Trastiva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRUSTIVA (TRUSTIVA)

Composition:

Active substances: efavirenz, emtricitabine, tenofovir disoproxil fumarate;

One tablet contains 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate;

Excipients: microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, hydroxypropylcellulose, magnesium stearate, colorant "Opadry II Pink 85F94172" (composition: polyethylene glycol (macrogol), polyvinyl alcohol, talc, titanium dioxide (E 171), iron oxide red (E 172), iron oxide black (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, pink in color, capsule-shaped, engraved with "H" on one side and "128" on the other.

Pharmacotherapeutic group. Direct-acting antiviral agents. Antiviral agents for treatment of HIV infection, combinations.

ATC code J05A R06.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Efavirenz inhibits HIV-1 reverse transcriptase non-competitively and does not significantly inhibit HIV-2 reverse transcriptase or cellular DNA polymerases—α, β, γ, and δ. Emtricitabine is a cytidine nucleoside analogue. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleotide analogue of adenosine monophosphate.

Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, leading to chain termination of viral DNA.

Emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases, and there is no evidence of mitochondrial toxicity either in vitro or in vivo.

Antiviral Activity in vitro. Efavirenz demonstrated antiviral activity against the most non-phylogenetically diverse subtypes B (subtypes A, AE, AG, C, D, F, G, J, and N), although its antiviral activity is reduced against group O viruses. Emtricitabine exhibits antiviral activity against HIV-1 subtypes A, B, C, D, T, F, and G. Tenofovir exhibits antiviral activity against HIV-1 subtypes A, B, C, D, T, F, G, and O. Emtricitabine and tenofovir have shown specific activity against HIV-2 strains and antiviral activity against hepatitis B virus (HBV).

In combined in vitro antiviral activity studies, synergistic antiviral effects were observed when efavirenz was used with emtricitabine, efavirenz with tenofovir, and emtricitabine with tenofovir.

Resistance. Resistance to efavirenz can be determined in vitro and is associated with substitution of one or more amino acids in HIV-1 reverse transcriptase, including L100I, V108I, V179D, and Y181C. K103N is the most common substitution in reverse transcriptase found in viral isolates from patients experiencing viral load rebound during efavirenz clinical trials. Substitutions have also been observed at positions 98, 100, 101, 108, 138, 188, 190, or 225 of reverse transcriptase, but less frequently and often only in combination with K103N. In vitro cross-resistance profiles for efavirenz, nevirapine, and delavirdine showed that the K103N substitution leads to loss of susceptibility to all three NNRTIs.

Cross-resistance between efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs) is unlikely due to different binding sites on the target enzyme and different mechanisms of action. Cross-resistance between efavirenz and protease inhibitors is also unlikely because the target enzymes differ.

Resistance to emtricitabine or tenofovir has been observed in vitro and in some HIV-1-infected patients, associated with M184V or M184I substitutions in reverse transcriptase when emtricitabine is used, or K65R substitution in reverse transcriptase when tenofovir is used. No other resistance pathways to emtricitabine or tenofovir have been identified. Emtricitabine-resistant viruses with M184V/I mutations exhibit cross-resistance to lamivudine but retain sensitivity to didanosine, stavudine, tenofovir, and zidovudine. The K65R mutation may also be selected by abacavir or didanosine and leads to reduced susceptibility to these agents as well as to lamivudine, emtricitabine, and tenofovir. Tenofovir disoproxil fumarate should not be administered to patients with HIV-1 harboring the K65R mutation. Both K65R and M184V/I mutations retain full susceptibility to efavirenz.

In patients with HIV-1 harboring mutations associated with three or more thymidine analogues (TAMs), including M41L or L210W amino acid substitutions in reverse transcriptase, reduced susceptibility to tenofovir disoproxil fumarate has been observed.

Resistance in vivo (in antiretroviral-naïve patients). Currently, there is limited resistance data available from patients treated with Truvada. However, in a 144-week open-label randomized study (GS-01-934) involving antiretroviral-naïve patients receiving efavirenz, emtricitabine, and tenofovir disoproxil fumarate as individual formulations (or efavirenz plus fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate from week 96 to 144), genotyping of HIV-1 isolates (from plasma) was performed in all patients with confirmed HIV RNA levels > 400 copies/mL at week 144 or upon early discontinuation:

• The M184V/I mutation emerged in 2 of 19 (10.5%) analyzed isolates from the efavirenz + emtricitabine + tenofovir disoproxil fumarate group and in 10 of 29 (34.5%) analyzed isolates from the efavirenz + lamivudine/zidovudine group (p-value < 0.05, Fisher’s exact test comparing emtricitabine + tenofovir disoproxil fumarate vs. lamivudine/zidovudine groups);
• None of the analyzed viruses had the K65R mutation.

Genotypic resistance to efavirenz, primarily the K103N mutation, occurred in 13 of 19 (68%) patients in the efavirenz + emtricitabine + tenofovir disoproxil fumarate group and in 21 of 29 (72%) patients in the efavirenz + lamivudine/zidovudine group.

Refer to individual product information for details on in vivo resistance.

Patients with HIV/HBV co-infection. Limited clinical experience in patients with HIV/HBV co-infection indicates that treatment with emtricitabine or tenofovir disoproxil fumarate as part of antiretroviral therapy (ART) for HIV control also results in reduction of HBV DNA levels (3 log10 reduction or 4–5 log10 reduction, respectively).

Pharmacokinetics.

The product is a fixed-dose combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate.

Separate pharmaceutical formulations of efavirenz, emtricitabine, and tenofovir disoproxil fumarate were used to determine the pharmacokinetic properties of efavirenz, emtricitabine, and tenofovir disoproxil fumarate when administered individually to HIV-infected patients. Bioequivalence of one film-coated tablet of the fixed-dose combination versus one film-coated tablet of efavirenz 600 mg + one hard capsule of emtricitabine 200 mg + one film-coated tablet of tenofovir disoproxil 245 mg (equivalent to 300 mg tenofovir disoproxil fumarate), taken simultaneously, was established following single-dose administration under fasting conditions in healthy volunteers.

Absorption. In HIV-infected patients, maximum plasma concentration of efavirenz is reached within 5 hours, and steady-state concentrations are achieved within 6–7 days. In 35 patients receiving efavirenz 600 mg once daily, the steady-state maximum concentration (Cmax) was 12.9 ± 3.7 µmol (29%) [mean ± standard deviation (SD) (% CV)], the steady-state minimum concentration (Cmin) was 5.6 ± 3.2 µmol (57%), and AUC was 184 ± 73 µmol•h (40%).

Emtricitabine is rapidly absorbed, reaching peak plasma concentrations within 1–2 hours after administration. After multiple oral doses of emtricitabine in 20 HIV-infected patients, the steady-state Cmax was 1.8 ± 0.7 µg/mL (mean ± SD) (39% CV), the steady-state Cmin was 0.09 ± 0.07 µg/mL (80% CV), and AUC was 10.0 ± 3.1 µg•h/mL (31%) over a 24-hour dosing interval.

After a single 300 mg dose of tenofovir disoproxil fumarate administered under fasting conditions to HIV-infected patients, peak tenofovir concentrations were reached within 1 hour, with Cmax and AUC (mean ± SD) (% CV) of 296 ± 90 ng/mL (30%) and 2,287 ± 685 ng•h/mL (30%), respectively. Oral bioavailability of tenofovir from tenofovir disoproxil fumarate under fasting conditions is approximately 25%.

Effect of Food. Truvada is recommended to be taken on an empty stomach because food may increase exposure to efavirenz, potentially increasing the risk of adverse reactions. Exposure to tenofovir (AUC) is expected to be approximately 30% lower when Truvada is taken on an empty stomach compared to when tenofovir disoproxil fumarate is taken with food.

Distribution. Efavirenz is highly bound (>99%) to plasma proteins, primarily albumin. In vitro, emtricitabine binding to plasma proteins is <4% and independent of concentration over the range of 0.02–200 µg/mL. After intravenous administration, the volume of distribution of emtricitabine is 1.4 L/kg. After oral administration, emtricitabine is widely distributed in all body tissues. The mean plasma-to-blood concentration ratio is approximately 1.0, and the mean semen-to-plasma concentration ratio is approximately 4.0. In vitro, binding of tenofovir to plasma and serum proteins of human blood is <0.7% and 7.2%, respectively, over a concentration range of 0.01–25 µg/mL. After intravenous administration, the volume of distribution of tenofovir is approximately 800 mL/kg. After oral administration, tenofovir is actively distributed throughout all body tissues.

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

After oral administration, the elimination half-life of emtricitabine is approximately 10 hours. Emtricitabine is primarily excreted by the kidneys, with nearly complete elimination of the dose in urine (approximately 86%) and feces (approximately 14%). 13% of the emtricitabine dose is excreted in urine as three metabolites. Systemic clearance of emtricitabine is approximately 307 mL/min.

After oral administration, the elimination half-life of tenofovir is approximately 12–18 hours. Tenofovir is primarily eliminated by the kidneys via both glomerular filtration and active tubular secretion, with approximately 70–80% of the dose excreted unchanged in urine after intravenous administration. Apparent clearance of tenofovir is approximately 307 mL/min. Renal clearance is approximately 210 mL/min, exceeding the glomerular filtration rate, indicating the importance of active tubular secretion in tenofovir elimination.

Clinical characteristics.

Indications.

Treatment of human immunodeficiency virus-1 (HIV-1) infection in patients aged 18 years and older with virological suppression of HIV-1 RNA < 50 copies/mL on current antiretroviral therapy for more than three months.

The patient’s history should not include virological failure during previous antiretroviral therapy, and prior to initiation of the first course of antiretroviral treatment, the absence of viral strains with mutations associated with high-level resistance to any component of the drug Truvada must be confirmed.

Contraindications.

• Hypersensitivity to any active or excipient ingredient contained in the drug.
• 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 by 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).
• Concomitant use with elbasvir/grazoprevir due to expected significant reduction in plasma concentrations of elbasvir and grazoprevir. This effect is caused by induction of CYP3A4 or P-gp by efavirenz and may lead to loss of therapeutic effect of elbasvir/grazoprevir.
• Concomitant use with voriconazole. Efavirenz significantly reduces voriconazole plasma concentrations, while voriconazole significantly increases efavirenz plasma concentrations. Since Truvada is a fixed-dose combination drug, dose adjustment of efavirenz is not possible.
• Concomitant use with herbal products containing St. John's wort (Hypericum perforatum), due to the risk of reduced plasma concentrations and diminished clinical effects of efavirenz.
• Use in patients with:
  • family history of sudden fatal outcome or congenital QTc prolongation 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;
  • severe electrolyte disturbances, such as hypokalemia or hypomagnesemia.
• Concomitant use with drugs known to prolong the QTc interval (antiarrhythmic agents).

These drugs include:

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

Interaction with other medicinal products and other types of interactions.

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

Since Truvada is a combination drug, it should not be used concomitantly with other medicinal products containing the same active substances—emtricitabine or tenofovir disoproxil fumarate. Truvada should not be used with medicinal products containing efavirenz, except in cases where dose adjustment is required (e.g., when used with rifampicin). Due to the similarity of emtricitabine, Truvada should not be used concomitantly with other cytidine analogues (e.g., lamivudine). Also, the drug 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 have lower plasma concentrations when used concomitantly with efavirenz. 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 decreased plasma concentrations of efavirenz.

Herbal products (e.g., Ginkgo biloba extract or St. John's wort) 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.

In vitro and clinical pharmacokinetic interaction studies have demonstrated a low potential for CYP450-mediated interactions involving emtricitabine and tenofovir disoproxil fumarate with other medicinal products.

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 by a more specific instrumental method is recommended.

Contraindicated concomitant use.

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

Elbasvir/grazoprevir. Concomitant use of Truvada with elbasvir/grazoprevir is contraindicated, as it may lead to loss of virological response to elbasvir/grazoprevir.

Voriconazole. Concomitant use of standard-dose efavirenz and voriconazole is contraindicated. Since Truvada is a fixed-dose combination drug, the dose of efavirenz cannot be changed; therefore, concomitant use of voriconazole and Truvada is not possible.

St. John's wort (Hypericum perforatum). Concomitant use of Truvada and herbal products containing St. John's wort is contraindicated. Plasma levels of efavirenz may decrease when used concomitantly with St. John's wort due to induction by the latter of metabolizing enzymes and/or transport proteins. If a patient is already using a St. John's wort product, it should be discontinued, viral levels should be checked, and, if possible, efavirenz levels should be monitored, as they may increase after discontinuation of the St. John's wort product. The inductive effect of St. John's wort may persist for at least 2 weeks after discontinuation of treatment.

Drugs that prolong the QTc interval. Truvada is contraindicated with concomitant use of drugs known to prolong the QTc interval and may lead to Torsade de Pointes, such as: class IA and III antiarrhythmic agents, neuroleptics and antidepressants, certain antibiotics from the following classes: macrolides, fluoroquinolones, imidazoles, and triazole antifungals, certain non-sedating antihistamines (terfenadine, astemizole), cisapride, flecainide, certain antimalarial agents, and methadone.

Concomitant use not recommended.

Atazanavir/ritonavir. Insufficient data are available to develop dosing recommendations for atazanavir/ritonavir in combination with Truvada. Therefore, concomitant use of atazanavir/ritonavir and Truvada is not recommended.

Didanosine. Concomitant use of didanosine and Truvada is not recommended.

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir. Concomitant use of Truvada with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended.

Drugs excreted by the kidneys. Since emtricitabine and tenofovir are primarily excreted by the kidneys, concomitant use of Truvada with drugs that impair renal function or compete for active tubular secretion (e.g., cidofovir) may increase serum concentrations of emtricitabine, tenofovir, and/or concomitantly administered drugs.

Administration of Truvada should be avoided during or shortly after administration of nephrotoxic drugs (e.g., but not limited to: aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2).

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

ANTIMICROBIAL AGENTS

Antiretroviral agents

Protease inhibitors

Atazanavir/ritonavir. Concomitant use with tenofovir leads to increased exposure to tenofovir. Higher tenofovir concentrations may lead to adverse reactions, including renal impairment. Concomitant use with efavirenz is not recommended. Interaction with emtricitabine has not been studied. Concomitant use of atazanavir/ritonavir and Truvada is not recommended.

Darunavir/ritonavir. Interaction with efavirenz and tenofovir: Truvada in combination with darunavir/ritonavir at a dose of 800/100 mg once daily may lead to suboptimal Cmin levels of darunavir. If Truvada is used in combination with darunavir/ritonavir, the darunavir/ritonavir combination should be administered at a dose of 600/100 mg twice daily. Darunavir/ritonavir should be used with caution in combination with Truvada (see ritonavir below). Interaction with emtricitabine has not been studied; since elimination pathways differ, interaction is not expected. Monitoring of renal function may be required, especially in patients with underlying systemic disease or kidney disease, and in patients receiving nephrotoxic drugs.

Fosamprenavir/ritonavir. No clinically significant pharmacokinetic interactions with efavirenz were observed. Interactions with emtricitabine and tenofovir disoproxil fumarate were not studied. Truvada and fosamprenavir/ritonavir may be used concomitantly without dose adjustment (see ritonavir below).

Indinavir. When indinavir at a dose of 1000 mg every 8 hours was used with efavirenz at a dose of 600 mg once daily, reduced exposure to indinavir (induction of CYP3A4) was observed. Insufficient data are available to provide dosing recommendations for indinavir when used with Truvada. Since the clinical significance of reduced indinavir concentrations is not established, the magnitude of the observed pharmacokinetic interaction should be considered when selecting a treatment regimen containing efavirenz (a component of Truvada) and indinavir.

Lopinavir/ritonavir. Concentrations of tenofovir exceeding 300 mg once daily may stimulate the development of adverse reactions, including renal impairment. Interaction with efavirenz: significant reduction in lopinavir exposure, requiring dose adjustment of lopinavir/ritonavir; when used in combination with efavirenz and two NRTIs, 533/133 mg lopinavir/ritonavir (soft capsules) twice daily results in similar plasma concentrations of lopinavir as 400/100 mg lopinavir/ritonavir (soft capsules) twice daily without efavirenz (historical data). Interaction with emtricitabine has not been studied. Insufficient data are available to provide dosing recommendations for lopinavir/ritonavir when used with Truvada. Concomitant use of lopinavir/ritonavir with Truvada is not recommended.

Ritonavir. Combination of efavirenz with ritonavir (500 mg or 600 mg twice daily) was poorly tolerated (dizziness, nausea, paresthesia, elevated liver enzymes occurred). Data on tolerability of efavirenz with low-dose ritonavir (100 mg once or twice daily) are insufficient. Interactions with emtricitabine and tenofovir disoproxil fumarate have not been studied. Concomitant use of ritonavir at a dose of 600 mg and Truvada is not recommended. When using Truvada with low-dose ritonavir, possible increased frequency of efavirenz-associated adverse reactions should be considered (due to possible pharmacodynamic interaction).

Saquinavir/ritonavir. Interactions with emtricitabine and efavirenz have not been studied. For concomitant use of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see ritonavir above. No clinically significant pharmacokinetic interactions were observed with concomitant use of tenofovir disoproxil fumarate with ritonavir and saquinavir. Insufficient data are available to provide dosing recommendations for saquinavir/ritonavir when used with Truvada. Concomitant use of saquinavir/ritonavir and Truvada is not recommended. Use of Truvada in combination with saquinavir as the sole protease inhibitor is not recommended.

CCR5 antagonists

Maraviroc. Concentrations of efavirenz and tenofovir were not measured; no effect is expected. Interaction with emtricitabine has not been studied. Refer to the maraviroc product information.

Integrase strand transfer inhibitor

Raltegravir. Interaction with emtricitabine has not been studied. Truvada and raltegravir may be used concomitantly without dose adjustment.

NRTIs and NNRTIs

NRTIs. No specific interaction studies between efavirenz and NRTIs (other than lamivudine, zidovudine, tenofovir disoproxil fumarate) have been conducted. Clinically significant interactions have not been observed and are not expected, since NRTIs and efavirenz are metabolized via different pathways, making competition for the same metabolic enzymes and elimination pathways unlikely. Due to the similarity of lamivudine and emtricitabine (a component of Truvada), they should not be used concomitantly.

NNRTIs. Interaction with efavirenz has not been studied. Since it has been confirmed that use of two NNRTIs is not favorable regarding efficacy and safety, concomitant use of Truvada and another NNRTI is not recommended.

Didanosine. Concomitant use of tenofovir disoproxil fumarate and didanosine leads to a 40–60% increase in systemic exposure to didanosine, which may increase the risk of adverse reactions associated with didanosine. Pancreatitis and lactic acidosis (sometimes fatal) have been rarely reported. Concomitant use of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with significant decline in CD4 cell count, possibly due to intracellular interaction increasing the level of phosphorylated (i.e., active) didanosine. Dose reduction of didanosine to 250 mg when used concomitantly with tenofovir disoproxil fumarate has been associated with reports of high rates of virological failure (in testing several combinations). Interactions with efavirenz and emtricitabine have not been studied. Concomitant use of Truvada and didanosine is not recommended.

Agents against hepatitis C virus

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

Glecaprevir/pibrentasvir. Concomitant use of glecaprevir/pibrentasvir with efavirenz, a component of Truvada, may significantly reduce plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Concomitant use of glecaprevir/pibrentasvir with Truvada is not recommended. For additional information, refer to the glecaprevir/pibrentasvir product information.

Ledipasvir/sofosbuvir. Dose adjustment is not recommended. Increased exposure to tenofovir may exacerbate adverse reactions associated with tenofovir disoproxil, including renal impairment. Renal function should be closely monitored.

Sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir. Concomitant use of Truvada with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is expected to reduce plasma concentrations of velpatasvir and voxilaprevir. Concomitant use of Truvada with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended.

Sofosbuvir. Truvada and sofosbuvir may be used concomitantly without dose adjustment.

Antibiotics

Clarithromycin. Rash occurred in 46% of uninfected volunteers receiving efavirenz and clarithromycin. Interactions with emtricitabine and tenofovir were not studied. The clinical significance of changes in plasma levels of clarithromycin is unknown. Consider using an alternative to clarithromycin (e.g., azithromycin). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with Truvada.

Antimycobacterial agents

Rifabutin. Interactions with emtricitabine and tenofovir were not studied. The daily dose of rifabutin should be increased by 50% when used with Truvada. Consider doubling the dose of rifabutin when used in regimens where rifabutin is administered 2 or 3 times weekly in combination with Truvada.

Rifampicin. Interaction with emtricitabine has not been studied. When Truvada is used with rifampicin, an additional dose of efavirenz of 200 mg/day (total 800 mg) in patients with body weight ≥50 kg may provide exposure comparable to that achieved with a 600 mg dose of efavirenz without rifampicin. The clinical effect of this dose adjustment has not been adequately evaluated. When adjusting the dose, individual tolerability and virological response should be considered. Dose adjustment of rifampicin is not recommended when used with Truvada.

Antifungals

Itraconazole. Interaction with efavirenz led to reduced itraconazole concentrations (induction of CYP3A4). Interactions with emtricitabine and tenofovir were not studied. Since no recommendations are available for itraconazole dosing when used with Truvada, consider alternative antifungal therapy.

Posaconazole. Interaction with efavirenz (400 mg once daily) led to significant reduction in AUC and Cmax (induction of UGT-glucuronosyltransferase). Interactions with emtricitabine and tenofovir were not studied. Concomitant use of posaconazole and Truvada should be avoided, except when benefit outweighs risk.

Voriconazole. Concomitant use of standard doses of efavirenz and voriconazole is contraindicated. Interactions with emtricitabine and tenofovir were not studied. Since Truvada is a fixed-dose combination drug, the dose of efavirenz cannot be changed; therefore, concomitant use of Truvada and voriconazole is not possible.

Antimalarial agents

Artemether/lumefantrine. Interactions with emtricitabine and tenofovir were not studied. Reduced concentrations of artemether, dihydroartemisinin, or lumefantrine may affect the reduction in antimalarial effect; concomitant use of Truvada and artemether/lumefantrine should be used with caution.

Atovaquone and proguanil hydrochloride. Interactions with emtricitabine and tenofovir were not studied. Concomitant use of atovaquone/proguanil with Truvada should be avoided if possible.

ANTICONVULSANTS

Carbamazepine. Interaction with efavirenz led to reduced carbamazepine concentrations (induction of CYP3A4) and reduced efavirenz concentrations (induction of CYP3A4 and CYP2B6); concomitant use of higher doses of efavirenz or carbamazepine has not been studied. Interactions with emtricitabine and tenofovir were not studied. No recommendations are available for use of carbamazepine and Truvada. Consider using an alternative anticonvulsant. Plasma levels of carbamazepine should be periodically monitored.

Phenytoin, phenobarbital, and other anticonvulsants that are substrates of CYP450 isoenzymes. Interaction with efavirenz, emtricitabine, or tenofovir disoproxil fumarate has not been studied. There is a possibility of reduced or increased plasma concentrations of phenytoin, phenobarbital, and other anticonvulsants that are substrates of CYP450 isoenzymes when used with efavirenz. When Truvada is used with an anticonvulsant that is a substrate of CYP450 isoenzymes, plasma levels of the anticonvulsant should be periodically monitored.

Valproic acid. No clinically significant effect on efavirenz pharmacokinetics. Limited data indicate no clinically significant effect on valproic acid pharmacokinetics. Interaction with emtricitabine or tenofovir was not studied. Truvada and valproic acid may be used concomitantly without dose adjustment. Patients should be monitored for seizure control.

Vigabatrin, gabapentin. Interaction has not been studied. Clinically significant interactions are not expected, since vigabatrin and gabapentin are excreted unchanged in urine, making competition with efavirenz for the same metabolic enzymes and elimination pathways unlikely. Truvada and vigabatrin may be used concomitantly without dose adjustment.

ANTICOAGULANTS

Warfarin, acenocoumarol. Interactions have not been studied. Plasma concentrations and effects of warfarin or acenocoumarol may be potentially increased or decreased by efavirenz. Dose adjustment of warfarin or acenocoumarol may be required when used concomitantly with Truvada.

ANTIDEPRESSANTS

Selective serotonin reuptake inhibitors (SSRIs)

Escitalopram. Interaction with emtricitabine and tenofovir was not studied. When used concomitantly with Truvada, escitalopram dose should be increased based on clinical response.

Paroxetine. Interaction with emtricitabine and tenofovir was not studied. Truvada and paroxetine may be used concomitantly without dose adjustment.

Fluoxetine. Interaction has not been studied. Since fluoxetine and paroxetine have similar metabolic profiles (e.g., strong inhibitory effect on CYP2D6), a similar lack of interaction with fluoxetine is expected.

Noradrenaline and dopamine reuptake inhibitors

Bupropion. Interaction with emtricitabine and tenofovir was not studied. Bupropion dose increase should depend on clinical response, but the maximum recommended dose should not be exceeded. No adjustment of efavirenz dose is necessary.

CARDIOVASCULAR AGENTS

Calcium channel blockers

Diltiazem. Increased pharmacokinetic parameters of efavirenz are not considered clinically significant. Interactions with emtricitabine and tenofovir were not studied. When used concomitantly with Truvada, diltiazem dose should be adjusted based on clinical response (see diltiazem product information).

Verapamil, felodipine, nifedipine, nicardipine. Interactions with efavirenz, emtricitabine, and tenofovir disoproxil fumarate have not been studied. When efavirenz is used concomitantly with calcium channel blockers that are substrates of CYP3A4, reduced plasma concentration of the calcium channel blocker is possible. When used concomitantly with Truvada, the dose of the calcium channel blocker should be adjusted based on clinical response (see product information for the calcium channel blocker).

AGENTS THAT LOWER LIPID LEVELS

HMG-CoA reductase inhibitors

Atorvastatin. Interaction with emtricitabine and tenofovir was not studied. Cholesterol levels should be periodically monitored. Dose adjustment of atorvastatin may be necessary when used concomitantly with Truvada (see atorvastatin product information).

Pravastatin. Interaction with emtricitabine and tenofovir was not studied. Cholesterol levels should be periodically monitored. Dose adjustment of pravastatin may be necessary when used concomitantly with Truvada (see pravastatin product information).

Simvastatin. Concomitant use of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect AUC and Cmax of efavirenz. Interaction with emtricitabine and tenofovir was not studied. Cholesterol levels should be periodically monitored. Dose adjustment of simvastatin may be necessary when used concomitantly with Truvada (see simvastatin product information).

Rosuvastatin. Interaction has not been studied. Rosuvastatin is primarily excreted unchanged in feces, so interaction with efavirenz is not expected. Truvada and rosuvastatin may be used concomitantly without dose adjustment.

HORMONAL CONTRACEPTIVES

Oral: ethinylestradiol + norgestimate. Efavirenz: no clinically significant interaction. The clinical significance of such effects is unknown. Interaction with emtricitabine has not been studied. In addition to hormonal contraceptives, a reliable barrier method of contraception should be used.

Injections: depot medroxyprogesterone acetate (DMPA). In a three-month interaction study, no significant differences in pharmacokinetic parameters of DMPA were observed between patients receiving antiretroviral therapy with efavirenz and those not receiving antiretroviral treatment. Similar results were observed by other researchers, although plasma levels of DMPA were more variable in the second study. In both studies, plasma progesterone levels in patients receiving efavirenz and DMPA remained low, indicating suppression of ovulation. Interaction with emtricitabine and tenofovir was not studied. Since data are very limited, in addition to hormonal contraceptives, a reliable barrier method of contraception should be used.

Implant: etonogestrel. Interaction has not been studied. Possible reduction in etonogestrel exposure (induction of CYP3A4). In the post-marketing period, isolated cases of contraceptive failure were reported in patients using etonogestrel with 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). Interaction with efavirenz has not been studied. Possible reduction in immunosuppressant exposure (induction of CYP3A4). It is not expected that immunosuppressants will affect efavirenz exposure. Dose adjustment of the immunosuppressant may be necessary. Careful monitoring of immunosuppressant concentration is recommended at the beginning and end of Truvada treatment for at least 2 weeks (until stable concentrations are achieved).

OPIOIDS

Methadone. Concomitant use of methadone with Truvada should be avoided due to the risk of QTc prolongation. In a study involving HIV-infected injection drug users, concomitant use of efavirenz and methadone led to reduced plasma levels of methadone and symptoms of opioid withdrawal. To alleviate withdrawal symptoms, the methadone dose was increased by an average of 22%. Interaction with emtricitabine has not been studied.

Buprenorphine/naloxone. No clinically significant pharmacokinetic interaction with efavirenz. Interaction with emtricitabine and tenofovir was not studied. Although buprenorphine exposure is reduced, withdrawal symptoms were not observed. Dose adjustment of buprenorphine may not be necessary when used concomitantly with Truvada.

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. The possibility of interaction with efavirenz or other azole antifungals (e.g., ketoconazole) has not been studied.

No clinically significant pharmacokinetic interaction was observed with concomitant use of emtricitabine with stavudine, zidovudine, or famciclovir, or clinically significant interaction with concomitant use of tenofovir disoproxil fumarate with emtricitabine or ribavirin.

Special precautions for use.

Concomitant use with other medicinal products.

Since Truvada is a fixed-dose combination product, it should not be co-administered with other medicinal products containing the same active substances — emtricitabine or tenofovir disoproxil fumarate. Truvada should not be used concomitantly with medicinal products containing efavirenz, except in cases where dose adjustment is required (e.g., when used with rifampicin). Due to the similarity of emtricitabine, Truvada should not be co-administered with other cytidine analogues (e.g., lamivudine). Truvada should also not be used concomitantly with adefovir dipivoxil or medicinal products containing tenofovir alafenamide.

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

Concomitant use of Truvada with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended, as reduced plasma concentrations of velpatasvir and voxilaprevir are expected when co-administered with efavirenz, leading to reduced therapeutic efficacy of sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir.

There are no data on the safety and efficacy of Truvada when used in combination with other antiviral agents.

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

Switching from a regimen containing a protease inhibitor.

Available data suggest that switching from an antiretroviral regimen containing a protease inhibitor to Truvada may reduce treatment response. 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.

Opportunistic infections.

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

HIV transmission.

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

Effect of food intake.

Taking Truvada with food may increase exposure to efavirenz and lead to a higher frequency of adverse reactions. Truvada is recommended to be taken on an empty stomach, preferably at bedtime.

Liver disease.

The pharmacokinetics, safety, and efficacy of Truvada in patients with severe liver disease have not been established. Truvada is contraindicated in patients with severe hepatic impairment and is not recommended in patients with moderate hepatic impairment. Since efavirenz is primarily metabolized by the cytochrome P450 (CYP450) system, Truvada should be used with caution in patients with mild hepatic impairment. Such patients should be closely monitored for efavirenz-related adverse effects, particularly neurological symptoms. Liver function should be periodically assessed via laboratory tests.

In patients with pre-existing hepatic dysfunction, including chronic active hepatitis, the frequency of abnormal liver function tests increases during combination antiretroviral therapy; these patients should be monitored according to standard practice. If signs of worsening liver disease or persistent elevation of serum transaminases (>5 times the upper limit of normal) occur, the benefits of continuing Truvada therapy should be weighed against the potential risks of severe hepatotoxicity. Temporary discontinuation or permanent withdrawal of treatment should be considered in such patients.

Patients receiving other medicinal products associated with hepatotoxicity should have liver enzyme levels monitored.

Hepatic reactions.

Post-marketing reports have described liver failure in patients without prior history of liver disease or known risk factors. All patients (regardless of hepatic function status or risk factors) should be considered for monitoring of liver enzyme levels.

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

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

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

If antiviral therapy for hepatitis B or C is administered concomitantly, the relevant product information for those agents should be consulted.

The safety and efficacy of Truvada for the treatment of chronic HBV infection have not been studied. Pharmacodynamic studies have shown that emtricitabine and tenofovir, alone and in combination, are active against HBV.

Limited clinical experience indicates anti-HBV activity of emtricitabine and tenofovir disoproxil fumarate when used in combination antiretroviral therapy for HIV control. Discontinuation of Truvada in patients with HIV and HBV may lead to severe acute exacerbation of hepatitis. HIV/HBV co-infected patients who discontinue Truvada should be closely monitored clinically and by laboratory testing for at least 4 months after stopping therapy. Hepatitis B treatment may need to be resumed. Discontinuation of therapy is not recommended in patients with progressive liver disease or cirrhosis, as post-treatment hepatitis flare may lead to hepatic decompensation.

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 known to carry a risk of Torsade de Pointes should be considered for alternative therapies to Truvada.

Psychiatric symptoms.

Psychiatric adverse reactions have been reported in patients receiving efavirenz. Patients with a history of psychiatric disorders are at higher risk of developing serious psychiatric adverse reactions. In particular, severe depression occurred more frequently in patients with a history of depression. Post-marketing reports include severe depression, fatal outcomes due to suicide, hallucinations, and psychosis-like behavior. 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 and, if so, whether the benefits of continuing treatment outweigh the risks.

Neurological symptoms.

Symptoms including (but not limited to) dizziness, insomnia, somnolence, impaired concentration, and abnormal dreams have frequently been reported in patients receiving efavirenz 600 mg in clinical trials. Dizziness was commonly reported in clinical trials of emtricitabine and tenofovir disoproxil fumarate. Headache was reported in emtricitabine 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 commonly occurring symptoms are likely to disappear with continued treatment and do not predict the development of less common psychiatric symptoms.

Seizures.

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

Renal function impairment.

Truvada is not recommended for patients with moderate to severe renal impairment (creatinine clearance <50 mL/min). In such patients, the doses of emtricitabine and tenofovir disoproxil fumarate cannot be adjusted when using the fixed-dose combination tablets. Truvada should be avoided if a nephrotoxic agent is co-administered or has recently been used. If concomitant use of Truvada and nephrotoxic agents (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2) is unavoidable, renal function should be monitored weekly.

Cases of acute renal failure have been reported after initiation of high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) in patients receiving tenofovir disoproxil and with risk factors for renal impairment. If Truvada is used concomitantly with NSAIDs, renal function should be appropriately monitored.

Renal failure, renal impairment, increased creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir disoproxil use in clinical practice.

It is recommended to calculate creatinine clearance in all patients before initiating Truvada therapy and to monitor renal function (creatinine clearance and serum phosphate) at 2–4 weeks after starting treatment, at 3 months, and every 3–6 months thereafter in patients without renal risk factors. Patients with a history of renal impairment or those at risk of renal impairment require more frequent monitoring of renal function.

If serum phosphate is <1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to <50 mL/min in any patient receiving Truvada, renal function should be re-evaluated within one week, including measurement of blood glucose, serum potassium, and glucose in urine (see section "Adverse reactions," proximal tubulopathy). Since Truvada is a fixed-dose combination product and the dosing intervals of individual components cannot be altered, treatment should be discontinued in patients with confirmed creatinine clearance <50 mL/min or serum phosphate levels decreasing to <1.0 mg/dL (0.32 mmol/L). Discontinuation of Truvada should also be considered in cases of progressive renal function decline when no other cause is identified. If discontinuation of one component of Truvada or dose adjustment is indicated, individual formulations of efavirenz, emtricitabine, and tenofovir disoproxil are available.

Effects on bone.

Bone abnormalities such as osteomalacia, which may present as persistent or worsening bone pain and rarely lead to fractures, may be associated with tenofovir disoproxil fumarate-induced proximal renal tubulopathy (see section "Adverse reactions").

Decreases in bone mineral density (BMD) have been observed with tenofovir disoproxil fumarate in clinical trials up to 144 weeks in HIV- or HBV-infected patients (see sections "Pharmacodynamics" and "Adverse reactions"). This BMD decline generally improves after discontinuation of treatment.

In other studies, the most pronounced BMD reduction was observed in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor.

Overall, due to bone abnormalities associated with tenofovir disoproxil fumarate and limited long-term data on the impact of tenofovir disoproxil fumarate on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis or a history of bone fractures.

Appropriate consultation should be sought if bone abnormalities are suspected or detected.

Skin reactions.

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

Body weight and metabolic parameters.

Weight gain and increases in 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 a 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 may affect mitochondrial function to varying degrees, most notably with stavudine, didanosine, and zidovudine. Mitochondrial dysfunction has been reported in HIV-negative children exposed in utero and/or postnatally to nucleoside analogues; these cases were primarily associated with zidovudine-containing regimens. Major adverse reactions included hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These effects are often transient. Rarely, delayed neurological disorders (hypertension, seizures, behavioral abnormalities) have been reported. It is not yet definitively known whether these neurological effects are transient or permanent. All children (even HIV-negative) exposed in utero to nucleoside or nucleotide analogues should undergo continued clinical and laboratory monitoring, and a full evaluation for possible mitochondrial dysfunction should be conducted if appropriate signs or symptoms appear. These data do not affect current national recommendations for the use of antiretroviral agents in pregnant women to prevent vertical HIV transmission.

Immune reconstitution syndrome.

In HIV-infected patients with severe immunodeficiency at the 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 symptom exacerbation. These reactions are typically observed within the first few weeks or months of cART. Important examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated as needed 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 these disorders varied, and they may occur many months after starting treatment.

Osteonecrosis.

Although the 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 disease and/or long-term cART. Patients should be advised to seek medical attention if they experience joint pain, stiffness, or difficulty moving joints.

Patients with HIV-1 mutations.

Truvada should be avoided in patients with HIV-1 mutations K65R, M184V/I, or K103N.

Use in the elderly.

Truvada has not been studied in patients aged 65 years and older. Impaired hepatic or renal function is more likely in elderly patients; therefore, Truvada should be used with caution in this population.

Excipients.

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

Use during pregnancy or breastfeeding.

Women of reproductive potential. Women receiving Truvada should not plan pregnancy. A pregnancy test should be performed in women of reproductive age before initiating treatment.

Contraception in men and women. Barrier methods should always be used in combination with other contraceptive methods (e.g., oral or other hormonal contraceptives) during treatment with Truvada. Since efavirenz has a long half-life, appropriate contraceptive methods are recommended for 12 weeks after discontinuation of Truvada.

Pregnancy.

Efavirenz. As of July 2013, the Antiretroviral Pregnancy Registry had received 904 reports of efavirenz exposure (component of the regimen) during the first trimester of pregnancy, resulting in 766 live births. One infant had a neural tube defect, and the frequency and nature of other congenital abnormalities were similar to those observed in infants exposed to regimens not containing efavirenz and in HIV-negative control infants. The frequency of neural tube defects in the general population is 0.5–1 per 1000 live births. Seven retrospective reports described events consistent with neural tube defects, including meningomyelocele; all involved women who received efavirenz-containing regimens during the first trimester (excluding any fixed-dose combination tablets containing efavirenz). Two additional cases (one prospective, one retrospective), including events consistent with neural tube defects, were reported with the use of a fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil. A causal relationship between these events and efavirenz use has not been established, and the total number of pregnant women exposed to efavirenz is unknown.

Since neural tube defects occur within the first 4 weeks of fetal development (before neural tube closure), the potential risk applies to women using efavirenz during the first trimester of pregnancy.

Fetal malformations were observed in monkeys treated with efavirenz.

Emtricitabine and tenofovir disoproxil fumarate. Available data in pregnant women (over 1000 pregnancy outcomes) indicate no malformations or fetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil fumarate. Animal studies with these agents did not reveal reproductive toxicity.

Truvada should not be used during pregnancy except when the woman's clinical condition requires treatment with efavirenz/emtricitabine/tenofovir disoproxil fumarate.

Breastfeeding. Efavirenz, emtricitabine, and tenofovir pass into human breast milk. There is insufficient information on the effects of efavirenz, emtricitabine, and tenofovir in neonates/infants. Risk to the newborn cannot be excluded; therefore, Truvada should not be used during breastfeeding.

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

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

Ability to drive or operate machinery.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. However, dizziness has been reported during treatment with efavirenz, emtricitabine, 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 initiated by a physician experienced in the management of HIV infection.

Method of Administration.

Truvada should be administered once daily.

Tablets should be swallowed whole with water.

Dosage.

Adults.

The recommended dose of Truvada is 1 tablet (orally) once daily. If a patient misses a dose of Truvada and less than 12 hours have passed since the scheduled time of administration, the patient should take the missed dose as soon as possible and then continue with the regular dosing schedule. If a patient misses a dose and more than 12 hours have passed since the scheduled time, the missed dose should not be taken; instead, the patient should continue with the regular dosing schedule.

If vomiting occurs within 1 hour after taking Truvada, the patient should take another tablet. If vomiting occurs more than 1 hour after administration, there is no need to take an additional tablet.

Truvada should be taken on an empty stomach, as food may increase exposure to efavirenz, potentially increasing the frequency of adverse reactions. To improve tolerability of efavirenz (particularly regarding nervous system-related side effects), the medication is recommended to be taken at bedtime.

If discontinuation of any component of Truvada is indicated or dose adjustment is required, patients should switch to separate formulations of efavirenz, emtricitabine, and tenofovir disoproxil fumarate. The prescribing information for these individual agents should be consulted.

When discontinuing Truvada, it is important to remember the long elimination half-life of efavirenz and the prolonged intracellular half-life of emtricitabine and tenofovir. Due to individual variations in these parameters and concerns regarding resistance development, guidance from HIV treatment recommendations should be followed, taking into account the reasons for discontinuation.

Dosage Adjustment. If Truvada is coadministered with rifampicin in patients with body weight ≥50 kg, consideration should be given to increasing the efavirenz dose by 200 mg/day (total 800 mg/day).

Special Patient Populations.

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

Patients with Renal Impairment. Truvada is not recommended for patients with moderate or severe renal impairment (creatinine clearance <50 mL/min). Dose adjustments for emtricitabine and tenofovir disoproxil fumarate are required in such patients, which cannot be achieved with fixed-dose combination tablets.

Patients with Hepatic Impairment. Patients with mild hepatic impairment (Child-Pugh Class A) may use Truvada at the standard recommended dose. These patients should be closely monitored for the development of adverse reactions, particularly nervous system symptoms associated with efavirenz use.

After discontinuation of Truvada, patients co-infected with HIV and HBV should be closely monitored for signs of hepatitis exacerbation.

Children.

The safety and efficacy of Truvada in children (under 18 years of age) have not been established; therefore, its use is not recommended in this patient group.

Overdose.

In patients who inadvertently received efavirenz at a dose of 600 mg twice daily, nervous system symptoms were intensified. One patient experienced involuntary muscle contractions.

In case of overdose, patients should be monitored for signs of toxicity and standard supportive treatment should be administered as needed.

Administration of activated charcoal may be beneficial to remove unabsorbed efavirenz. There is no specific antidote for efavirenz. Due to the high plasma protein binding of efavirenz, it is unlikely that significant amounts of the drug will be removed by dialysis.

Hemodialysis may remove up to 30% of emtricitabine and approximately 10% of tenofovir from the body. It is unknown whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

Adverse Reactions

Short description of the safety profile

The combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate has been studied in 460 patients who received either fixed-dose combination tablets (Study AI266073) or the individual components of the drug (Study GS-01-934). Adverse reactions were generally similar to those observed in previous studies with the individual components. The most commonly reported adverse reactions considered possibly or probably related to the fixed-dose combination during the 48-week period of Study AI266073 were: psychiatric disorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%).

Serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have been reported; neuropsychiatric adverse reactions (including severe depression, suicide with fatal outcome, psychosis-like behavior, seizures); serious liver reactions; pancreatitis and lactic acidosis (sometimes fatal).

Rare cases of renal dysfunction, renal failure, and proximal renal tubulopathy (including Fanconi syndrome) have also been reported, sometimes accompanied by bone abnormalities (including infrequent fractures). Renal function monitoring is recommended in patients receiving treatment with Trastiva.

Discontinuation of Trastiva in patients with HIV and HBV co-infection may lead to acute severe exacerbation of hepatitis.

Administration of Trastiva with food may increase efavirenz exposure and the frequency of adverse reactions.

Adverse Reaction Table

Adverse reactions observed during clinical trials and post-marketing use of the fixed-dose combination and its individual components in antiretroviral therapy (ART) are listed in the table below (by system organ class, frequency, and the drug component associated with the adverse reaction). Within each frequency group, adverse reactions are listed in order of decreasing severity. Frequency is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), or rare (≥1/10,000 to <1/1000).

Adverse reactions associated with the use of the fixed-dose combination

Adverse reactions considered possibly or probably related to the fixed-dose combination in Study AI266073 (over 48 weeks; n=203), not associated with any single component of the drug, include: common – anorexia; uncommon – dry mouth, incoherent speech, increased appetite, decreased libido, myalgia.

Adverse reactions associated with the fixed-dose combination (by causative component).

Table

1 Anaemia occurred frequently when emtricitabine was used in children, skin discolouration (increased pigmentation) – very frequently.

2 This adverse reaction may occur as a result of renal proximal tubulopathy. In the absence of such a condition, it is not considered causally related to the use of tenofovir disoproxil fumarate.

3 See subsection "Description of selected adverse reactions" below.

4 This adverse reaction has been identified during post-marketing surveillance with efavirenz, emtricitabine or tenofovir disoproxil fumarate. The frequency has been estimated by statistical estimation based on the total number of patients who received efavirenz in clinical trials (n=3,969) or emtricitabine in randomized clinical trials (n=1,563) or tenofovir disoproxil fumarate in randomized clinical trials and expanded access programs (n=7,319).

5 The frequency of this adverse reaction was estimated based on safety data from various clinical trials with tenofovir disoproxil fumarate in HBV-infected patients (see also sections "Pharmacodynamics" and "Special warnings and precautions for use").

Description of selected adverse reactions.

Skin rash. In clinical trials, skin rash associated with efavirenz was generally mild to moderate maculopapular rash and occurred within the first two weeks of starting efavirenz therapy. In most patients, the rash resolved within one month while continuing efavirenz treatment. TRUVADA* therapy may be resumed in patients who discontinued treatment due to rash. When reinitiating TRUVADA*, appropriate antihistamines and/or corticosteroids are recommended.

Psychiatric symptoms. Patients with a history of psychiatric disorders have a higher risk of developing serious psychiatric adverse reactions (listed in the table).

Neurological symptoms. Neurological symptoms are frequently observed with efavirenz (a component of TRUVADA*). In controlled clinical trials of efavirenz, neurological symptoms (mild to moderate severity) occurred in 19% of patients (severe symptoms 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 TRUVADA* is taken with food, possibly due to increased plasma levels of efavirenz. Taking the medication at bedtime improves tolerability of these symptoms.

Hepatic failure with efavirenz use. Based on post-marketing experience, hepatic failure, including in patients without pre-existing liver disease or other risk factors, has sometimes been fulminant in nature and in some cases progressed to require liver transplantation or resulted in death.

Renal function disorders. Since TRUVADA* may cause renal impairment, monitoring of renal function is recommended (see section "Special warnings and precautions for use"). Proximal renal tubulopathy usually 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 of renal impairment (such as those with baseline renal risk factors, advanced HIV disease, or those receiving concomitant nephrotoxic agents) are at increased risk of incomplete recovery of renal function despite discontinuation of tenofovir disoproxil (see section "Special warnings and precautions for use").

Lactic acidosis. Cases of lactic acidosis have been reported with tenofovir disoproxil used alone or in combination with other antiretroviral agents. Patients with predisposing factors, such as severe hepatic impairment (Child-Pugh class C), or those receiving concomitant medications known to induce lactic acidosis, are at increased risk of developing severe lactic acidosis during treatment with tenofovir disoproxil, including fatal outcomes.

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

Immune reconstitution syndrome. In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (cART), inflammatory responses 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 has been 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 cART use. The frequency of this disorder is unknown (see section "Special warnings and precautions for use").

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °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 address and 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.