment protocols should be consulted, and the reasons for discontinuation of therapy should also be considered.

Missed Dose and Vomiting after Administration

It is very important that the patient takes the medication regularly as prescribed. Missed doses increase the risk of developing resistance to Elvir and reduce its effectiveness.

If the patient misses a dose and less than 12 hours have passed since the scheduled time of administration, the patient should take the missed dose as soon as possible. If more than 12 hours have passed since the scheduled time, the patient should not take the missed dose and should take the next dose at the usual time. The patient should not take a double dose.

If vomiting occurs within 1 hour after taking Elvir, the patient should take another tablet. If vomiting occurs more than 1 hour after administration, an additional tablet should not be taken; the next dose should be taken at the usual time.

Children

Elvir is not recommended for patients weighing less than 35 kg due to insufficient data on dose adjustment when using the fixed-dose combination product.

Overdose

Symptoms

Some patients who mistakenly took efavirenz 600 mg twice daily reported increased nervous system-related symptoms. One patient experienced uncontrolled muscle contractions.

No specific symptoms or signs after acute lamivudine overdose, other than those listed in the adverse reactions section, have been identified.

Treatment

In case of overdose, the patient should be monitored for signs of toxicity (see section "Adverse Reactions"), and appropriate standard supportive treatment should be administered. Administration of activated charcoal may be beneficial for elimination of unabsorbed efavirenz. There is no specific antidote for efavirenz overdose. Because efavirenz is highly protein-bound, significant elimination from blood via dialysis is unlikely.

Since the amount of lamivudine removed by (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis is very low, it is unknown whether sustained hemodialysis provides clinical benefit in lamivudine overdose.

Approximately 10% of a tenofovir dose is removed by hemodialysis; the median clearance of tenofovir disoproxil during hemodialysis is 134 mL/min. It is unknown whether tenofovir is removed by peritoneal dialysis.

Adverse reactions

In controlled clinical trials evaluating the use of efavirenz, lamivudine, and tenofovir disoproxil in the treatment of HIV-infected patients, the following adverse reactions were observed.

Serious skin reactions have been reported, including Stevens-Johnson syndrome and erythema multiforme, as well as neurological and psychiatric events (including severe depression, completed suicide, psychosis-like behavior, and seizures); severe hepatic events; pancreatitis; and lactic acidosis (sometimes fatal).

There have also been reports of rare cases of renal impairment, renal failure, and proximal renal tubulopathy (including Fanconi syndrome), which occasionally led to bone abnormalities (sometimes contributing to fractures). Monitoring of renal function is recommended in patients receiving Eltvir (see section "Special precautions for use").

Administration of Eltvir with food may increase exposure to efavirenz, which could result in an increased frequency of adverse reactions.

Below is a list of adverse reactions classified as having at least a possible causal relationship to therapy, organized by system organ class and frequency. The frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000).

In addition, information on adverse reactions identified during the post-marketing period is provided (frequency category: "frequency not known"). Since these reactions are reported voluntarily and the population size is unknown, it is not possible to reliably estimate their frequency. These events are included based on their potential association with the active components of Eltvir, as well as their severity and number of reported cases.

The following adverse reactions have been identified during post-marketing experience for each of the individual components of the fixed-dose combination (efavirenz, lamivudine, and tenofovir disoproxil fumarate). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions were selected for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal relationship with efavirenz, lamivudine, and tenofovir disoproxil fumarate.

Efavirenz

General disorders: allergic reactions, asthenia, redistribution/accumulation of body fat.

Nervous system disorders: coordination disorder, ataxia, encephalopathy, cerebellar coordination and balance disorder, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, dizziness.

Endocrine disorders: gynecomastia.

Gastrointestinal disorders: constipation, malabsorption.

Cardiovascular disorders: flushing, palpitations.

Hepatobiliary disorders: increased liver enzymes, liver failure, hepatitis.

Metabolism and nutrition disorders: hypercholesterolemia, hypertriglyceridemia.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, myopathy.

Psychiatric disorders: aggressive reactions, agitation, delirium, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia.

Respiratory, thoracic and mediastinal disorders: dyspnea.

Skin and subcutaneous tissue disorders: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome.

Sensory organ disorders: visual disturbances, tinnitus.

Lamivudine

General disorders: redistribution/accumulation of body fat.

Endocrine disorders: hyperglycemia.

General: weakness.

Blood and lymphatic system disorders: anemia (including pure red cell aplasia and severe anemias progressing during therapy).

Hepatobiliary disorders: lactic acidosis and hepatic steatosis, hepatitis B flare after treatment.

Hypersensitivity: anaphylaxis, urticaria.

Musculoskeletal and connective tissue disorders: muscle weakness, increased CPK, rhabdomyolysis.

Skin and subcutaneous tissue disorders: alopecia, pruritus.

Tenofovir disoproxil fumarate

Immune system disorders: allergic reactions, including angioedema.

Metabolism and nutrition disorders: lactic acidosis, hypokalemia, hypophosphatemia.

Respiratory, thoracic and mediastinal disorders: dyspnea.

Gastrointestinal disorders: pancreatitis, increased amylase levels, abdominal pain.

Renal and urinary disorders: renal failure, acute renal failure, renal impairment, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, increased proteinuria, increased proteinuria.

Hepatobiliary disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT).

Skin and subcutaneous tissue disorders: rash.

Musculoskeletal and connective tissue disorders: decreased bone mineral density, rhabdomyolysis, osteomalacia (manifested as bone pain and may contribute to fractures), muscle weakness, myopathy.

General disorders and administration site conditions: asthenia.

The following adverse reactions listed in the organ system sections above may occur as a result of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscle weakness, myopathy, hypophosphatemia.

Description of selected adverse reactions.

Rash. In clinical trials of efavirenz, rash was generally characterized as mild to moderate maculopapular skin rash and occurred within the first two weeks of initiating efavirenz therapy. In most patients, the rash resolved within one month while continuing efavirenz treatment. Treatment with Eltvir may be resumed in patients who discontinued therapy due to rash. When restarting Eltvir therapy, appropriate antihistamines and/or corticosteroids are recommended.

Renal function impairment. Since Eltvir may cause renal impairment, monitoring of renal function is recommended (see section "Special warnings and precautions for use"). Proximal renal tubulopathy generally resolves or improves after discontinuation of tenofovir disoproxil. However, in some patients, reduced creatinine clearance does not completely resolve despite discontinuation of tenofovir disoproxil. Patients at risk for renal impairment (such as those with baseline renal risk factors, advanced HIV disease, or those receiving concomitant nephrotoxic agents) have an increased risk of incomplete recovery of renal function despite discontinuation of tenofovir disoproxil (see section "Special warnings and precautions for use").

Renal tubulopathy. The following adverse reactions listed in the organ system sections above may occur as a result of proximal renal tubulopathy associated with tenofovir disoproxil fumarate: rhabdomyolysis, osteomalacia (manifested as bone pain, sometimes contributing to fractures), hypokalemia, muscle weakness, myopathy, and hypophosphatemia. These events are not classified as causally related to efavirenz, lamivudine, and tenofovir disoproxil in the absence of proximal renal tubulopathy.

Psychiatric symptoms. Patients with a history of psychiatric disorders have a higher risk of developing serious psychiatric adverse reactions.

Neurological symptoms. Neurological symptoms are commonly observed during efavirenz therapy. In controlled clinical trials of efavirenz, neurological symptoms (moderate to severe) occurred in 19% of patients (severe in 2%), and 2% of patients discontinued treatment due to these symptoms. Symptoms typically occurred within the first 1–2 days of efavirenz therapy and resolved within 2–4 weeks of treatment. Adverse reactions may occur more frequently when Eltvir is taken with food, possibly due to increased plasma levels of efavirenz. Taking the medication before bedtime improves tolerance of these symptoms.

Liver failure with efavirenz. According to post-marketing experience, liver failure, including in patients without prior liver disease or other risk factors, has sometimes been fulminant, progressing in some cases to the need for transplantation or resulting in death.

Interaction with didanosine. Concomitant administration of Eltvir and didanosine is not recommended, as it leads to a 40–60% increase in systemic exposure to didanosine, resulting in an increased risk of didanosine-associated adverse reactions (see section "Interaction with other medicinal products and other forms of interaction"). There have been rare reports of pancreatitis and lactic acidosis, sometimes fatal.

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

Immune Reconstitution Inflammatory Syndrome (IRIS). In HIV-infected patients with severe immunodeficiency (at the time of initiation of ART), inflammatory reactions to asymptomatic or residual opportunistic infections may develop. Autoimmune disorders (e.g., Graves' disease, autoimmune hepatitis) have also been reported; however, the time to onset of such disorders was variable, and these reactions may occur many months after initiation of treatment (see section "Special warnings and precautions for use").

Osteonecrosis. Cases of osteonecrosis have been reported, particularly in patients with well-recognized risk factors, advanced HIV disease, or long-term use of ART. The frequency of this disorder is unknown (see section "Special warnings and precautions for use").

Special patient populations

Children and adolescents

Adverse reactions in children and adolescents receiving therapy with tenofovir disoproxil or lamivudine as individual agents were similar to those observed in clinical trials involving adults.

There have been reports of decreased bone mineral density (BMD) in children and adolescents receiving tenofovir disoproxil. In HIV-infected adolescents receiving tenofovir disoproxil, BMD Z-scores were lower than in placebo group patients. In HIV-infected children switched to tenofovir disoproxil, BMD Z-scores were lower than in patients continuing regimens containing stavudine or zidovudine.

Elderly patients

The efficacy and safety of the combination of efavirenz, lamivudine, and tenofovir disoproxil in patients aged over 65 years have not been studied. Caution is advised, as elderly patients are more likely to have decreased renal function.

Patients with HIV and concomitant HBV or HCV infection

Only a limited number of patients with concomitant HBV or HCV infection were included in clinical trials. The adverse reaction profile of efavirenz, lamivudine, and tenofovir disoproxil in patients with concomitant HBV or HCV infection was similar to that in HIV-infected patients without concomitant infections.

However, as expected for this patient population, elevations in AST and ALT were more frequent than in the general population of HIV-infected patients.

Hepatitis flare after discontinuation of therapy

In HIV-infected patients with concomitant HBV infection, clinical and laboratory signs of hepatitis may occur after discontinuation of therapy (see section "Special warnings and precautions for use").

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30°C, in a place inaccessible to children.

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

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's location and address of place of business.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.