Kocitaf

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

Composition:

Active substances: dolutegravir, emtricitabine, tenofovir alafenamide;

One film-coated tablet contains dolutegravir (as dolutegravir sodium) 50.0 mg, emtricitabine 200.0 mg, tenofovir alafenamide (as tenofovir alafenamide fumarate) 25.0 mg;

Excipients: mannitol; microcrystalline cellulose; sodium starch glycolate; povidone; lactose monohydrate; sodium croscarmellose; magnesium stearate; Opadry II White 85F18422 (polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: tablets from white to almost white, oval, biconvex with beveled edges, film-coated, with engraving «M» on one side and «TD1» on the other.

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

ATC code J05AR.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The combination of dolutegravir, emtricitabine, and tenofovir alafenamide has not been studied.

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).

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and a nucleoside analogue of 2′-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication by incorporation into viral DNA by HIV reverse transcriptase (RT), leading to DNA chain termination. Emtricitabine is active against HIV-1, HIV-2, and hepatitis B virus (HBV).

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and a phosphonoamidate prodrug of tenofovir (an analogue of 2′-deoxyadenosine monophosphate). Tenofovir alafenamide penetrates into cells and, due to increased plasma stability and intracellular activation via cathepsin A hydrolysis, is more efficient than tenofovir disoproxil fumarate, concentrating in peripheral blood mononuclear cells (PBMCs) or HIV target cells. Subsequently, intracellular tenofovir is phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication by incorporation into viral DNA by HIV RT, leading to DNA chain termination. Tenofovir is active against HIV-1, HIV-2, and HBV.

Pharmacodynamic effects

Antiviral activity in vitro

The IC50 value for dolutegravir in various laboratory strains using PBMCs was 0.5 nM, and using MT-4 cells ranged from 0.7 to 2 nM. Similar IC50 values were observed in clinical isolates without significant differences between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F, and G and group O, the mean IC50 was 0.2 nM (range 0.02–2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range 0.09–0.61).

In 100% human serum, protein binding increased the IC90 by an average of 75-fold, resulting in a protein-adjusted IC90 of 0.064 µg/mL. No antagonistic effect was observed in vitro when dolutegravir was used with other studied antiretroviral agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, and raltegravir. No antagonistic effects were observed between dolutegravir and adefovir, and ribavirin had no apparent effect on dolutegravir activity.

Emtricitabine and tenofovir alafenamide demonstrated synergistic antiviral activity in cell culture. No antagonism was observed when emtricitabine or tenofovir alafenamide were used with other antiretroviral agents.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was evaluated in lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The 50% effective concentration (EC50) values for emtricitabine ranged from 0.0013 to 0.64 µM. Emtricitabine showed antiviral activity in cell culture against HIV-1 subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 µM) and demonstrated specific activity against HIV-2 strains (EC50 values ranged from 0.007 to 1.5 µM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1 subtype B was evaluated in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes. The EC50 values for tenofovir alafenamide ranged from 2.0 to 14.7 nM. Tenofovir alafenamide demonstrated antiviral activity in cell culture against all groups of HIV-1 (M, N, and O), including subtypes A, B, C, D, E, F, and G (EC50 values from 0.10 to 12.0 nM) and showed specific activity against HIV-2 strains (EC50 values ranged from 0.91 to 2.63 nM).

Resistance in vitro

Dolutegravir

To study the development of resistance in vitro, serial passages were used. Using the laboratory strain HIV-1 IIIB, mutations appeared slowly over 112 days, with substitutions at positions S153Y and F, leading to a maximum change in sensitivity of 4 (range 2–4). These mutations were not observed in patients receiving dolutegravir in clinical trials. In the NL432 strain, mutations E92Q (FC 3) and G193E (also FC 3) were observed. The E92Q mutation was found in patients with pre-existing resistance to raltegravir who subsequently received dolutegravir (classified as a secondary mutation for dolutegravir).

In further experiments involving subtype B cultures, the R263K mutation was observed in all five cultures (after 20 weeks or later). In subtype C (n = 2) and A/G (n = 2) cultures, the integrase substitution R263K was observed in one culture, and G118R in two cultures. The R263K mutation was reported in two patients receiving antiretroviral therapy who had not received integrase inhibitors (INI) with subtypes B and C, but without affecting in vitro sensitivity to dolutegravir. The G118R mutation reduced sensitivity to dolutegravir in site-directed mutants (FC 10), but was not observed in patients receiving dolutegravir in phase III trials.

Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, and T66I) did not affect in vitro sensitivity to dolutegravir as single mutations. When secondary mutations associated with integrase inhibitors (for raltegravir/elvitegravir) were added to these primary mutations in site-directed mutant experiments, sensitivity to dolutegravir remained unchanged (FC < 2 compared to wild-type virus), except in cases of Q148 mutations, where in combination with known secondary mutations, the FC value was 5–10 or higher. The impact of Q148 mutations (H/R/K) was also confirmed in passage experiments with site-directed mutants. In serial passages with the NL432 strain, starting with site-directed mutants harboring the N155H or E92Q mutations, no resistance was observed (FC values remained unchanged, close to 1). On the other hand, starting with site-directed mutants harboring the Q148H mutation (FC 1), various secondary mutations were observed, leading to an increase in the FC value to >10.

Clinically significant phenotypic values (FC compared to wild-type virus) were not defined; genotypic resistance was a better predictor of outcome.

705 raltegravir-resistant cultures were analyzed for sensitivity to dolutegravir. Dolutegravir had an FC ≤ 10 in 94% of the 705 clinical cultures.

Emtricitabine

Reduced sensitivity to emtricitabine is associated with M184V/I mutations in HIV-1 RT.

Tenofovir alafenamide

HIV-1 isolates with reduced sensitivity to tenofovir alafenamide express the K65R mutation in HIV-1 RT; additionally, the K70E mutation in HIV-1 RT was transiently observed.

Resistance in vivo

In treatment-naïve patients receiving dolutegravir in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in phase IIb and phase III trials, no emergence of resistance to integrase inhibitors or NRTI-class drugs was observed (n = 1118, follow-up 48–96 weeks).

In patients with prior treatment failure who had not received integrase inhibitors (SAILING study), integrase inhibitor substitutions were observed in 4 out of 354 patients (follow-up 48 weeks) receiving dolutegravir in combination with an investigator-selected background regimen (BR). Of these four patients, two had the unique integrase substitution R263K with a maximum FC of 1.93, one had the polymorphic integrase substitution V151V/I with a maximum FC of 0.92, and one had pre-existing integrase mutations, suggesting prior exposure to integrase inhibitors or infection with integrase inhibitor-resistant virus. The R263K mutation was also isolated in vitro.

In cases of resistance to integrase inhibitor class drugs (VIKING-3 study), at week 24, 32 patients (all receiving dolutegravir 50 mg twice daily + optimized background regimen) with protocol-defined virologic failure (PDVF) had the following mutations identified with paired genotypes: 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 that emerged during treatment typically occurred in patients with a history of Q148 mutation (baseline or historical control). In five other patients with PDVF between weeks 24 and 28, mutations that emerged during treatment were observed in two of these five. The mutations that emerged during treatment, or combinations of mutations: L74I (n = 1), N155H (n = 2).

The VIKING-4 study evaluated the use of dolutegravir (plus optimized background therapy) in volunteers with primary genotypic resistance to INIs at screening in 30 volunteers. Mutations emerging during treatment corresponded to those observed in the VIKING-3 study.

Cross-resistance

HIV strains resistant to emtricitabine with the M184V/I substitution were cross-resistant to lamivudine but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

Mutations K65R and K70E lead to reduced sensitivity to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine.

Multinucleoside-resistant HIV-1 with the T69S double insertion mutation or the Q151M mutation complex, including K65R, showed reduced susceptibility to tenofovir alafenamide.

Effect on electrocardiogram parameters

No effect on the QT interval was observed when a dose approximately three times higher than the recommended dose of dolutegravir was administered.

Pharmacokinetics.

The pharmacokinetics of dolutegravir are similar in healthy and HIV-infected individuals. The variability of dolutegravir pharmacokinetics is low to moderate. In phase I studies in healthy volunteers, the %CV for area under the concentration-time curve (AUC) and maximum concentration (Cmax) ranged from ~20 to 40%, and for Ctrough from 30 to 65% across all studies. The variability of dolutegravir pharmacokinetics was higher in HIV-infected patients compared to healthy volunteers. The within-patient variability (%CVw) is lower than between-patient variability.

Absorption

Dolutegravir is rapidly absorbed after oral administration, with a median Tmax of 2–3 hours after tablet intake.

Food intake increased the extent and slowed the rate of dolutegravir absorption. Dolutegravir bioavailability depends on food composition: low-, medium-, and high-fat meals increased the 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, compared to 2 hours under fasting conditions. This increase in pharmacokinetic parameters may be clinically significant in patients with existing resistance to integrase inhibitors. Therefore, the drug is recommended to be taken with food in HIV-infected patients with resistance to integrase inhibitors.

The absolute bioavailability of dolutegravir has not been determined.

Emtricitabine is rapidly and well absorbed after oral administration, with peak plasma concentrations achieved within 1–2 hours after dose intake. After multiple oral doses of emtricitabine in 20 HIV-infected patients, the maximum plasma concentration of emtricitabine at steady state (Cmax) was 1.8 ± 0.7 µg/mL, and the area under the plasma concentration-time curve over the 24-hour dosing interval (AUC) was 10.0 ± 3.1 µg•h/mL. The mean steady-state minimum plasma concentration 24 hours after dosing was equal to or greater than the mean IC90 in vitro value for activity against HIV-1.

Systemic exposure to emtricitabine was not affected by concomitant food intake.

After food intake in healthy volunteers, peak plasma concentrations were observed approximately 1 hour after tenofovir alafenamide intake. Administration of tenofovir alafenamide with a high-fat meal (~800 kcal, 50% fat) resulted in a reduction in Cmax of tenofovir alafenamide (15–37%) and an increase in AUClast (17–77%).

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 17–20 L in HIV-infected patients. Dolutegravir binding to plasma proteins is independent of dolutegravir concentration. The overall blood-to-plasma ratio of radioactivity associated with the drug ranges from 0.441 to 0.535, indicating minimal binding of radioactivity to blood cellular components. The unbound fraction of dolutegravir in plasma increases with low serum albumin levels (<35 g/L), which may be observed in patients with moderate hepatic impairment.

Dolutegravir is detected in cerebrospinal fluid (CSF). In 13 treatment-naïve patients currently on a stable regimen of dolutegravir in combination with abacavir/lamivudine, the CSF concentration of dolutegravir averaged 18 ng/mL (at the level of unbound drug concentration in plasma and exceeding the IC50 value).

Dolutegravir is detected in the genital tracts of men and women. 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.

In vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration within the range of 0.02–200 µg/mL. At peak plasma concentration, the mean ratio of drug concentration in plasma was ~1.0, and the mean ratio of drug concentration in semen to plasma was ~4.0.

In vitro binding of tenofovir to human plasma proteins is <0.7% and independent of concentration within the range of 0.01–25 µg/mL. Binding of tenofovir alafenamide to human plasma proteins ex vivo in samples collected during clinical trials was approximately 80%.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme and to a lesser extent by CYP3A. Dolutegravir circulates mainly in blood 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 entirely or partially related to unabsorbed drug or biliary excretion of the glucuronide conjugate, which may subsequently degrade to form the parent compound in the intestinal lumen. 32% of the total orally administered dose is excreted in urine as dolutegravir glucuronide (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and metabolite formed by oxidation at the benzyl carbon (3% of total dose).

In vitro studies show that emtricitabine is not an inhibitor of human CYP enzymes. After administration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (~86%) and feces (~14%). 13% of the dose was excreted in urine as three predicted metabolites. Biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomer (approximately 9% of dose) and conjugation with glucuronic acid to form the 2'-O-glucuronide (approximately 4% of dose). No other metabolites were identified.

Metabolism is the primary route of elimination of tenofovir alafenamide in humans, accounting for >80% of the oral dose. In vitro studies showed that tenofovir alafenamide is metabolized to tenofovir (the major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target cells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide is hydrolyzed in cells to form tenofovir (the major metabolite), which is phosphorylated to the active metabolite tenofovir diphosphate. In clinical studies involving humans after administration of an oral dose of tenofovir alafenamide (given with emtricitabine, elvitegravir, and cobicistat), the concentration of tenofovir diphosphate was more than 4 times higher in PBMCs, and the concentration of tenofovir was more than 90% lower in plasma compared to corresponding values after administration of a 245 mg oral dose of tenofovir disoproxil (as fumarate) (given with emtricitabine, elvitegravir, and cobicistat).

In vitro, tenofovir alafenamide is not metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is minimally metabolized by CYP3A4. When co-administered with the moderate CYP3A inducer efavirenz, exposure to tenofovir alafenamide was not significantly altered.

Elimination

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

Emtricitabine is primarily eliminated by the kidneys—approximately 86%, with approximately 14% eliminated in feces. 13% of the emtricitabine dose was detected in urine as three metabolites. Systemic clearance of emtricitabine averaged 307 mL/min. After oral administration, the elimination half-life of emtricitabine is approximately 10 hours.

Renal excretion of intact tenofovir alafenamide is minimal, with <1% of the dose excreted in urine. Tenofovir alafenamide is primarily eliminated after its metabolism to tenofovir. The mean elimination half-life in plasma of tenofovir alafenamide and tenofovir is 0.51 and 32.37 hours, respectively. Tenofovir is eliminated from the body by the kidneys via glomerular filtration and active tubular secretion.

Age, sex, and ethnicity

Data from studies in adults did not reveal a clinically significant effect of patient sex or race on dolutegravir concentration. Pharmacokinetic parameters of dolutegravir after single oral administration in Japanese volunteers were similar to those in volunteers from the United States.

No clinically significant pharmacokinetic differences related to emtricitabine and tenofovir alafenamide were observed based on patient age, sex, or ethnicity.

Elderly patients

Population pharmacokinetic analysis of dolutegravir use in adults infected with HIV-1 showed no clinically significant effect of age on dolutegravir exposure.

Pharmacokinetic data for dolutegravir in patients over 65 years of age are limited.

Children

The pharmacokinetics of dolutegravir in 10 children receiving antiretroviral therapy (aged 12 to <18 years) showed that after oral administration of 50 mg dolutegravir once daily, concentrations were similar to those in adults.

Linearity/non-linearity

The linearity of dolutegravir pharmacokinetics depends on dose and dosage form. After oral administration of tablet forms, dolutegravir generally exhibited non-linear pharmacokinetics with dose-dependent increases in plasma concentration in the dose range of 2 mg to 100 mg; however, the increase in dolutegravir concentration was proportional to the dose in the range of 25 mg to 50 mg for the tablet form. When 50 mg was administered twice daily, the 24-hour concentration approximately doubled compared to 50 mg once daily.

Renal impairment

Renal clearance of unchanged active substance is a minor elimination pathway for dolutegravir. Pharmacokinetic studies of dolutegravir were conducted in patients with severe renal impairment (CrCL <30 mL/min). Dolutegravir concentration decreased by approximately 40% in patients in this group. The mechanism of this decrease is unknown. Dose adjustment is not required for patients with renal impairment. The use of dolutegravir in patients on dialysis has not been studied.

No clinically significant differences were observed between the pharmacokinetics of tenofovir alafenamide or tenofovir in patients with normal renal function and patients with severe renal impairment (CrCl from >15 to <30 mL/min). There are no data on the pharmacokinetics of tenofovir alafenamide in patients with CrCl <15 mL/min. The mean systemic exposure to emtricitabine in patients with severe renal impairment (CrCl <30 mL/min) (33.7 µg•h/mL) was higher than in patients with normal renal function (11.8 µg•h/mL).

Hepatic impairment

Dolutegravir is primarily metabolized and eliminated by the liver. A single 50 mg dose of dolutegravir was administered to 8 patients with moderate hepatic impairment (Child-Pugh class B) and 8 healthy volunteers. Although total plasma exposure to dolutegravir was similar, a 1.5–2-fold increase in unbound dolutegravir concentration was observed in patients with moderate hepatic impairment compared to healthy volunteers. Dose adjustment is not required for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on dolutegravir pharmacokinetics has not been studied.

Concomitant hepatitis B and/or hepatitis C virus infection

Population pharmacokinetic analysis showed that concomitant hepatitis C virus infection had no clinically significant effect on dolutegravir exposure. Data in patients with concomitant hepatitis B virus infection are limited.

The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in patients co-infected with HBV and/or HCV.

Polymorphism of drug-metabolizing enzymes

There is no evidence that common polymorphisms of drug-metabolizing enzymes significantly alter dolutegravir pharmacokinetics. In a meta-analysis using pharmacogenomic samples collected in clinical trials in healthy volunteers, patients with UGT1A1 genotypes (n = 7) associated with impaired dolutegravir metabolism had 32% lower dolutegravir clearance and 46% higher AUC compared to patients with genotypes associated with normal metabolism via UGT1A1 (n = 41).

Clinical characteristics.

Indications.

The medicinal product is indicated in combination with other antiretroviral medicinal products for the treatment of adults and children (aged 12 years and older with body weight at least 40 kg) infected with human immunodeficiency virus type 1 (HIV-1).

Contraindications.

Hypersensitivity to the active substances or to any of the excipients. Concomitant use with medicinal products having a narrow therapeutic window that are substrates of organic cation transporter 2 (OCT2), particularly fumarate (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.

Interaction studies have been conducted only in adults.

The medicinal product should not be taken concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil (as fumarate), emtricitabine, lamivudine or adefovir dipivoxil.

Dolutegravir

Effect of other medicinal products on the pharmacokinetics of dolutegravir

In the presence of resistance to integrase inhibitors, factors reducing dolutegravir concentrations should be avoided. Dolutegravir is primarily eliminated via metabolism mediated by the enzyme UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp and BCRP; therefore, medicinal products that induce these enzymes may reduce plasma concentrations of dolutegravir and diminish its therapeutic effect. Concomitant administration of dolutegravir with other medicinal products that inhibit these enzymes may increase plasma concentrations of dolutegravir.

The absorption of dolutegravir is reduced by certain antacid medicinal products.

Effect of dolutegravir on the pharmacokinetics of other medicinal products

In vivo, dolutegravir does not affect midazolam – a CYP3A4 probe. Based on in vivo and in vitro data, no effect of dolutegravir on the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 or P-gp is expected.

In vitro, dolutegravir inhibits the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE)1*. In vivo*, patients have shown a 10–14% reduction in creatinine clearance (the secretory fraction depends 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).

In vitro, dolutegravir inhibits renal uptake transporters, organic anion transporters (OAT1) and OAT3. Given the limited effect 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 specific antiretroviral and non-antiretroviral medicinal products are described in Table 1.

Emtricitabine

In vitro studies and clinical pharmacokinetic interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low. Concomitant administration of emtricitabine with medicinal products that are eliminated via active tubular secretion may increase the concentration of emtricitabine and/or the co-administered medicinal product. Medicinal products that reduce renal function may increase emtricitabine concentrations.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Medicinal products that strongly affect the activity of P-gp and BCRP may alter the absorption of tenofovir alafenamide. It is expected that medicinal products inducing P-gp activity (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) will reduce the absorption of tenofovir alafenamide, leading to decreased plasma concentrations of tenofovir alafenamide and loss of therapeutic effect and development of resistance. Concomitant administration of the medicinal product with other medicinal products that inhibit P-gp (such as cobicistat, ritonavir, cyclosporine) is expected to increase the absorption and plasma concentration of tenofovir alafenamide. Based on in vitro data, concomitant administration of the medicinal product with xanthine oxidase inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo.

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6 in vitro. It is not an inhibitor of CYP3A4 in vivo. Tenofovir alafenamide is a substrate of OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the body may be influenced by the activity of OATP1B1 and OATP1B3.

Other interactions

Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT) 1A1 in vitro. It is unknown whether tenofovir alafenamide inhibits other UGT enzymes. Emtricitabine did not inhibit glucuronidation of a non-specific UGT substrate in vitro.

Potential interactions of dolutegravir with concomitantly administered medicinal products and individual substances are presented in Table 1, and potential interactions of emtricitabine and tenofovir alafenamide are presented in Table 2 (increase is indicated by symbol ↑, decrease by ↓, no change by ↔, area under the concentration-time curve – AUC, maximum observed concentration – Cmax, concentration at the end of the dosing interval – Cτ).

The described interactions are based on studies conducted with the active substances of the medicinal product as individual agents and/or their combinations, or are potential interactions with the medicinal product.

Table 1

Interaction of dolutegravir with other medicinal products

Children

Interaction studies have been conducted only in adults.

Table 2

Interaction between emtricitabine, tenofovir alafenamide as individual components and other medicinal products

Special precautions for use.

Embryo-fetal toxicity

Observational study data have shown that dolutegravir is associated with an increased risk of neural tube defects in the fetus when used at the time of conception and in early pregnancy. Due to limited understanding of the reported types of neural tube defects associated with dolutegravir use, and because the exact date of conception cannot be determined precisely, dolutegravir use should be avoided at the time of conception and during the first trimester of pregnancy.

If pregnancy is planned or first-trimester pregnancy is confirmed during dolutegravir treatment, a switch to an alternative antiretroviral regimen should be considered, if possible.

Before initiating dolutegravir, all patients of reproductive potential should be tested for pregnancy to exclude use of dolutegravir during the first trimester of pregnancy.

All patients of reproductive potential should use effective contraception.

Although effective viral suppression with antiretroviral agents has been shown to substantially reduce the risk of sexual transmission, residual transmission risk cannot be excluded. Preventive measures to avoid transmission of the virus should be taken in accordance with national guidelines.

Integrase inhibitor resistance of particular concern

When considering the use of dolutegravir in the presence of integrase inhibitor resistance, it should be noted that dolutegravir activity is significantly reduced in patients infected with virus strains harboring secondary mutations Q148+≥2 from G140A/C/S, E138A/K/T, L74I. It is unknown whether dolutegravir provides additional efficacy in the presence of such integrase inhibitor resistance.

Hypersensitivity reactions

Hypersensitivity reactions, characterized by rash, constitutional findings, and sometimes organ dysfunction, including severe hepatic reactions, have been reported with dolutegravir use. Dolutegravir and other suspected agents associated with possible hypersensitivity reactions should be discontinued immediately if signs or symptoms of such reactions occur (including severe rash or rash accompanied by elevated liver enzymes, fever, malaise, fatigue, joint or muscle pain, blistering, mucosal lesions, conjunctivitis, facial swelling, eosinophilia, or angioedema). Clinical status, including monitoring of hepatic aminotransferases and bilirubin levels, should be closely monitored. Delay in discontinuing dolutegravir or other suspected agents after onset of hypersensitivity reactions may lead to life-threatening allergic reactions.

HIV-infected patients with concomitant hepatitis B or C virus infection

HIV-infected patients with chronic hepatitis B or C undergoing antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse reactions.

The safety and efficacy of the medicinal product in patients co-infected with HIV-1 and hepatitis C virus have not been established. Tenofovir alafenamide is active against hepatitis B virus. Discontinuation of treatment in patients with concomitant HIV and HBV infection may be associated with severe acute exacerbation of hepatitis. Patients with concomitant HIV and HBV infection who discontinue treatment should be closely monitored both clinically and with laboratory testing for several months after stopping treatment.

The medicinal product should not be taken concomitantly with medicinal products containing tenofovir disoproxil (as fumarate), lamivudine, or adefovir dipivoxil used for the treatment of HBV infection.

Hepatic impairment

The safety and efficacy of the medicinal product in patients with pre-existing severe hepatic impairment have not been established.

Patients with pre-existing hepatic impairment, including chronic active hepatitis, have a higher frequency of hepatic function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If evidence of worsening liver disease is observed, interruption or discontinuation of treatment should be considered.

Body weight and metabolic parameters

Weight gain and increases in serum lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to therapy and lifestyle. In some cases, treatment effects on lipid levels have been observed, but there is no substantial evidence of weight gain due to any specific drug. Current HIV treatment guidelines recommend monitoring of blood lipid and glucose levels. If clinically indicated, lipid abnormalities should be treated.

Mitochondrial dysfunction following in utero exposure

Nucleoside and nucleotide analogues may affect mitochondrial function to varying degrees, most notably with stavudine, didanosine, and zidovudine. Reports of mitochondrial dysfunction in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally have been received; these mostly involved regimens containing zidovudine. The main adverse events reported were hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events were often transient. Rarely, delayed-onset neurological disorders (hypertension, seizures, abnormal behavior) have been reported. It is currently unknown whether such neurological disorders are transient or permanent. These findings should be considered in any child presenting with serious clinical manifestations of unknown etiology, particularly neurological, and with in utero exposure to nucleoside or nucleotide analogues. These findings do not affect current national recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune reconstitution syndrome

In HIV-infected patients with advanced immunodeficiency at the start of combination antiretroviral therapy (CART), an inflammatory response to asymptomatic or residual opportunistic infections may occur, leading to severe clinical manifestations or worsening of symptoms. Such reactions are typically observed within the first few weeks or months after initiating CART. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated, and treatment initiated if necessary. Autoimmune disorders (such as Graves' disease) have also been reported during immune reconstitution. However, the reported onset of these conditions is more variable, and they may occur many months after starting treatment.

Increased biochemical markers of liver function have been observed in some patients co-infected with hepatitis B and/or C virus at the start of dolutegravir treatment. Monitoring of liver function tests is recommended in patients co-infected with hepatitis B and/or C virus. Particular caution is required when initiating or maintaining effective hepatitis B therapy in patients co-infected with hepatitis B virus when starting a dolutegravir-based regimen.

Patients with HIV-1 mutations

The medicinal product should be avoided in patients previously treated with antiretroviral agents who have HIV-1 strains with the K65R mutation.

Trial nucleoside therapy

Reports of high rates of virological failure and early emergence of resistance have been received when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine once daily. Therefore, similar issues may arise when the medicinal product is taken with a third nucleoside analogue.

Opportunistic infections

Patients receiving the medicinal product or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection and should remain under ongoing clinical supervision by physicians experienced in managing HIV-1-infected patients.

Interaction with other medicinal products

In patients with resistance to integrase inhibitors, factors reducing the effect of dolutegravir should be avoided. These include concomitant use of medicinal products that reduce dolutegravir concentrations (such as antacids containing magnesium/aluminum, iron or calcium supplements, multivitamins, stimulants, etravirine [without boosted protease inhibitors], tipranavir/ritonavir, rifampicin, St. John’s wort, and certain antiepileptic drugs).

Dolutegravir increases metformin concentrations. Dose adjustment of metformin should be considered at initiation and discontinuation of concomitant dolutegravir and metformin for glycemic control. Metformin is eliminated by the kidneys; therefore, renal function should be monitored during concomitant treatment with dolutegravir. This combination may increase the risk of lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45–59 mL/min), so a cautious approach is recommended. The physician should consider adjusting the metformin dose.

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, and high body mass index), cases have been reported in patients with advanced HIV infection and/or long-term CART exposure. Patients should be advised to consult a physician if they experience joint pain, stiffness, or difficulty moving.

Nephrotoxicity

The potential risk of nephrotoxicity due to long-term low-dose exposure to tenofovir from tenofovir alafenamide cannot be excluded.

Renal function should be assessed in all patients before or at the start of treatment with the medicinal product and monitored during treatment in all patients as clinically indicated. Discontinuation of the medicinal product should be considered if patients develop clinically significant renal function decline or signs of proximal renal tubulopathy.

Patients with end-stage renal disease on chronic hemodialysis

The medicinal product should generally be avoided; however, it may be used in adults with end-stage renal disease (estimated CrCl < 15 mL/min) on chronic hemodialysis if the potential benefit outweighs the potential risk. In a study of the combination of emtricitabine + tenofovir alafenamide with elvitegravir + cobicistat as a fixed-dose combination tablet in HIV-infected adults with end-stage renal disease (estimated CrCl < 15 mL/min) on chronic hemodialysis, efficacy was maintained over 48 weeks, but emtricitabine exposure was significantly higher than in patients with normal renal function. Although no new safety concerns were identified, the consequences of increased emtricitabine exposure remain uncertain.

Concomitant use of other medicinal products

Concomitant use of the medicinal product with anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, and phenytoin), antimycobacterial agents (rifampicin, rifabutin, rifapentine), St. John’s wort, and HIV protease inhibitors other than atazanavir, lopinavir, and darunavir is not recommended.

The medicinal product should not be used concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine, or adefovir dipivoxil.

Excipients

The medicinal product contains 120 mg of lactose monohydrate. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Women of childbearing potential should be counselled about the potential risk of neural tube defects in newborns (see below) and advised to use effective contraception before initiating dolutegravir.

If a woman plans to become pregnant, the benefits and risks of dolutegravir treatment should be evaluated.

Pregnancy

In a Botswana birth outcomes surveillance study, a slightly increased incidence of neural tube defects in newborns was observed: 7 cases of neural tube defects were reported among 3,591 births (0.19%; 95% CI 0.09%, 0.40%) in women who received a dolutegravir-containing regimen from conception, compared with 21 cases among 19,361 births (0.11%; 95% CI 0.07%, 0.17%) in women who received a non-dolutegravir-containing regimen from conception.

The background incidence of neural tube defects in the general population ranges from 0.5 to 1 case per 1,000 live births (0.05–0.1%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If pregnancy is confirmed during the first trimester while on dolutegravir treatment, the benefits and risks of continuing dolutegravir should be evaluated, and a switch to alternative antiretroviral regimens should be considered based on gestational age and the critical period of neural tube defect development.

Data from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major fetal defects in over 600 women who received dolutegravir during pregnancy. However, these data are insufficient to resolve concerns regarding the risk of neural tube defects.

Reproductive toxicity studies of dolutegravir in animals did not show adverse effects on fetal development, including neural tube defects. Dolutegravir crosses the placenta in animals.

Over 1,000 outcomes of dolutegravir exposure in the second and third trimesters indicate no increased risk of fetal/neonatal toxicity. Dolutegravir may be used in the second and third trimesters of pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus.

There are no adequate and well-controlled studies of emtricitabine and tenofovir alafenamide in pregnant women. Data on the use of tenofovir alafenamide in pregnant women are lacking or limited (fewer than 300 pregnancy outcomes). However, a large number of data from pregnant women (over 1,000 identified outcomes) indicate no malformations or fetal/neonatal toxicity associated with emtricitabine use.

Animal studies do not indicate a direct or indirect harmful effect of emtricitabine on fertility, pregnancy, embryonal/fetal development, parturition, or postnatal development. Animal studies of tenofovir alafenamide showed no evidence of harmful effects on fertility, pregnancy, or fetal development.

Breastfeeding

Dolutegravir is excreted in human breast milk in small amounts.

Information on the effects of dolutegravir on newborns/infants is insufficient.

HIV-infected women should under no circumstances breastfeed their infants to avoid HIV transmission.

It is unknown whether tenofovir alafenamide is excreted in human milk. Emtricitabine is excreted in human milk. Animal studies have shown that tenofovir alafenamide is excreted in milk.

Information on the effects of emtricitabine and tenofovir alafenamide on newborns/infants is insufficient. Therefore, the medicinal product should not be used during breastfeeding.

Fertility

Data on the effect of the medicinal product on fertility in men and women are lacking. Animal studies showed no effect of dolutegravir, emtricitabine, or tenofovir alafenamide on fertility in males or females.

Ability to affect reaction speed when driving or operating machinery.

Patients should be informed that dizziness has been reported during treatment with dolutegravir, emtricitabine, and tenofovir alafenamide. The patient's clinical condition and adverse reaction profile should be considered when assessing the patient's ability to drive or operate machinery.

Method of Administration and Dosage

Therapy should be initiated by a physician experienced in the treatment of HIV infection.

Dosing

Adults and children aged 12 years and older with body weight of at least 40 kg

HIV-1-infected patients without confirmed or clinically suspected resistance to integrase inhibitors

The fixed-dose combination of dolutegravir, emtricitabine, and tenofovir alafenamide 50 mg/200 mg/25 mg should be administered orally once daily.

Adults

HIV-1-infected patients with confirmed or clinically suspected resistance to integrase inhibitors

If an HIV-1-infected patient has confirmed or suspected resistance to integrase inhibitors, additional doses of dolutegravir are required. For additional information, refer to the dolutegravir product information.

Missed Doses

If a patient misses a dose within 18 hours of the usual dosing time, the tablet should be taken as soon as possible, and the regular dosing schedule should be resumed. If a dose is missed for more than 18 hours, 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 the tablet, another tablet should be taken.

Pregnancy Testing Prior to Initiating Dolutegravir

Pregnancy testing should be performed prior to initiating dolutegravir in all patients of reproductive potential.

Elderly Patients

Data on the use of the drug in patients aged 65 years and older are limited. However, no dose adjustment of the recommended daily adult dose is necessary.

Renal Impairment

No dose adjustment is required for adults or children aged 12 years and older with body weight of at least 35 kg and a calculated creatinine clearance ≥ 30 mL/min.

The drug should not be initiated in patients with creatinine clearance < 30 mL/min, as there are no data on the use of dolutegravir, emtricitabine, and tenofovir alafenamide in this population, although differences in pharmacokinetics are not expected.

The drug should be discontinued if, during treatment, a patient's creatinine clearance decreases to below 30 mL/min.

Hepatic Impairment

No dose adjustment is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Dolutegravir, emtricitabine, and tenofovir alafenamide have not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore, the drug is not recommended for use in patients with severe hepatic impairment.

Method of Administration

The drug should be taken with food. When resistance to integrase inhibitors is present, the drug should preferably be taken with food to enhance exposure (particularly in patients with the Q148 mutation).

The film-coated tablet must not be chewed, crushed, or split.

Children

There are no data on the safety and efficacy of the drug in children under 12 years of age or with body weight < 40 kg. Insufficient data are available to recommend a dose of dolutegravir in children with resistance to integrase inhibitors.

Overdose

In case of overdose, the patient should be monitored for signs of toxicity. Management of overdose consists of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status.

Experience with dolutegravir overdose is limited.

Based on limited experience with single high doses (up to 250 mg in healthy volunteers), no additional specific symptoms were observed beyond those listed as adverse reactions.

There is no specific antidote for dolutegravir overdose. In case of overdose, the patient should receive symptomatic treatment with appropriate monitoring, if necessary. Since dolutegravir is highly protein-bound, it is unlikely that significant amounts will be removed by hemodialysis.

Up to 30% of an emtricitabine dose can be removed by hemodialysis (3-hour dialysis session) if performed within 1.5 hours after emtricitabine administration. Tenofovir is efficiently removed by hemodialysis, with an extraction coefficient of approximately 54%. It is unknown whether emtricitabine or tenofovir is removed by peritoneal dialysis.

Adverse reactions

Dolutegravir

The most severe adverse reaction observed in an individual patient was a hypersensitivity reaction, which included rash and serious liver effects. The most commonly reported adverse reactions during treatment were nausea (13%), diarrhea (18%), and headache (13%).

Emtricitabine and tenofovir alafenamide

In clinical trials, the most frequently reported adverse reactions were diarrhea (7%), nausea (11%), and headache (6%).

Summary table of adverse reactions observed with the combination of dolutegravir, emtricitabine, and tenofovir alafenamide

The adverse reactions listed in Table 3 are presented by system organ class and frequency. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Table 3

List of adverse reactions

* Especially in patients with depression or psychiatric disorders in their medical history.

** See below in the section "Description of selected adverse reactions".

*** In combination with elevated transaminases.

Description of selected adverse reactions

Changes in laboratory biochemistry

An increase in serum creatinine levels was observed during the first week of treatment with dolutegravir and remained stable through 48 weeks. The mean change from baseline was 9.96 µmol/L after 48 weeks of treatment. The increase in creatinine levels was comparable across different background regimens. These changes are not considered clinically significant, as they do not reflect a change in glomerular filtration rate.

Concomitant hepatitis B or hepatitis C virus infection

The safety profile in patients with concomitant hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection was similar to that observed in patients without concomitant infection, although higher rates of AST and ALT elevations were observed in the subgroup of patients with hepatitis B and/or C. In some patients with concomitant HBV and/or HCV infection, initiation of dolutegravir therapy was associated with increased liver chemistry tests consistent with immune reconstitution syndrome, particularly in those who discontinued anti-hepatitis B therapy.

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the start of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported onset time is more variable, and these events 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 known risk factors, advanced HIV disease, or long-term exposure to combination antiretroviral therapy. The frequency of these cases is unknown.

Changes in lipid laboratory parameters

At week 144 of treatment, increases in fasting total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides were observed in both the tenofovir alafenamide and tenofovir disoproxil fumarate treatment groups.

Metabolic parameters

During antiretroviral therapy, increases in blood lipid and glucose levels may occur.

Children

Based on limited available data on the use of dolutegravir in 172 pediatric patients (aged from 4 weeks to 18 years and with body weight of at least 3 kg), no additional types of adverse reactions were observed beyond those seen in adults.

The safety of emtricitabine and tenofovir alafenamide was evaluated over 48 weeks in an open-label clinical trial in which antiretroviral-naïve HIV-1-infected children aged 12 to 18 years received emtricitabine and tenofovir alafenamide as a fixed-dose combination tablet. The safety profile of emtricitabine and tenofovir alafenamide in 50 children was similar to that observed in adults.

Other special populations

Patients with renal impairment

The safety of emtricitabine and tenofovir alafenamide was evaluated over 144 weeks in an open-label clinical trial involving 248 patients with HIV-1 who were either antiretroviral-naïve (n = 6) or virologically suppressed (n = 242), with mild to moderate renal impairment (estimated glomerular filtration rate by Cockcroft-Gault [eGFRCG] 30–69 mL/min), who received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile in patients with mild to moderate renal impairment was similar to that in patients with normal renal function.

Patients co-infected with HIV and hepatitis B virus (HBV)

The safety of emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose tablet was evaluated in 72 patients with HIV/HBV co-infection. Given this limited experience, the safety profile of dolutegravir, emtricitabine, and tenofovir alafenamide in patients with HIV/HBV co-infection is similar to that in patients with HIV-1 monoinfection.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Packaging. 30 tablets in a bottle with desiccant or 180 tablets in a bottle with desiccant, with 1 bottle in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Mylan Laboratories Limited

Mylan Laboratories Limited

Manufacturer's address and location of operations.

Plot No. 11, 12 & 13, Indore Special Economic Zone, Pharma Zone, Phase-II, Sector-III, Pithampur, District Dhar, Madhya Pradesh, 454775, India

Marketing Authorization Holder.

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom

The medicinal product is manufactured under licenses from Gilead Sciences Inc., the Medicines Patent Pool, and ViiV Healthcare. The medicinal product is not authorized for supply to the private market. Any other use is prohibited.