TELDI

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

Composition:

Active substances: dolutegravir, lamivudine, tenofovir disoproxil fumarate;

One film-coated tablet contains 50 mg of dolutegravir (as dolutegravir sodium), lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate, sodium starch glycolate, hydroxypropylcellulose, mannitol, povidone, sodium stearyl fumarate, Opadry II Orange 85F530128 (polyvinyl alcohol (E 1203), titanium dioxide (E 171), macrogol (E 1521), talc (E 553b), iron oxide yellow (E 172), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, orange-colored, modified capsule-shaped, biconvex, with the inscription «H» on one side and «D17» on the other.

Pharmacotherapeutic group. Direct-acting antiviral agents for systemic use. Antiviral agents for treatment of HIV infection in combination. ATC code J05A R27.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Dolutegravir inhibits HIV integrase by binding to the active site of the integrase enzyme and blocking the integration step of retroviral deoxyribonucleic acid (DNA), which is essential for the replication cycle of human immunodeficiency virus (HIV).

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

Tenofovir disoproxil is converted in vivo to tenofovir—a nucleoside monophosphate (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, resulting in chain termination of DNA. Both compounds are active against HIV-1 and HIV-2, as well as against hepatitis B virus.

Antiviral activity in cell culture

Dolutegravir. The IC50 of dolutegravir against various laboratory strains of HIV-1 using peripheral blood mononuclear cells (PBMCs) was 0.5 nM, and ranged from 0.7 to 2 nM when using MT-4 cells. The IC50 was similar for clinical isolates with no significant difference among subtypes (A, B, C, D, E, F, and G). The mean IC50 value for three HIV-2 isolates was 0.18 nM (range: 0.09–0.61 nM).

Lamivudine. The antiviral activity of lamivudine against HIV-1 was evaluated in several cell lines, including monocytes and PBMCs, using standard susceptibility assays. EC50 values ranged from 0.003 to 15 µM against HIV-1 subtypes A–G and group O viruses.

Tenofovir disoproxil. The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was evaluated in T-lymphoblastoid cell lines, primary monocyte/macrophage cells, and PBMCs. EC50 values for tenofovir ranged from 0.04 to 8.5 µM. Tenofovir demonstrated antiviral activity in cell culture against HIV-1 subtypes A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 to 2.2 µM).

Antiviral activity in combination with other antiviral agents

No antagonistic effects were observed in vitro between dolutegravir and other tested antiretroviral agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, and raltegravir. Additionally, no antagonistic effects were observed between dolutegravir and adefovir; ribavirin had no apparent effect on dolutegravir activity.

No antagonistic effects were observed in vitro between lamivudine and other antiretroviral drugs (tested agents: abacavir, didanosine, nevirapine, and zidovudine).

Effect of human serum

In 100% human serum, the inhibitory concentration (IC) of dolutegravir changed on average by 75-fold, resulting in a protein binding-corrected IC90 of 0.064 µg/mL.

Resistance in vitro (dolutegravir)

In the NL432 strain, mutations E92Q (FC 3) and G193E (also FC 3) were observed. The E92Q mutation occurred in patients with pre-existing resistance to raltegravir who subsequently received dolutegravir (classified as a secondary mutation for dolutegravir).

In the clinical program using clinical isolates of subtypes B, C, and A/G, the R263K mutation was observed. In cultures of subtypes C and A/G, the integrase substitution R263K was observed in one culture, and G118R in two cultures. The R263K mutation was reported in two patients with subtypes B and C who received antiretroviral therapy but not integrase inhibitors, without affecting sensitivity to dolutegravir in vitro. The G118R mutation reduced sensitivity to dolutegravir in site-directed mutants (FC 10), but was not observed in patients receiving dolutegravir in the phase III program.

Primary raltegravir/elvitegravir mutations (Q148H/R/K, N155H, Y143R/H/C, E92Q, and T66I) do not affect in vitro sensitivity to dolutegravir as single mutations. When mutations associated with secondary inhibitors (for raltegravir/elvitegravir) are added to these primary mutations in site-directed mutant experiments, sensitivity to dolutegravir remains unchanged (FC < 2 compared to wild-type virus), except for Q148 mutations, where FC is 5–10 or higher with certain secondary mutation combinations. The effect of Q148 (H/R/K) mutations was also tested in site-directed mutant passage experiments. Sequential passage with strain NL432 starting from site-directed mutants containing N155H or E92Q did not result in further resistance selection (FC index remained unchanged, close to 1). In contrast, for mutants carrying the Q148H mutation (FC 1), various secondary mutations were observed with subsequent increases in the FC index to values > 10. The clinically significant level of phenotypic shift (FC against wild-type virus) has not been defined; genotypic resistance was a better predictor of outcomes.

In an analysis of susceptibility to dolutegravir in raltegravir-resistant isolates from patients previously treated with raltegravir, dolutegravir had an FC ≤ 10 in 94% of 705 clinical cultures.

Resistance in vivo (dolutegravir)

In previously untreated patients receiving dolutegravir + 2 nucleoside reverse transcriptase inhibitors (NRTIs) in clinical trials, resistance did not develop to integrase inhibitors or NRTIs (n = 1118, follow-up 48–96 weeks).

In patients with prior antiretroviral treatment failure who had not received an integrase inhibitor, integrase inhibitor substitutions occurred in 4 of 354 patients (further follow-up 48 weeks) receiving dolutegravir plus investigator-selected background regimen. Of these four patients, two had the unique integrase substitution R263K (maximum FC 1.93), one had the polymorphic substitution V151V/I (maximum FC 0.92), and one had pre-existing integrase mutations and was considered to have been treated with integrase inhibitors or infected with integrase inhibitor-resistant virus. The R263K mutation was also selected in vitro (see above).

In the presence of resistance to the integrase inhibitor class, the following mutations were selected after 24 weeks in 32 patients with protocol-defined virological failure (VVF) and paired genotypes (all received dolutegravir 50 mg twice daily + optimized background agents): L74L/M (n = 1), E92Q (n = 2), T97A (n = 9), E138K/A/T (n = 8), G140S (n = 2), Y143H (n = 1), S147G (n = 1), Q148H/K/R (n = 4), N155H (n = 1), and E157E/Q (n = 1). Resistance to integrase inhibitors emerging prior to treatment generally appears in patients with a history of Q148 mutation (baseline or historical). Five additional subjects had VVF between 24 and 48 weeks, and 2 of these 5 had treatment-emergent mutations. The observed mutations or mutation mixtures were L74I (n = 1), N155H (n = 2). Treatment-emergent mutations in 30 subjects with primary genotypic resistance to integrase inhibitors receiving dolutegravir (plus optimized background therapy) at screening were consistent with these findings.

Resistance in vitro and in vivo (lamivudine and tenofovir)

The K65R mutation is selected in vitro when HIV-1 is cultured in the presence of increasing concentrations of tenofovir. This mutation may also appear in vivo upon virological failure of a regimen containing tenofovir. The K65R mutation reduces sensitivity to tenofovir in vitro by approximately 2-fold and is associated with lack of response to tenofovir-containing therapy. In clinical trials of treatment-experienced patients, the anti-HIV activity of tenofovir against HIV-1 strains resistant to nucleoside inhibitors was evaluated. Results indicated that patients whose HIV had developed 3 or more thymidine analogue-associated mutations (TAMs), including either M41L or L210W reverse transcriptase mutations, showed reduced response to tenofovir therapy.

In many cases where lamivudine-containing regimens fail (although less frequently when the regimen includes a ritonavir-boosted protease inhibitor), the M184V mutation may emerge early in treatment. The M184V mutation causes high-level resistance to lamivudine (reduction in sensitivity by more than 300-fold). Viral replication with the M184V mutation is lower than that of the wild-type virus. In vitro data suggest that continuing lamivudine as part of antiretroviral therapy despite the development of M184V may provide residual antiretroviral activity (likely due to impaired viral fitness). The clinical significance of these data is not established. Therefore, maintenance therapy with lamivudine in the presence of the M184V mutation may be considered only if there is a high risk of failure of the primary nucleoside reverse transcriptase inhibitor regimen.

Cross-resistance caused by the M184V mutation is limited to nucleoside/nucleotide inhibitors within the class of antiretroviral agents. M184V confers complete cross-resistance to emtricitabine. [Based on a systematic review, emtricitabine and lamivudine are considered pharmacologically equivalent and thus clinically interchangeable for HIV infection therapy. Therefore, data obtained for emtricitabine are also referenced here.] Zidovudine and stavudine retain their antiretroviral activity against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activity against lamivudine-resistant HIV-1 containing only the M184V mutation. The M184V mutation demonstrates < 4-fold reduction in sensitivity to didanosine; the clinical significance of this is unknown.

Effect on electrocardiographic parameters

No effect on the QTc interval was observed when doses three times higher than the clinical dose were administered.

Clinical results

Several clinical trials have confirmed the efficacy of individual components of this fixed-dose combination product. Dolutegravir, lamivudine, and tenofovir disoproxil have been used as individual agents in various combination regimens. No clinical trials have been conducted with the combination of dolutegravir, lamivudine, and tenofovir disoproxil.

When emtricitabine and tenofovir disoproxil were combined with dolutegravir in two clinical trials involving previously untreated patients with HIV-1 infection, the proportion of patients (ITT) with HIV RNA < 50 copies/mL was 93% and 94% at week 48.

Pharmacokinetics.

Absorption characteristics of TELDI were determined after a single dose administered fasting to healthy volunteers.

Dolutegravir

The pharmacokinetics of dolutegravir are similar in healthy and HIV-infected individuals. The pharmacokinetic variability of dolutegravir is low to moderate. Absolute bioavailability of dolutegravir has not been determined.

Absorption

Dolutegravir is rapidly absorbed after oral administration, with a median Tmax of 3.01 (± 1.60) hours after tablet intake. Oral bioavailability is at least 32%. Cmax and AUC values were 36.7% and 43.3%, respectively.

Food intake increases the extent and slows the rate of dolutegravir absorption. Dolutegravir bioavailability depends on food composition: low-, medium-, and high-fat meals increased AUC(0-∞) of dolutegravir by 33%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, and prolonged Tmax to 3, 4, and 5 hours, respectively. This increase in pharmacokinetic parameters may be clinically significant in patients with existing resistance to integrase inhibitor class drugs. Therefore, the drug is recommended to be taken with food in HIV-infected patients with resistance to integrase inhibitor class drugs (see section "Dosage and administration").

Distribution

Dolutegravir has a high binding capacity (> 99%) to plasma proteins, as determined from in vitro data. Based on population pharmacokinetic analysis, the apparent volume of distribution is 17–21 L in HIV-infected patients. The unbound fraction of dolutegravir in plasma increases with low serum albumin levels, which may be observed in patients with moderate hepatic insufficiency.

Dolutegravir is detectable in cerebrospinal fluid (CSF); CSF concentrations of dolutegravir averaged 18 ng/mL (at the level of unbound drug concentration in plasma and above IC50).

Dolutegravir is detectable in male and female genital tracts. AUC in cervical-vaginal secretions, cervical tissue, and vaginal tissue was 6–10% of the corresponding plasma value at steady state. AUC in semen and rectal tissue was 7% and 17% of the corresponding plasma value at steady state, respectively.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme and to a lesser extent by CYP3A. Dolutegravir circulates mainly in plasma; renal excretion of unchanged active substance is low (< 1% of dose). 53% of the total orally administered dose is excreted unchanged in feces. It is unknown whether this is fully or partially related to unabsorbed drug or biliary excretion of the glucuronide conjugate, which may subsequently be hydrolyzed to release the parent compound in the intestinal lumen. 32% of the total orally administered dose is excreted in urine as glucuronide ether (19% of total dose), N-dealkylation metabolite, and metabolite formed by oxidation at the benzyl carbon.

Elimination

The elimination half-life of dolutegravir is ~14 hours. The apparent total plasma clearance of the drug (CL/F) is approximately 1 L/hour in HIV-infected patients, as determined from population pharmacokinetic analysis.

Drug interaction (in vitro)

Transporters: no significant inhibition of P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2, or MRP4; not a substrate of OATP1B1, OATP1B3, or OCT1.

Metabolizing enzymes: no significant inhibition of (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyltransferases (UGT) 1A1, or UGT2B7; no induction of CYP1A2, CYP2B6, or CYP3A4.

Tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate is a water-soluble prodrug ester that is rapidly converted in vivo to tenofovir and formaldehyde.

Tenofovir is intracellularly converted to tenofovir monophosphate and to the active component—tenofovir diphosphate.

Absorption

After oral administration in HIV-infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. Oral bioavailability is 25%. Cmax and AUC values were 35.9% and 24.0%, respectively; Tmax was 1.03 (± 0.60) hours.

Administration of tenofovir disoproxil fumarate with a high-fat meal increased oral bioavailability, increasing AUC of tenofovir by approximately 40% and Cmax by approximately 14%. However, administration of tenofovir disoproxil fumarate with a light meal had no significant effect on tenofovir pharmacokinetics.

Distribution

After intravenous administration, the steady-state volume of distribution of tenofovir was approximately 800 mL/kg. In vitro binding of tenofovir to plasma or serum proteins 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; after intravenous administration, approximately 70–80% of the dose is excreted unchanged in urine. Total clearance was observed at approximately 230 mL/h/kg (about 300 mL/min). Renal clearance was observed at the rate of glomerular filtration at approximately 160 mL/h/kg (about 210 mL/min). This indicates that tubular secretion is an important component of tenofovir elimination. After oral administration, the terminal elimination half-life of tenofovir is 12 to 18 hours. In non-replicating human peripheral blood mononuclear cells, the half-life of tenofovir diphosphate is approximately 50 hours, whereas in phytohemagglutinin-stimulated PBMCs, it is approximately 10 hours.

A study established that tenofovir is eliminated via active tubular secretion, passing through proximal tubular cells via human organic ion transporters (hOAT) 1 and 3, and excreted in urine via the multidrug-resistant protein 4 (MRP4).

In vitro studies showed that neither tenofovir nor tenofovir disoproxil fumarate are substrates of the CYP450 enzyme system. No significant inhibition of CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2 was observed.

Lamivudine

Lamivudine is rapidly absorbed after oral administration.

Lamivudine bioavailability is 80–85%.

Cmax and AUC values were 27.2% and 22.5%, respectively; Tmax was 2.11 (± 0.86) hours. Concomitant administration of lamivudine with food results in prolonged Tmax and reduced Cmax by 47%. However, the amount of lamivudine absorbed (as indicated by AUC) does not change.

Distribution

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

Metabolism

Lamivudine undergoes minimal metabolism. Lamivudine is primarily excreted unchanged by the kidneys. The likelihood of metabolic interaction with lamivudine is low because only a small amount of lamivudine is metabolized by the liver (5–10%), and due to its low plasma protein binding.

Elimination

The elimination half-life of lamivudine is 5 to 7 hours. The intracellular half-life of lamivudine triphosphate is approximately 22 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, with predominantly renal clearance (> 70%), including tubular secretion via the organic cation transport system.

Special patient groups

Children

Pharmacokinetic (PK) studies of dolutegravir in 10 HIV-1-infected adolescents aged 12 to 18 years with prior antiretroviral therapy experience demonstrated that a dolutegravir dose of 50 mg once daily resulted in dolutegravir exposure comparable to that in adults receiving 50 mg once daily. Pharmacokinetic studies in children aged 6 to 12 years showed that doses of 25 mg once daily in patients with body weight ≥ 20 kg and 35 mg once daily in patients with body weight ≥ 30 kg resulted in dolutegravir exposure comparable to that in adults. Additionally, population PK modeling and simulation analysis indicated that weight-based dosing (20, 25, 35, and 50 mg) in children aged ≥ 6 years with body weight ≥ 15 kg provides comparable exposure to that in adults (50 mg), with the lowest weight range of 15–20 kg corresponding to a daily dose of 20 mg.

Exposure to tenofovir achieved in adolescent patients receiving oral daily doses of 245 mg of tenofovir disoproxil was similar to that achieved in adults receiving single daily doses of tenofovir disoproxil 245 mg.

Pharmacokinetic studies of tenofovir disoproxil at a dose of 245 mg in tablet form have not been conducted in children under 12 years of age or in patients with renal impairment.

Available limited data on adolescents receiving a daily dose of 300 mg lamivudine. Pharmacokinetic parameters are comparable to those in adults.

Elderly patients

Population pharmacokinetic analysis of dolutegravir using data obtained in HIV-infected adults showed no clinically significant effect of patient age on dolutegravir pharmacokinetics.

Pharmacokinetic data for dolutegravir, tenofovir, and lamivudine in individuals over 65 years of age are limited.

Renal impairment

Pharmacokinetic data were obtained separately for dolutegravir, tenofovir, and lamivudine.

Renal clearance of unchanged active substance is a minor elimination pathway for dolutegravir. Dolutegravir pharmacokinetics were studied in adults with severe renal impairment (creatinine clearance < 30 mL/min) and compared to healthy control subjects. Dolutegravir exposure decreased by approximately 40% in individuals with severe renal impairment. The mechanism of this decrease is unknown. Dose adjustment is not required for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis.

Lamivudine studies show that plasma concentration (AUC) increases in patients with renal impairment due to reduced clearance. Based on lamivudine data, TELDI is not recommended for patients with creatinine clearance < 50 mL/min.

Compared to patients with normal renal function, mean tenofovir exposure increased from 2,185 ng•h/mL in individuals with creatinine clearance > 80 mL/min, not infected with HIV or hepatitis B virus, to 3,064 ng•h/mL, 6,009 ng•h/mL, and 15,985 ng•h/mL in patients with mild, moderate, and severe renal impairment, respectively.

It is expected that recommendations to increase dosing intervals in patients with renal impairment will result in higher peak plasma concentrations and lower Cmin compared to patients with normal renal function. The clinical implications of this are unknown.

In patients with end-stage renal disease (ESRD) (creatinine clearance < 10 mL/min) requiring hemodialysis, tenofovir concentration significantly increases between dialysis sessions over 48 hours, reaching a mean Cmax of 1,032 ng/mL and a mean AUC0-48h of 42,857 ng•h/mL. It is recommended to adjust the dosing interval of tenofovir disoproxil 245 mg in patients with creatinine clearance < 50 mL/min or in patients with ESRD requiring dialysis.

Pharmacokinetics of tenofovir in patients with creatinine clearance < 10 mL/min not on hemodialysis, and in patients with ESRD receiving peritoneal or other forms of dialysis, have not been studied.

Hepatic impairment

Pharmacokinetic data were obtained separately for dolutegravir, tenofovir, and lamivudine. Dolutegravir is primarily metabolized and eliminated by the liver. When a single 50 mg dose of dolutegravir was administered to 8 subjects with moderate hepatic insufficiency (Child-Pugh class B) and 8 healthy adults for control, total plasma concentration of dolutegravir was similar. However, a 1.5–2-fold increase in unbound dolutegravir was observed in individuals with moderate hepatic impairment compared to healthy control groups. Dose adjustment is not considered necessary for patients with mild to moderate hepatic impairment. The impact of severe hepatic impairment on dolutegravir pharmacokinetics has not been studied.

No significant changes in pharmacokinetics of lamivudine and tenofovir disoproxil were observed in individuals with varying degrees of liver impairment.

Polymorphisms in drug-metabolizing enzymes

No common polymorphisms in drug-metabolizing enzymes were found to alter dolutegravir pharmacokinetics in a clinically significant manner. In a meta-analysis using pharmacogenomics in subjects with UGT1A1 genotypes, a 32% lower clearance and 46% higher AUC of dolutegravir were observed compared to subjects with genotypes associated with normal metabolism via UGT1A1.

Sex

Analysis of pooled pharmacokinetic data obtained in studies involving adults did not reveal a clinically significant effect of sex on dolutegravir pharmacokinetics. There is no evidence that dose adjustment of dolutegravir, tenofovir, or lamivudine is required based on sex effects on pharmacokinetic parameters.

Race

Analysis of pooled pharmacokinetic data obtained in studies involving adults did not reveal a clinically significant effect of race on dolutegravir exposure. There is no evidence that dose adjustment of dolutegravir, tenofovir, or lamivudine is required based on race effects on pharmacokinetic parameters.

Concomitant hepatitis B or C infection

Pharmacokinetic analysis showed that hepatitis C co-infection has no clinically significant effect on dolutegravir pharmacokinetics. Data in individuals with hepatitis B co-infection are limited.

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of adults and children aged 12 years and older, with body weight of at least 40 kg, infected with human immunodeficiency virus (HIV).

Contraindications.

Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

Concomitant use with dofetilide. Concomitant use with medicinal products having a narrow therapeutic window that are substrates of organic cation transporter 2 (OCT2), including fampridine (also known as dalfampridine) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Studies on interactions of TELDY with other medicinal products have not been conducted. Any interactions identified when using dolutegravir, lamivudine, and tenofovir disoproxil separately may be possible when these substances are used in combination. Interaction studies with the above-mentioned substances were conducted only in adults.

Interactions related to dolutegravir

In the presence of HIV-1 integrase inhibitor-resistant virus, factors reducing dolutegravir plasma concentrations should be avoided, including concomitant use of medicinal products that reduce blood concentrations of dolutegravir (such as antacids containing magnesium or aluminum, iron and calcium supplements, multivitamins, and inducers, etravirine (without boosting by protease inhibitors), tipranavir/ritonavir, rifampicin, St. John's wort, and certain antiepileptic medicinal products) (see table below).

Dolutegravir is primarily eliminated via metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP; therefore, medicinal products inducing these enzymes may reduce plasma concentrations of dolutegravir and diminish its therapeutic effect (see table below). Concomitant use of dolutegravir with other medicinal products that inhibit these enzymes may increase plasma concentrations of dolutegravir (see table below).

In vivo, dolutegravir did not affect midazolam – a CYP3A4 probe. Based on in vivo and in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9, and P-gp (see section "Pharmacokinetics").

In vitro, dolutegravir inhibits the renal protein – organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE-1). In vivo, patients showed a 10–14% reduction in creatinine clearance (secretory fraction dependent on OCT2 and MATE-1 transporters). In vivo, dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OCT2 or MATE-1 (such as fampridine (also known as dalfampridine), metformin) (see table).

In vitro, dolutegravir inhibits renal substrate uptake transporters, organic anion transporters OAT1 and OAT3. Given the limited impact of tenofovir substrate on OAT pharmacokinetics in vivo, inhibition of OAT1 in vivo is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OAT3.

Established and theoretically possible interactions with individual antiretroviral and other medicinal products are listed in the table below; pharmacokinetic data reflect results from studies in adults.

Interactions related to lamivudine

The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding, and nearly complete renal clearance.

Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40% increase in lamivudine exposure via the trimethoprim component; the sulfamethoxazole component did not interact. However, if the patient has no renal impairment, dosage adjustment of lamivudine is not required (see section "Dosage and administration"). Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. When concomitant administration is justified, patients should be monitored clinically. Concomitant use of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis should be avoided.

Potential interactions with other concurrently administered medicinal products should be considered, especially when the primary elimination pathway is active renal secretion via the organic cation transport system, e.g., trimethoprim. Other medicinal products (e.g., ranitidine, cimetidine) are partially cleared via this mechanism, and have been shown not to interact with lamivudine. Nucleoside analogs (e.g., didanosine), such as zidovudine, are not cleared by this mechanism and are unlikely to interact with lamivudine.

A slight increase in Cmax (28%) of zidovudine was observed when lamivudine was administered, but overall exposure (AUC) was not significantly altered. Zidovudine does not affect the pharmacokinetics of lamivudine (see section "Pharmacokinetics").

Due to the composition of TELDY, it should not be used concomitantly with other cytidine analogs such as emtricitabine. TELDY should also not be taken with any other medicinal products containing lamivudine.

Lamivudine in vitro inhibits intracellular phosphorylation of cladribine, leading to a potential risk of reduced efficacy of cladribine when combined clinically. Some clinical data also support a possible interaction between lamivudine and cladribine. Therefore, concomitant use of lamivudine with cladribine is not recommended (see section "Special precautions").

Metabolism of lamivudine does not involve CYP3A, making interactions with medicinal products metabolized by this system (e.g., protease inhibitors) unlikely.

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

Interactions related to tenofovir

Since tenofovir is primarily eliminated by the kidneys, concomitant use of tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via hOAT1, hOAT3, or MRP4 transport proteins (e.g., cidofovir) may increase serum concentrations of tenofovir or the concomitantly administered medicinal product, or both.

Concomitant use of tenofovir disoproxil with nephrotoxic medicinal products should be avoided. This particularly includes high or repeated doses of non-steroidal anti-inflammatory drugs, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2 (see section "Special precautions").

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

Based on in vitro experimental results and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions between tenofovir and other medicinal products is low.

TELDY must not be prescribed with any other medicinal products containing:

– tenofovir disoproxil,

– tenofovir alafenamide,

– adefovir dipivoxil,

• didanosine.

Interactions between TELDY and concomitantly administered medicinal products are listed in the table below (increases are indicated by ↑, decreases by ↓, no change by ↔, area under the concentration-time curve – AUC, maximum observed concentration – Cmax, concentration at the end of the dosing interval – Cτ).

Special precautions for use.

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

HIV transmission

Effective antiretroviral therapy can substantially reduce the risk of sexual transmission of HIV. However, the risk may not be completely eliminated. Therefore, it is important to take safety precautions according to national and other authoritative guidelines to prevent transmission.

HIV-1 resistant to integrase inhibitors

When considering the use of dolutegravir in the presence of HIV-1 resistance to integrase inhibitors, it should be noted that dolutegravir has significantly reduced activity against viral strains with Q148 plus two or more secondary mutations at G140A/C/S, E138A/K/T, or L74I. Dolutegravir is unlikely to be effective when used to treat HIV-1 with this type of resistance to integrase inhibitors.

Hypersensitivity reactions

Hypersensitivity reactions associated with dolutegravir are characterized by rash, constitutional symptoms, and sometimes organ dysfunction, including severe hepatic reactions. Dolutegravir and other drugs should be discontinued immediately if hypersensitivity reactions occur (such as severe rash or rash accompanied by elevated liver enzymes, fever, malaise, fatigue, joint or muscle pain, blisters, oral mucosal lesions, conjunctivitis, facial swelling, eosinophilia, or angioedema). Clinical status, including levels of liver aminotransferases and bilirubin, should be monitored. Delay in discontinuing dolutegravir or other drugs upon onset of hypersensitivity reactions may lead to a life-threatening allergic reaction.

Immune reconstitution syndrome

In HIV-infected patients with severe immune deficiency, an inflammatory response to asymptomatic or residual opportunistic pathogens may occur at the initiation of combination antiretroviral therapy (cART), leading to serious clinical conditions or exacerbation of symptoms. These reactions typically occur within the first few weeks or months of cART. Examples include cytomegalovirus retinitis, generalized or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treated as necessary.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported, occurring during immune recovery. However, the reported onset time is more variable, and these events may occur many months after starting treatment.

Elevated liver enzymes consistent with immune reconstitution syndrome have been observed in some patients with hepatitis B or C at the start of dolutegravir therapy. Liver function monitoring is recommended for patients with hepatitis B or C. Particular caution should be exercised when initiating or maintaining effective hepatitis B therapy (in accordance with treatment guidelines) at the start of dolutegravir-based therapy in patients with hepatitis B.

Pancreatitis

Treatment with TELDI should be discontinued immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur (see section "Adverse reactions").

Renal function

Lamivudine and tenofovir disoproxil are primarily eliminated by the kidneys via glomerular filtration and active tubular secretion. TELDI is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Patients with moderate or severe renal impairment require dose adjustments of lamivudine and tenofovir disoproxil, which cannot be achieved with the fixed-dose combination tablet (see sections "Dosage and administration" and "Pharmacokinetics"). Renal failure, renal dysfunction, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir disoproxil in clinical practice (see section "Adverse reactions").

Creatinine clearance/glomerular filtration rate should be calculated for all patients before starting therapy and, if clinically appropriate, during TELDI therapy. If creatinine testing is regularly available, estimated glomerular filtration rate should be used at baseline before initiating therapy containing tenofovir disoproxil. If creatinine testing is not routinely available, urine dipstick testing may be used in patients without risk factors to detect glycosuria or significant nephrotoxicity from tenofovir disoproxil. Creatinine testing is particularly recommended for patients at high risk of renal impairment (elderly patients, those with pre-existing kidney disease, long-standing diabetes, uncontrolled hypertension, or receiving protease inhibitors or nephrotoxic drugs) to detect further progression of renal dysfunction and prevent it. The benefits and risks should be carefully weighed. In these patients, serum phosphate levels should also be monitored if possible. 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 receiving this medication, renal function should be reassessed within one week, including measurement of blood glucose, serum potassium concentration, and urine glucose (see section "Ad游戏副本

Method of Administration and Dosage

TIVICAY should be prescribed by a physician experienced in managing HIV infection.

Dosage

Adults

The dose of TIVICAY is 1 tablet once daily.

Dose Adjustment

If discontinuation of one of the components of TIVICAY or a dose adjustment is required, separate formulations of dolutegravir, lamivudine, and tenofovir disoproxil should be used. Please refer to the respective product information for these medicinal products.

When resistance to integrase inhibitors is known or suspected in a patient with HIV-1 infection, additional doses of dolutegravir are required. For further information, please consult the dolutegravir product information.

Children aged 12 years and older with body weight at least 40 kg

The dose for children aged 12 years and older with body weight at least 40 kg and HIV-1 infection that is not resistant to integrase inhibitors is 1 tablet of TIVICAY once daily. There is insufficient information on the use of dolutegravir in children with integrase inhibitor-resistant HIV-1 infection.

Children

TIVICAY should not be used in children with body weight below 40 kg, as appropriate dose adjustments of this medicinal product cannot be achieved. Separate formulations containing lower amounts of dolutegravir, tenofovir disoproxil, or lamivudine are required.

Elderly Patients

TIVICAY should be used with caution in elderly patients (see section "Special Warnings and Precautions for Use").

Renal Impairment

Mild renal impairment (creatinine clearance 50–80 mL/min)

No dose adjustment is required in patients with mild renal impairment.

Moderate or severe renal impairment (creatinine clearance < 50 mL/min)

TIVICAY is not recommended for patients with creatinine clearance < 50 mL/min (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics") because appropriate dose adjustments are not feasible. These patients should receive separate formulations of dolutegravir, lamivudine, and tenofovir disoproxil.

Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). There are no data on the use of dolutegravir in patients with severe hepatic impairment (Child-Pugh class C); therefore, TIVICAY should be used with caution in such patients.

Discontinuation of Therapy

If TIVICAY therapy is discontinued in patients co-infected with HIV and hepatitis B virus (HBV), these patients should be closely monitored for signs of hepatitis flare (see section "Special Warnings and Precautions for Use").

Missed Dose

If a patient misses a dose of TIVICAY, the missed dose should be taken as soon as possible, provided that more than 12 hours remain before the next scheduled dose. If less than 12 hours remain before the next dose, the missed dose should not be taken; the next dose should be taken at the usual time.

Method of Administration

Oral administration.

The TIVICAY tablet should be swallowed whole with water.

TIVICAY can generally be taken with or without food.

If HIV-1 is resistant to integrase inhibitors, TIVICAY should preferably be taken with food to enhance absorption (particularly in patients with Q148 mutations).

Children

TIVICAY is administered to children aged 12 years and older with body weight at least 40 kg. TIVICAY should not be used in children with body weight below 40 kg, as appropriate dose adjustments of this medicinal product cannot be achieved.

Overdose.

In case of overdose, the patient should be monitored for signs of toxicity (see section "Adverse Reactions") and standard supportive treatment should be administered.

There is no specific antidote for overdose with TIVICAY. In the event of overdose, supportive care with appropriate monitoring should be provided as needed. Since only a small amount of lamivudine has been removed by (4-hour) haemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is unknown whether prolonged haemodialysis would be clinically beneficial in lamivudine overdose. Tenofovir disoproxil can be removed by haemodialysis; the average haemodialysis clearance of tenofovir disoproxil is 134 mL/min. Elimination of tenofovir disoproxil by peritoneal dialysis has not been studied. Since dolutegravir is highly protein-bound, it is unlikely to be removed significantly during dialysis.

Adverse reactions

Data from clinical trials were used to assess the frequency of adverse events associated with dolutegravir treatment. The most severe adverse reactions are hypersensitivity reactions, which include rash and significant hepatic effects. The most common adverse effects of dolutegravir are nausea (13%), diarrhea (18%), and headache (13%).

In patients receiving tenofovir disoproxil, rare cases of renal dysfunction, renal failure, and proximal renal tubulopathy (including Fanconi syndrome) have been reported, sometimes leading to bone abnormalities (infrequently contributing to fractures). Monitoring of renal function is recommended for patients receiving TELDY (see section "Special precautions").

Adverse reactions associated with the use of dolutegravir, tenofovir disoproxil, and lamivudine are listed below by system organ class and absolute frequency.

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

Description of selected adverse reactions

Changes in serum creatinine

Serum creatinine may increase during the first week of treatment with dolutegravir and then remain stable. The mean change from baseline was 10 µmol/litre after 48 weeks of treatment. Increases in creatinine were comparable across different treatment regimens. These changes are not considered clinically significant, as they do not reflect changes in glomerular filtration rate.

Immune reconstitution syndrome

In HIV-infected patients with severe immune deficiency at the start of combination antiretroviral therapy (cART), an inflammatory reaction to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (e.g., Graves’ disease and autoimmune hepatitis) have also been reported; however, the onset is more variable, and these events may occur many months after initiation of treatment (see section "Special warnings and precautions for use").

Renal function disorders

Since lamivudine and tenofovir disoproxil 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, creatinine clearance does not fully normalize despite discontinuation of tenofovir disoproxil. Patients at risk of renal function impairment (e.g., patients with baseline renal risk factors, advanced HIV disease, or those receiving concomitant nephrotoxic agents) have an increased risk of incomplete recovery of renal function despite discontinuation of tenofovir disoproxil (see section "Special warnings and precautions for use").

Renal tubulopathy

Adverse reactions that may occur as a result of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested by bone pain and rarely contributing to fractures), hypokalemia, muscle weakness, myopathy, and hypophosphatemia. These reactions are unlikely to be caused by tenofovir disoproxil therapy in the absence of proximal renal tubulopathy.

Interaction with didanosine

Concomitant use of tenofovir disoproxil and didanosine is not recommended, as it leads to a 40–60% increase in systemic exposure to didanosine, which may increase the risk of didanosine-related adverse reactions (see section "Interaction with other medicinal products and other forms of interaction"). Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported.

Metabolic parameters

Body weight, and levels of blood lipids and glucose may increase during antiretroviral therapy (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 exposure to cART. The frequency is unknown (see section "Special warnings and precautions for use").

Hepatitis B or C co-infection

In clinical trials, the safety profile of dolutegravir in patients co-infected with hepatitis B and/or C was similar to that in patients without hepatitis, provided baseline liver function tests did not exceed five times the upper limit of normal. However, AST and ALT abnormalities were more frequent in patients with hepatitis B or C co-infection. Elevations in liver enzymes consistent with immune reconstitution syndrome occurred in some individuals with hepatitis B or C co-infection at the initiation of dolutegravir therapy, particularly in those who had discontinued treatment for hepatitis B.

Limited data in patients co-infected with HIV/HBV or HIV/HCV suggest that the safety profile of emtricitabine and tenofovir disoproxil in patients co-infected with HIV/HBV or HIV/HCV is similar to that in HIV-infected patients without co-infection. However, as expected, elevations in AST and ALT occurred more frequently than in the general HIV-infected population.

Worsening of hepatitis after discontinuation of therapy

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

Special patient groups

Paediatric population

Limited data on the use of dolutegravir in children and adolescents (aged 6 to 18 years and weighing at least 15 kg) indicate no additional adverse reactions beyond those observed in adults.

Adverse reactions observed in paediatric patients receiving tenofovir disoproxil or lamivudine as individual agents were consistent with those observed in clinical trials in adults.

Decreases in bone mineral density (BMD) have been reported in children receiving tenofovir disoproxil. In HIV-infected adolescents receiving tenofovir disoproxil, the BMD Z-score was lower than in patients receiving placebo. In HIV-infected children who switched to tenofovir disoproxil, the BMD Z-score was lower than in patients who remained on stavudine- or zidovudine-containing regimens.

Elderly patients

Caution should be exercised, as decreased renal function is more commonly observed in elderly patients.

Shelf life. 2 years.

Storage conditions.

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

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

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's address and location of operations.

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