Efavirenz, lamivudine and tenofovir disoproxil fumarate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate

Composition:

Active substances: 1 film-coated tablet contains efavirenz 600 mg, lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg equivalent to 245 mg tenofovir disoproxil;

Excipients: lactose monohydrate, sodium croscarmellose, poloxamer, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, microcrystalline cellulose, pregelatinized starch;

coating: hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: bilayer convex, capsule-shaped tablets, film-coated, white to almost white, smooth on both sides.

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 human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (NNRTI). Efavirenz inhibits HIV-1 reverse transcriptase non-competitively and does not significantly inhibit reverse transcriptase of human immunodeficiency virus type 2 (HIV-2) or cellular DNA polymerases α, β, γ, and δ.

Lamivudine is the negative enantiomer of 2’-deoxy-3’-thiacytidine, a dideoxynucleoside analogue.

Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleotide analogue of 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 by causing DNA chain termination. Both compounds are active against HIV-1 and HIV-2, as well as against hepatitis B virus.

Resistance.

Resistance to efavirenz may develop in a significant proportion of patients who experience virological failure during efavirenz therapy. The primary mutations associated with efavirenz use are K103N, G190S/A/E, and Y188L; the presence of any one of these mutations is sufficient to cause high-level resistance. Cross-resistance exists between efavirenz and nevirapine or delavirdine; therefore, patients who have experienced virological failure with any of these agents are likely to exhibit resistance to efavirenz, and vice versa. With accumulation of NNRTI mutations, susceptibility to etravirine may also be reduced.

Efavirenz has a long elimination half-life. After discontinuation of effective antiretroviral therapy containing efavirenz, functional monotherapy with efavirenz may persist. In such cases, significant resistance is likely to develop, rendering subsequent use of efavirenz, nevirapine, or delavirdine ineffective.

In many cases of treatment failure with regimens containing lamivudine, the M184V mutation emerges early. M184V causes high-level resistance to lamivudine (>300-fold reduction in susceptibility). However, virus with the M184V mutation replicates less efficiently than wild-type virus.

In vitro data generally indicate that continuing lamivudine as part of antiretroviral therapy despite the emergence of M184V may still provide residual antiretroviral activity (likely due to impaired replicative capacity). The clinical significance of these findings has not been established.

Cross-resistance due to the M184V mutation is limited to nucleoside/nucleotide reverse transcriptase inhibitors. M184V confers complete cross-resistance to emtricitabine.

Zidovudine and stavudine retain their antiretroviral activity against lamivudine-resistant HIV-1.

Abacavir retains antiretroviral activity against lamivudine-resistant HIV-1 with the M184V mutation only. Virus with M184V shows <4-fold reduced susceptibility to didanosine; the clinical significance of this is unknown.

The K65R mutation has been identified in vitro during cultivation of HIV-1 under increasing concentrations of tenofovir. It may also occur naturally during virological failure of regimens containing tenofovir. The K65R mutation reduces susceptibility to tenofovir in vitro by approximately two-fold and is associated with lack of response to tenofovir-containing regimens. K65R may also be induced by abacavir or didanosine and leads to reduced susceptibility to these agents when used in combination with lamivudine, emtricitabine, and tenofovir. Virus with the K65R mutation remains fully susceptible to efavirenz. Additionally, the K70E mutation of HIV-1 has been observed during tenofovir use, which may lead to a slight reduction in susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.

In patients with at least three HIV mutations, including either M41L or L210W, reduced efficacy of tenofovir has been observed.

Clinical results.

When tenofovir and lamivudine were used in combination with efavirenz in treatment-naïve HIV-1-infected patients, the percentage of patients with HIV-RNA <50 copies/mL was 76.3% at week 48 and 67.8% at week 144.

No separate studies of the combination of tenofovir, lamivudine, and efavirenz have been conducted in children.

Pharmacokinetics.

Efavirenz.

Absorption and bioavailability.

Bioavailability under fasting conditions ranges from 40% to 45%. Food intake significantly increases absorption. Time to peak plasma concentration (3–5 hours) remains unchanged after multiple dosing, and steady-state plasma concentrations are achieved within 6–7 days.

Following single-dose administration of efavirenz/lamivudine/tenofovir disoproxil fumarate tablets 600 mg/300 mg/300 mg to healthy volunteers, mean maximum plasma concentration (Cmax) of efavirenz was 2.81 µg/mL (0.69 µg/mL), and mean area under the concentration-time curve (AUC) was 59.89 µg×h/mL (15.75 µg×h/mL). Mean elimination half-life (t_½) of efavirenz was 3.88 hours (1.23 hours).

Efavirenz is highly (>99%) bound to human plasma proteins, primarily albumin. In HIV-infected patients receiving efavirenz at doses of 200–600 mg daily for at least one month, the mean concentration in cerebrospinal fluid was 0.69% of the corresponding plasma concentration. This ratio is approximately three times higher than the unbound (free) fraction of efavirenz in plasma.

Metabolism. Efavirenz is primarily metabolized by the cytochrome P450 system into hydroxylated metabolites. These metabolites are generally inactive against HIV-1. In vitro studies, confirmed by in vivo data, suggest that CYP3A4 and CYP2B6 are the main isoenzymes responsible for efavirenz metabolism.

Efavirenz is an inducer of P450 enzymes, leading to auto-induction of its own metabolism.

Elimination. Efavirenz has a relatively long elimination half-life ranging from 17 to 154 hours after a single dose and 40–55 hours after multiple doses.

Patients with known CYP2B6 genotype mutations (e.g., T/T genotype with G516T) may experience prolonged terminal half-life and enhanced efavirenz effects.

Such genotypes are common among Africans and African Americans. In patients with hepatic impairment, reduced efavirenz clearance and enhanced effects have been observed.

Approximately 14–34% of radiolabeled efavirenz is recovered in urine, with less than 1% of the dose excreted unchanged in urine.

Lamivudine.

Absorption and bioavailability.

Lamivudine is rapidly absorbed after oral administration. Bioavailability ranges from 80% to 85%. Following single-dose administration of efavirenz/lamivudine/tenofovir disoproxil fumarate tablets 600 mg/300 mg/300 mg to healthy volunteers, mean Cmax of lamivudine was 3.10 µg/mL (709 µg/mL), and mean AUC was 15.27 µg×h/mL (3.38 µg×h/mL). Mean t_max of lamivudine was 1.6 hours (0.70 hours).

Concomitant administration of lamivudine with food prolongs t_max and reduces Cmax (by 47%). However, food intake does not affect the overall extent of lamivudine absorption (based on AUC).

Distribution.

Studies indicate that after intravenous administration, the mean volume of distribution of lamivudine is 1.3 L/kg. Lamivudine exhibits linear pharmacokinetics within the therapeutic dose range and shows limited binding to the main plasma protein, albumin (<36% bound to serum albumin in vitro).

Metabolism.

The active intracellular metabolite lamivudine triphosphate has a prolonged terminal half-life within cells (16–19 hours), compared to the plasma half-life of lamivudine (5–7 hours). In 60 healthy adult volunteers receiving lamivudine 300 mg once daily, intracellular triphosphate AUC and Cmax were equivalent to those observed after 150 mg twice daily.

Lamivudine is predominantly excreted unchanged by the kidneys. The likelihood of metabolic drug interactions with lamivudine is low due to minimal hepatic metabolism (5–10%) and low plasma protein binding.

Elimination.

Mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, with predominantly renal clearance (>70%), including tubular secretion via the organic cation transporter system.

Renal impairment.

Studies in patients with renal impairment show that lamivudine elimination is dependent on renal function. Dose adjustment is recommended for patients with creatinine clearance ≤50 mL/min.

Tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate is a prodrug, a water-soluble ester that rapidly converts in vivo to tenofovir and formaldehyde. Within the intracellular environment, tenofovir is converted to tenofovir monophosphate and the active component tenofovir diphosphate.

Absorption.

After oral administration, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir in HIV-infected patients. Oral bioavailability of tenofovir from tenofovir disoproxil fumarate in patients taking the drug fasting is approximately 25%.

Concomitant oral administration of tenofovir disoproxil fumarate with a high-fat meal increases bioavailability, increasing AUC of tenofovir by approximately 40% and Cmax by approximately 14%.

Following single-dose administration of efavirenz/lamivudine/tenofovir disoproxil fumarate tablets 600 mg/300 mg/300 mg to healthy volunteers, mean Cmax of tenofovir was 0.32 µg/mL (0.09 µg/mL) and corresponding AUC was 2.70 µg×h/mL (0.63 µg×h/mL). Mean t_max of tenofovir was 1.38 hours (0.55 hours).

Distribution.

After intravenous administration, the steady-state volume of distribution of tenofovir is approximately 800 mL/kg. Binding of tenofovir to serum or plasma proteins in vitro across a concentration range of 0.01–25.0 µg/mL was less than 0.7% and 7.2%, respectively.

Elimination.

Tenofovir is primarily eliminated by the kidneys, via both glomerular filtration and active tubular transport. Approximately 70–80% of an intravenous dose is excreted unchanged in urine. Total clearance is approximately 230 mL/h/kg (approximately 300 mL/min).

Renal clearance is approximately 160 mL/h/kg (approximately 210 mL/min), exceeding glomerular filtration rate, indicating that active tubular secretion plays a significant role in tenofovir elimination.

After oral administration, the elimination half-life of tenofovir is approximately 12–18 hours.

Studies have shown that tenofovir undergoes active tubular secretion through human proximal tubular cells via organic anion transporters (hOAT) 1 and 3, and is excreted into urine via the multidrug resistance protein 4 (MRP4). In vitro studies indicate that tenofovir disoproxil fumarate and tenofovir are not substrates of CYP450 enzymes.

Special patient groups.

Age, sex, race. Limited pharmacokinetic data do not show significant differences between men and women.

Tenofovir exposure was similar in adults and adolescents after oral administration of tenofovir 300 mg daily.

No pharmacokinetic studies of efavirenz, lamivudine, or tenofovir have been conducted in elderly patients (age >65 years).

No specific pharmacokinetic studies have been conducted in different ethnic groups.

Renal impairment.

Pharmacokinetic parameters of tenofovir after single-dose administration of tenofovir disoproxil fumarate 300 mg were evaluated in 40 HIV-negative, hepatitis B-negative patients with varying degrees of renal impairment based on baseline creatinine clearance (CrCl): (normal renal function, CrCl >80 mL/min; mild renal impairment, CrCl=50–79 mL/min; moderate renal impairment, CrCl=30–49 mL/min; severe renal impairment, CrCl=10–29 mL/min).

Compared to patients with normal renal function, mean tenofovir exposure (%CV) increased from 2.19 (12%) µg×h/mL in patients with CrCl >80 mL/min to 3.06 (30%) µg×h/mL, 6.01 (42%) µg×h/mL, and 15.99 (45%) µg×h/mL in patients with mild, moderate, and severe renal impairment, respectively.

Extending the dosing interval in patients with renal impairment may lead to higher peak plasma concentrations and lower trough levels (Cmin) compared to patients with normal renal function. The clinical implications of this are unknown.

In patients with end-stage renal disease (CrCl <10 mL/min) requiring hemodialysis, tenofovir concentrations increased significantly between dialysis sessions over 48 hours, reaching a mean Cmax of 1.03 µg/mL and mean AUC of 42.86 µg×h/mL. Dose interval adjustment of tenofovir disoproxil fumarate 300 mg is recommended for patients with CrCl <50 mL/min and for those with end-stage renal disease requiring dialysis.

The pharmacokinetics of tenofovir in patients not on hemodialysis with CrCl <10 mL/min, or in patients with end-stage renal disease receiving peritoneal dialysis or other forms of dialysis, have not been studied.

Hepatic impairment.

Tenofovir disoproxil fumarate 300 mg was administered as a single dose to HIV-negative, hepatitis B-negative patients with varying degrees of hepatic impairment according to Child-Turcotte-Pugh classification. Pharmacokinetic parameters of tenofovir are practically unchanged in patients with liver disease; therefore, dose adjustment is not required. Mean AUC and Cmax of tenofovir were 0.22 (34.8%) µg/mL and 2.05 (50.8%) µg×h/mL in healthy volunteers, compared to 0.29 (46.0%) µg/mL and 2.31 (43.5%) µg×h/mL in volunteers with moderate hepatic impairment, and 0.31 (24.8%) µg/mL and 2.74 (44.0%) µg×h/mL in those with severe hepatic impairment.

Intracellular pharmacokinetics.

Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells.

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adults and children aged 10 years and older with body weight greater than 35 kg.

When selecting this medicinal product, individual viral resistance testing and/or the patient's prior treatment history should be taken into account.

Contraindications.

The medicinal product is contraindicated in patients with clinically significant hypersensitivity to efavirenz, lamivudine, tenofovir disoproxil fumarate, or to any of the excipients of the product.

Concomitant use with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids (ergotamine, dihydroergotamine, ergonovine, and methylergonovine), voriconazole, or with the combination of dasabuvir and ombitasvir/paritaprevir/ritonavir is contraindicated.

Concomitant use with herbal products containing St. John’s wort is contraindicated due to the risk of reduced plasma concentrations of efavirenz and diminished clinical effect.

Interaction with other medicinal products and other forms of interaction.

Studies on drug interactions with this medicinal product have not been conducted. This medicinal product contains efavirenz, lamivudine, and tenofovir disoproxil fumarate; therefore, interactions associated with each individual component may occur during its use. Interaction studies for the individual active substances were conducted only in adults.

Concomitant use contraindicated

With terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, and ergot alkaloids (ergotamine, dihydroergotamine, ergonovine, and methylergonovine), because competition by efavirenz for cytochrome P450 (CYP) 3A4 may lead to inhibition of metabolism of these drugs and create conditions for serious complications and/or life-threatening events (e.g., cardiac arrhythmias, prolonged sedative effect, or respiratory depression).

Voriconazole

Voriconazole is contraindicated for concomitant use with this medicinal product, as efavirenz significantly reduces voriconazole levels, while voriconazole significantly increases efavirenz plasma concentrations. Dose adjustment of efavirenz is not feasible when administered as part of a fixed-dose combination product.

Dasabuvir + ombitasvir/paritaprevir/ritonavir

Concomitant use with dasabuvir + ombitasvir/paritaprevir/ritonavir is contraindicated, as it may lead to increased ALT levels. Furthermore, concomitant use is expected to reduce plasma concentrations of dasabuvir + ombitasvir/paritaprevir/ritonavir and diminish their therapeutic effect.

St. John’s wort (Hypericum perforatum)

Herbal medicinal products containing St. John’s wort (Hypericum perforatum) are contraindicated for concomitant use with this product due to the potential for reduced plasma concentrations and decreased clinical efficacy of efavirenz. If a patient is already taking St. John’s wort, treatment should be discontinued, and levels of St. John’s wort and, if possible, efavirenz should be monitored. After discontinuation of St. John’s wort, efavirenz levels may increase. The inhibitory effect of St. John’s wort may persist for up to 2 weeks after discontinuation.

Concomitant use not recommended

This medicinal product should not be co-administered with medicinal products containing efavirenz unless specifically recommended for dose adjustment (e.g., when used with rifampicin).

This medicinal product should not be co-administered with other cytidine analogues, such as emtricitabine, due to similarity to lamivudine.

This medicinal product should not be co-administered with adefovir dipivoxil.

Efavirenz is an in vivo inducer of CYP3A4, CYP2B6, and UGT1A1 enzymes. Plasma concentrations of compounds that are substrates of these enzymes may be reduced when co-administered with efavirenz.

Efavirenz may induce CYP2C19 and CYP2C9 enzymes; however, in vitro studies have also shown inhibition of these enzymes, so the net effect of concomitant use with substrates of these enzymes is not fully known.

The effect of efavirenz may be enhanced when used with other medicinal products (e.g., ritonavir) or certain foods (e.g., grapefruit juice) that inhibit CYP3A4 or CYP2B6 enzyme activity. Herbal products (e.g., Ginkgo biloba and St. John’s wort) that induce these enzymes may lead to reduced plasma concentrations of efavirenz. Concomitant use with St. John’s wort is contraindicated. Concomitant use with Ginkgo biloba extracts is not recommended.

In vitro studies and clinical pharmacokinetic interaction studies have shown that the potential for CYP-mediated interactions involving lamivudine and tenofovir disoproxil fumarate with other medicinal products is low.

Trimethoprim/sulfamethoxazole

Administration of trimethoprim/sulfamethoxazole at a dose of 160 mg/800 mg increases lamivudine exposure by 40% due to trimethoprim; sulfamethoxazole does not interact with the components of this product. However, if the patient has no renal impairment, dose adjustment of lamivudine is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Clinical monitoring of patients is recommended during concomitant use. Co-administration of lamivudine with high-dose co-trimoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis should be avoided.

Atazanavir/ritonavir

Insufficient data are available to recommend dosing of atazanavir/ritonavir in combination with this medicinal product. Therefore, concomitant use of atazanavir/ritonavir and this medicinal product is not recommended.

Didanosine

Concomitant use of this medicinal product with didanosine is not recommended.

Posaconazole

Concomitant use with posaconazole should be avoided due to reduced plasma concentrations of posaconazole.

MEDICINAL PRODUCTS ELIMINATED BY THE KIDNEYS

Since lamivudine and tenofovir are primarily eliminated by the kidneys, concomitant use of this medicinal product with medicinal products that impair renal function or compete for active tubular secretion (e.g., cidofovir) may lead to increased serum concentrations of lamivudine, tenofovir, and/or the co-administered medicinal product.

Concomitant use of this medicinal product with nephrotoxic medicinal products should be avoided, as well as if such products have been recently administered. These include, in particular, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2.

Interaction with cannabinoid testing

Efavirenz does not bind to cannabinoid receptors.

In HIV-negative volunteers receiving efavirenz, false-positive results for urinary cannabinoid testing were obtained using screening assays. More specific methods such as gas chromatography/mass spectrometry are recommended.

Studies conducted with other medicinal products

No clinically significant pharmacokinetic interactions were observed when efavirenz was co-administered with azithromycin, cetirizine, fosamprenavir/ritonavir, lorazepam, zidovudine, nelfinavir, magnesium/aluminum hydroxide antacids, famotidine, or fluconazole. Potential interactions between efavirenz and other antifungal agents, such as ketoconazole, have not been studied.

No clinically significant interactions were identified with concomitant administration of tenofovir disoproxil fumarate and adefovir dipivoxil, emtricitabine, nelfinavir, or ribavirin.

Special precautions for use.

The drug should not be used simultaneously with other medicinal products containing the same active components: efavirenz, lamivudine, or tenofovir disoproxil fumarate. Concomitant use with efavirenz may be considered only when dose adjustment is required, for example, when used with rifampicin in patients with body weight ≥ 50 kg.

The drug should not be used simultaneously with adefovir dipivoxil.

Concomitant administration with didanosine is not recommended, as the concentration of didanosine significantly increases when used together with tenofovir disoproxil fumarate. Rare cases of pancreatitis and lactic acidosis, including fatal outcomes, have been reported.

There are no data on the safety and efficacy of the combination of efavirenz, lamivudine, and tenofovir disoproxil fumarate when used with other antiretroviral agents.

Concomitant use with Ginkgo biloba extract is not recommended.

Switching from antiretroviral therapy with protease inhibitors

Current data indicate a trend toward switching from antiretroviral therapy with protease inhibitors to therapy with the combination of efavirenz/lamivudine/tenofovir disoproxil fumarate 600 mg/300 mg/300 mg, which may lead to reduced therapeutic effect. Such patients should be closely monitored for viral load rebound, as the safety profile of efavirenz differs from that of protease inhibitors.

Liver function

In patients with known or suspected history of liver disease, hepatitis B or C virus infection, and in patients previously treated with other hepatotoxic drugs, monitoring of liver enzymes is recommended. In patients with persistent elevation of serum transaminases more than 5 times above the upper limit of normal, the benefit of continuing treatment should be weighed against the unknown risks of severe hepatotoxicity.

Patients with prior liver dysfunction, including chronic active hepatitis, have shown increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If signs of worsening liver disease or persistent elevation of serum transaminases more than 5–10 times above normal are observed, the benefit of treatment should be weighed against the potential risk of significant liver toxicity. Discontinuation of treatment is recommended if hepatotoxicity is symptomatic or if transaminase levels exceed the upper limit of normal by more than 10 times.

Patients co-infected with HIV and hepatitis B (HBV) or hepatitis C (HCV).

Physicians must refer to current guidelines for the treatment of HIV infection to optimally manage patients co-infected with HBV or HCV.

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

Elevations in transaminase levels may occur about one month after starting efavirenz treatment and are more frequently observed in patients co-infected with HBV and/or HCV.

Lamivudine and tenofovir disoproxil fumarate are also active against HBV. Therefore, discontinuation of the drug in patients co-infected with HIV and HBV may be associated with severe hepatitis flares. Patients with HIV/HBV co-infection who discontinue therapy should be closely monitored clinically and by laboratory tests for at least four months after stopping treatment. Resumption of specific anti-hepatitis therapy may be warranted if necessary. In patients with progressive liver disease or hepatic cirrhosis, specific anti-hepatitis therapy should be resumed without interruption.

Psychiatric symptoms. Psychoneurological adverse reactions have been observed in patients treated with efavirenz. Patients with prior history of psychoneurological disorders had an increased risk of such adverse reactions. In particular, severe depression occurred more frequently in individuals with previous psychiatric history. Reports of fatal suicide, manic episodes, and psychosis have been reported, although a causal relationship with efavirenz use cannot be established from these reports. Patients should be informed that if symptoms of severe depression, psychosis, or suicidal thoughts occur, they should immediately consult a physician to determine whether these symptoms are related to efavirenz use and, if confirmed, whether the benefits of continuing treatment outweigh the risks.

Neurological symptoms.

During clinical trials, patients receiving daily efavirenz 600 mg frequently reported adverse reactions with symptoms including, but not limited to, dizziness, insomnia, somnolence, difficulty concentrating, and abnormal dreams. Dizziness has also been reported in studies with lamivudine and tenofovir disoproxil fumarate.

Headache has been reported in lamivudine clinical trials.

Neurological symptoms associated with efavirenz usually begin within the first 1–2 days and typically resolve after the first 2–4 weeks of treatment. Patients should be advised that symptoms are likely to improve with continued treatment. The subsequent occurrence of any less common psychiatric symptoms is unlikely.

Seizures.

Seizures have been observed in patients receiving efavirenz. Such patients usually had a history of seizures. Patients receiving anticonvulsants—drugs primarily metabolized by the liver, such as phenytoin, carbamazepine, and phenobarbital—may require periodic monitoring of plasma levels. In a drug interaction study, plasma carbamazepine concentrations increased when carbamazepine was co-administered with efavirenz. Precautions should be taken for all patients with a history of seizures.

Skin reactions.

Moderate to mild rash has been reported as a reaction to individual components of the drug. Rashes caused by efavirenz usually resolve with continued treatment. Appropriate antihistamines and/or corticosteroids may improve tolerability and accelerate resolution of the rash. Severe rash characterized by blistering, ulceration, or moist desquamation occurred in less than 1% of patients taking efavirenz. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%. Treatment with the drug must be discontinued if patients develop severe rash with blistering, ulceration, moist desquamation, or fever. Experience with efavirenz in patients who discontinued other non-nucleoside reverse transcriptase inhibitors due to rash is limited. Therefore, the drug is not recommended for patients who previously experienced severe skin reactions (such as Stevens-Johnson syndrome) due to non-nucleoside reverse transcriptase inhibitors.

Patients who discontinued other non-nucleoside reverse transcriptase inhibitors due to rash have an increased risk of developing rash when treated with this drug.

Renal impairment.

Lamivudine and tenofovir disoproxil fumarate are primarily eliminated by the kidneys via glomerular filtration and active tubular secretion. The drug is not recommended for patients with moderate or severe renal impairment (CrCl < 50 mL/min). Patients with moderate to severe renal impairment require dose adjustments for lamivudine and tenofovir disoproxil fumarate, which cannot be achieved with a fixed-dose combination product.

Renal impairment, renal dysfunction, elevated creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have occurred with tenofovir disoproxil fumarate in clinical practice.

It is recommended to calculate creatinine clearance/glomerular function in all patients before initiating treatment with the drug. If creatinine monitoring is continuously available, use calculated glomerular filtration rate at baseline before starting tenofovir disoproxil fumarate. If creatinine testing is not continuously available, urine test strips may be used to detect glucosuria or severe nephrotoxicity due to tenofovir disoproxil fumarate in individuals without risk factors. Creatinine monitoring is recommended for patients at increased risk (elderly, pre-existing kidney disease, diabetes, uncontrolled hypertension, chronic use of proton pump inhibitors, or nephrotoxic drugs) to detect and limit further progression of kidney injury. The benefit-risk ratio of using the drug should be carefully evaluated. If serum phosphate levels fall below 1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to < 50 mL/min in any patient taking the drug, renal function should be assessed weekly, including blood glucose, serum potassium, and urine glucose measurements (see section "Adverse reactions," proximal tubulopathy). Since the drug is a fixed-dose combination and individual component doses cannot be adjusted, treatment with the drug should be discontinued in patients with creatinine clearance < 50 mL/min or serum phosphate levels < 1 mg/dL (0.32 mmol/L). In cases where one of the components needs to be discontinued or dose adjustment is required, individual administration of efavirenz, tenofovir disoproxil fumarate, or lamivudine may be considered.

Concomitant use of the drug with nephrotoxic agents should be avoided. If concomitant administration with nephrotoxic drugs is unavoidable (high-dose or repeated use of nonsteroidal anti-inflammatory drugs, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2), weekly monitoring of renal function is recommended.

Elderly patients. The drug should be prescribed with caution in elderly patients due to the increased risk of renal dysfunction associated with tenofovir disoproxil fumarate.

Skeletal system.

In a 144-week study in adult patients, decreased bone mineral density in the spine and changes in bone biomarkers were observed compared to baseline in treatment groups. Baseline values were significantly higher in the group receiving tenofovir disoproxil fumarate compared to the comparator group receiving stavudine (each in combination with lamivudine and efavirenz). Decreases in femoral bone mineral density were significantly greater in this group up to week 96. However, no increased risk of fractures or evidence of clinically significant bone disorders was observed over 144 weeks.

Bone lesions (rarely leading to fractures) may be associated with proximal renal tubulopathy. Patients should receive appropriate consultation if bone involvement is suspected.

Renal and skeletal disorders in children.

Tenofovir has been studied in HIV-1-infected children aged 12 years and older. Under normal conditions, bone mineral density increases rapidly in this age group. In this study, the average rate of bone mass accrual was lower in the tenofovir group compared to the placebo group. Skeletal growth (height) was not affected. Bone metabolism markers in children aged 12 years and older taking tenofovir showed increased bone turnover, consistent with observations in adults.

Long-term renal and skeletal toxicities are not fully understood. Additionally, the reversibility of renal toxicity cannot be fully established. Therefore, it is recommended to carefully evaluate the benefit-risk ratio for each patient individually, determine appropriate monitoring during treatment (including decisions regarding discontinuation), and consider the need for additional medications.

If renal dysfunction is suspected or detected during treatment with tenofovir disoproxil fumarate, consultation with a nephrologist regarding treatment interruption is required. Treatment interruption should be considered if progressive decline in renal function is not attributable to any other factor.

Currently, it is unknown whether changes in bone mineral density after tenofovir disoproxil fumarate use may affect future bone health and fracture risk.

If bone abnormalities are detected or suspected in pediatric patients, consultation with an endocrinologist and/or nephrologist is recommended.

Cases of osteonecrosis, including in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy, have been reported. The etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, high body mass index). Patients should consult a physician if they experience joint pain, limited joint mobility, or difficulty walking.

Body weight and metabolic parameters.

Weight gain and increased blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to disease control and lifestyle. The impact of antiretroviral therapy on lipid redistribution is likely, while its effect on weight gain is not fully established. Monitoring of blood lipid and glucose levels should be performed according to established HIV treatment guidelines. Lipid disorders should be managed according to clinical recommendations.

Mitochondrial dysfunction.

Nucleoside and nucleotide analogs have demonstrated mitochondrial damage both in vitro and in vivo. Reports of mitochondrial dysfunction have been reported in HIV-negative children exposed to nucleoside analogs in utero and postnatally. Major adverse reactions reported include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events are often transient. Some late neurological disorders (hypertension, seizures, behavioral disturbances) have been reported. It remains unclear whether neurological disorders are transient or permanent. Pediatric patients exposed in utero to nucleoside and nucleotide analogs require laboratory testing and comprehensive medical evaluation for possible mitochondrial dysfunction if symptoms occur. These data do not affect current national recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical HIV transmission.

Immune reconstitution syndrome.

In HIV-infected patients with advanced immunodeficiency, initiation of combination antiretroviral therapy (cART) may trigger inflammatory responses to asymptomatic or residual opportunistic pathogens (e.g., cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia), leading to serious clinical conditions or worsening symptoms.

Autoimmune disorders (such as Graves' disease) have also been reported during immune reconstitution; however, the onset of these disorders varies widely and may manifest several months after starting treatment. Treatment should be initiated if necessary.

Effect of food intake.

Taking the drug with food may increase efavirenz concentrations and lead to an increased frequency of adverse reactions. To improve efavirenz tolerability and prevent neurological adverse effects, the drug should be taken on an empty stomach before bedtime.

General precautions.

HIV transmission. Patients should be informed that antiretroviral therapy, including treatment with this drug, does not eliminate the risk of HIV transmission to others through sexual contact or blood. Preventive measures should continue to be used as before starting treatment.

Opportunistic infections. Antiretroviral therapy may be accompanied by the development of opportunistic infections and other complications of HIV infection. Therefore, continuous clinical monitoring by a physician experienced in managing HIV-infected patients is necessary.

Important information on other drug components.

The drug contains lactose monohydrate; therefore, it should not be used in patients with rare hereditary conditions of galactose intolerance, such as galactosemia, Lapp lactase deficiency, or glucose-galactose malabsorption.

One tablet contains 9.1 mmol (43 mg) of sodium. Caution is advised when prescribing to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy

Efavirenz

Cases of neural tube defects have been reported in infants whose mothers used efavirenz during the first trimester of pregnancy.

A systematic review and meta-analysis of studies showed birth outcomes in women who took efavirenz during the first trimester. The analysis did not reveal an increased risk of overall congenital malformations in a large number of women (over 2000 pregnancy cases) who used efavirenz compared to other antiretroviral agents. However, fetal risks cannot be excluded.

Animal studies with efavirenz showed reproductive toxicity, including teratogenic effects.

Tenofovir disoproxil fumarate and lamivudine

Animal studies do not indicate a direct or indirect harmful effect of tenofovir disoproxil fumarate or lamivudine on reproductive toxicity.

A sufficient number of patients were observed during the first trimester of pregnancy to detect at least a two-fold increase in the risk of any congenital defects. No increase in congenital malformations was observed.

The use of the drug may be considered during pregnancy.

Breastfeeding

Efavirenz, lamivudine, and tenofovir pass into breast milk. Information on the effects of efavirenz, lamivudine, and tenofovir in newborns/infants is insufficient. A negative effect of the drug on the infant cannot be excluded.

Current guidelines on HIV and breastfeeding (e.g., WHO) should be followed when counseling patients on this issue. The optimal option may vary depending on local conditions.

Fertility

Clinical data on the effect of the drug on fertility are not available. Animal studies do not indicate harmful effects of efavirenz, lamivudine, or tenofovir on fertility.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the drug on reaction speed when driving or operating machinery have not been conducted. However, reports of dizziness after taking efavirenz and tenofovir disoproxil fumarate have been received.

Efavirenz may also cause lack of concentration and/or somnolence. Patients should be informed 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 initiated by a physician experienced in the management of HIV-1 infection.

Adults and Children

The recommended dose is one tablet once daily, taken orally.

Method of Administration

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

The drug should be taken at bedtime due to the potential neuropsychiatric side effects of efavirenz.

Missed Dose and Vomiting after Administration

It is important that patients take the medication regularly as prescribed. Missing a dose may increase the risk of developing resistance to the drug and reduce its effectiveness.

If a dose is missed, the patient should take it as soon as possible, provided that less than 12 hours have passed since the scheduled time. If more than 12 hours have passed, the patient should skip the missed dose and take the next scheduled dose at the usual time. The patient must not take a double dose.

If vomiting occurs within 1 hour after taking the dose, the patient should take another tablet. If vomiting occurs more than 1 hour after administration, the patient should not take an additional dose and may take the next dose according to the prescribed schedule.

Dose Adjustment and Discontinuation of Therapy

If therapy with one of the components of the drug needs to be discontinued or the dose adjusted, individual formulations of efavirenz, lamivudine, and tenofovir disoproxil fumarate should be used according to the respective product information.

If treatment with the drug is discontinued, the long half-life of efavirenz and the prolonged intracellular half-lives of tenofovir and lamivudine should be taken into account.

Due to variability in these parameters among patients, guidance on HIV treatment should be consulted regarding issues related to resistance development, and the reason for discontinuation of therapy should be considered.

If the drug is co-administered with rifampicin in patients with body weight ≥ 50 kg, an additional dose of efavirenz 200 mg/day (total 800 mg/day) may be considered.

Special Patient Populations

Hepatic Impairment. The drug should be used with caution in patients with mild to moderate hepatic impairment. It is contraindicated in patients with severe hepatic impairment.

Renal Impairment. The drug is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min).

Studies in patients with renal impairment indicate that lamivudine may contribute to renal dysfunction.

Patients with moderate or severe renal impairment require dose adjustment and altered dosing frequency of lamivudine and tenofovir disoproxil fumarate, which cannot be achieved with fixed-dose combination tablets.

Children

The drug is not recommended for use in children under 10 years of age or weighing less than 35 kg, as dose adjustment of this fixed-dose combination product is not feasible.

Overdose

Efavirenz

Symptoms

Following accidental administration of efavirenz 600 mg twice daily, some patients experienced increased neuropsychiatric symptoms. One case of involuntary muscle contractions has been reported.

Treatment

In case of overdose, patients should be monitored for signs of toxicity, and standard supportive therapy should be administered as needed. Activated charcoal should be used to reduce absorption of unmetabolized efavirenz. There is no specific antidote for efavirenz overdose.

Due to the high degree of protein binding of efavirenz, dialysis is unlikely to be effective.

Lamivudine

Symptoms

Data on acute lamivudine overdose in humans are limited. All reported cases resulted in full recovery. No specific symptoms were observed.

Treatment

There is no specific treatment for lamivudine overdose. Patients should be monitored, and standard supportive therapy should be administered as needed. Since only a small fraction of lamivudine is removed by 4-hour hemodialysis, continuous ambulatory peritoneal dialysis, or automated peritoneal dialysis, it is unknown whether continuous hemodialysis would provide clinical benefit in cases of lamivudine overdose.

Tenofovir

Approximately 10% of a tenofovir dose is removed by hemodialysis. It is unknown whether peritoneal dialysis is effective in eliminating tenofovir.

Adverse Reactions

For the fixed-dose combination product, there are only limited data available on adverse reactions. Since the product contains efavirenz, lamivudine, and tenofovir disoproxil fumarate, adverse reactions associated with these individual antiretroviral agents may occur.

Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000).

In addition, adverse reactions identified during the post-marketing period (frequency category – not known) are listed. Since information on such adverse events comes from spontaneous reports in patients, it is not possible to determine their frequency reliably. These adverse events are listed according to their potential causal relationship with the use of the active substances in the medicinal product, as well as their severity and the number of reported cases.

Metabolism and nutritional disorders: very common – hypophosphatemia; common – increased fasting triglycerides, total cholesterol, high-density and low-density lipoproteins, hyperglycemia; uncommon – hypokalemia, hypercholesterolemia; rare – lactic acidosis.

Blood and lymphatic system disorders: uncommon – neutropenia, anemia, thrombocytopenia; very rare – pure red cell aplasia, vascular disorders.

Cardiac disorders: uncommon – edema.

Immune system disorders: uncommon – hypersensitivity.

Nervous system disorders: very common – dizziness; common – sleep disorders, insomnia, attention disturbances, somnolence, cerebellar coordination and balance disorders, headache; uncommon – agitation, amnesia, ataxia, coordination disturbances, confusion, convulsions, thinking abnormalities, tremor; very rare – peripheral neuropathy (or paresthesia).

Psychiatric disorders: common – anxiety, depression; uncommon – mood lability disorders, aggression, euphoria, hallucinations, mania, paranoia, suicide attempts, suicidal ideation, psychosis; rare – neurosis*, delirium*, completed suicide*.

Hepatobiliary disorders: common – increased liver enzymes; uncommon – acute hepatitis; rare – liver failure*, hepatic steatosis.

Skin and subcutaneous tissue disorders: very common – rash.

Musculoskeletal and connective tissue disorders: uncommon – rhabdomyolysis, muscle weakness, myalgia, arthralgia, myopathy; rare – osteomalacia (manifested as bone pain and often contributing to fractures)*.

Reproductive system disorders: uncommon – gynaecomastia.

Eye disorders: uncommon – blurred vision.

Ear and labyrinth disorders: uncommon – dizziness, tinnitus.

Respiratory, thoracic and mediastinal disorders: common – cough, nasal congestion.

Gastrointestinal disorders: very common – diarrhea, nausea, vomiting; common – increased lipase and amylase levels, including pancreatic amylase elevation, abdominal pain, dyspepsia, flatulence, anorexia; uncommon – pancreatitis.

Renal and urinary disorders: uncommon – increased creatinine, proteinuria; rare – renal failure (acute and chronic), proximal renal tubulopathy including Fanconi syndrome, acute tubular necrosis, nephritis (including acute interstitial nephritis)*, nephrogenic diabetes insipidus.

General disorders: very common – asthenia; common – pruritus, hair loss, increased fatigue, malaise, fever; uncommon – erythema multiforme, angioneurotic edema, Stevens-Johnson syndrome; rare – photoallergic dermatitis; not known – immune reconstitution syndrome.

*Adverse reactions identified during the post-marketing period following the use of efavirenz, lamivudine, or tenofovir disoproxil fumarate. The frequency category for these adverse reactions was determined using a statistical calculation based on the total number of patients treated with any of the active substances contained in this medicinal product.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of the reach of children.

Packaging.

30 tablets and 2 sachets of silica gel in a plastic container, 1 container in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and place of business.

Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.