Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets 50 mg/300 mg/300 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dolutegravir, Lamivudine and Tenofovir Disoproxil Fumarate Tablets 50 mg/300 mg/300 mg

Composition:

Active substances: dolutegravir, lamivudine, tenofovir disoproxil fumarate;

One film-coated tablet contains dolutegravir sodium equivalent to dolutegravir 50 mg, lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg;

Excipients: mannitol (E 421), microcrystalline cellulose*, sodium starch glycolate, povidone, lactose monohydrate, sodium croscarmellose, hypromellose, colloidal anhydrous silicon dioxide, talc, magnesium stearate, Opadry II 85F18422 White coating**;

* microcrystalline cellulose PH101 and PH112 are used;

** composition of Opadry II 85F18422 White coating: polyvinyl alcohol, macrogol, talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: bilayer convex capsule-shaped tablets with beveled edges, film-coated, white in color, embossed with "L160" on one side and smooth on the other.

Pharmacotherapeutic group.

Direct-acting antiviral agents for systemic use. Antiviral agents for the treatment of HIV infection in combination. ATC code J05A R.

Pharmacological Properties.

Pharmacodynamics.

Dolutegravir

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 nucleoside analogue.

Tenofovir disoproxil fumarate 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 (RT), leading to 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 in MT-4 cells ranged from 0.7 to 2 nM. IC50 values were similar for clinical isolates with no significant differences between subtypes (A, B, C, D, E, F, and G). The mean IC50 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.

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 effect was observed in vitro between dolutegravir and other tested antiretroviral agents such as stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, and raltegravir. Additionally, no antagonistic effect was observed between dolutegravir and adefovir: ribavirin had no significant effect on dolutegravir activity.

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

Effect of Human Serum

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

Resistance in vitro (dolutegravir)

Mutations E92Q (FC 3) and G193E (also FC 3) were observed in the NL432 strain. Mutation E92Q 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, 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 were receiving antiretroviral therapy but had not received integrase inhibitors, with no impact on dolutegravir sensitivity in vitro. 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 of raltegravir/elvitegravir (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 the NL432 strain, 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. A clinically significant level of phenotypic shift (FC against wild-type virus) was not defined; genotypic resistance was a better predictor of outcomes.

In an analysis of dolutegravir susceptibility 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 antiretroviral treatment-naïve 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 for 48–96 weeks).

In patients with prior antiretroviral treatment failure who had not received an integrase inhibitor, integrase resistance developed in 4 of 354 patients (further follow-up for 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 at Week 24 in 32 patients with protocol-defined virological failure (VPF) 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 typically occurs in patients with a history of Q148 mutation (baseline or historical). Five other subjects had VPF between Weeks 24 and 48, and 2 of these 5 had treatment-emergent mutations. The observed mutations or 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 corresponded to 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 during 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, anti-HIV activity of tenofovir against HIV-1 strains with resistance to nucleoside inhibitors was evaluated. Results indicate that patients with HIV harboring 3 or more thymidine-analogue associated mutations (TAMs), including either the M41L mutation or the reverse transcriptase L210W mutation, showed reduced response to tenofovir treatment.

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). Replication of virus with the M184V mutation is lower than that of 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 in cases of high risk of failure of the primary NRTI regimen.

Cross-resistance caused by the M184V mutation is limited to nucleoside/nucleotide inhibitors within the antiretroviral agent class. 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 QTc interval was observed when the medicinal product was administered at doses three times higher than the clinical dose.

Clinical Results

Several clinical studies have confirmed the efficacy of individual components of this fixed-dose combination product. Dolutegravir, lamivudine, and tenofovir disoproxil have been used as separate agents in various combination regimens. Clinical studies with the combination of dolutegravir, lamivudine, and tenofovir disoproxil have not been conducted.

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.

Dolutegravir

The pharmacokinetics of dolutegravir are similar in healthy volunteers and HIV-infected patients. The variability of dolutegravir pharmacokinetics is low to moderate. The absolute bioavailability of dolutegravir has not been determined.

Absorption

Dolutegravir is rapidly absorbed after oral administration, with a median time to reach maximum concentration (Tmax) of 2–3 hours after tablet intake.

Food intake increased the extent and slowed the rate of absorption of dolutegravir. Dolutegravir bioavailability depends on food composition: low-, medium-, and high-fat meals increased the area under the concentration-time curve (AUC(0–∞)) of dolutegravir by 33%, 41%, and 66%, increased maximum concentration (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 certain resistance to integrase inhibitor class drugs. Therefore, the medicinal product is recommended to be taken with food in HIV-infected patients with resistance to integrase inhibitor class drugs (see section "Dosage and Administration").

The absolute bioavailability of dolutegravir has not been determined.

Distribution

Dolutegravir has a high binding capacity (> 99%) to plasma proteins, as determined from in vitro data. The apparent volume of distribution is 17–20 L in HIV-infected patients based on population pharmacokinetic analysis. Total blood-to-plasma and plasma-to-serum ratios of radioactivity associated with the drug range from 0.441 to 0.535, indicating minimal binding of radioactivity to blood cellular components. The unbound fraction of dolutegravir in plasma increases at 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 dolutegravir regimen in combination with abacavir/lamivudine, the concentration of dolutegravir in CSF averaged 18 ng/mL (at the level of unbound drug concentration in plasma and above IC50).

Dolutegravir is detected in the genital tract of males and females. AUC in cervical-vaginal secretions, cervical tissue, and vaginal tissue was 6–10% of the corresponding plasma value at steady state. AUC in seminal fluid 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 minor extent by CYP3A. Dolutegravir circulates predominantly 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 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).

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 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 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, and Tmax was 1.03 (± 0.60) hours.

When tenofovir disoproxil fumarate was taken with a high-fat meal, oral bioavailability increased, with AUC of tenofovir increasing 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 filtration and active tubular transport, with approximately 70–80% of the dose excreted unchanged in urine after intravenous administration. Total clearance was approximately 230 mL/h/kg (approximately 300 mL/min). Renal clearance was observed at the rate of glomerular filtration of approximately 160 mL/h/kg (approximately 210 mL/min). This indicates that tubular secretion is an important part 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, while in phytohemagglutinin-stimulated PBMCs it is approximately 10 hours.

A study demonstrated 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 multidrug resistant protein 4 (MRP 4).

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

Lamivudine

Lamivudine is rapidly absorbed after oral administration.

Lamivudine bioavailability is 80–85%.

Cmax and AUC values were 27.2% and 22.5%, respectively, and 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% 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, as only a small amount of lamivudine is metabolized by the liver (5–10%) and protein binding in plasma is low.

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. In a PK study in children aged 6 to 12 years, 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 showed that weight-based dosing (20 mg, 25 mg, 35 mg, and 50 mg) in children aged 6 years and older with body weight ≥15 kg provides exposure comparable to that in adults (50 mg), with the lowest weight range of 15–20 kg corresponding to a 20 mg daily dose.

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

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

Limited data are available for 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 aged 65 years and older 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 volunteers. 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, the medicinal product 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 the dosing interval in patients with renal impairment will result in higher peak plasma concentrations and lower Cmin compared to patients with normal renal function. The clinical consequences of this are unknown.

In patients with end-stage renal disease (ESRD) (creatinine clearance <10 mL/min) requiring hemodialysis, tenofovir concentration between dialysis sessions significantly increases over 48 hours, reaching a mean Cmax of 1032 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.

The 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 patients with moderate hepatic impairment (Child-Pugh class B) and 8 healthy adult controls, 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 volunteers. Dose adjustment is not considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on dolutegravir pharmacokinetics has not been studied.

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

Polymorphisms in Drug-Metabolizing Enzymes

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

Sex

Analysis of pooled pharmacokinetic data from studies in 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 the effect of sex on pharmacokinetic parameters.

Race

Analysis of pooled pharmacokinetic data from studies in 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 the effect of race on pharmacokinetic parameters.

Concurrent 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.

Treatment of adults and children aged 12 years and older with body weight greater than 40 kg who are 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 types of interactions").

Interaction with other medicinal products and other types of interactions.

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

Dolutegravir

Effect of other medicinal products on the pharmacokinetics of dolutegravir

When resistance to integrase inhibitor class drugs exists, factors that reduce 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 (breast cancer resistance protein); 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.

Absorption of dolutegravir is reduced by certain antacids (see Table 1).

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 transporter protein organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE-1). In vivo, in patients, a 10–14% reduction in creatinine clearance has been observed (the secretory component 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 dofetilide, 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 individual antiretroviral and other medicinal products are listed in Table 1; 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 due to 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 "Posology and method of 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-dose 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, particularly when the primary route of elimination is active renal secretion via the organic cation transport system, such as trimethoprim. Other medicinal products (e.g., ranitidine, cimetidine) are partially eliminated via this mechanism, but have been shown not to interact with lamivudine. Nucleoside analogues (e.g., didanosine), such as zidovudine, are not eliminated by this mechanism and are unlikely to interact with lamivudine.

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

Due to similarity, lamivudine should not be used concomitantly with other cytidine analogues such as emtricitabine. The combination should also not be used 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 warnings and precautions for use").

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 in lamivudine AUC∞ by 14%, 32%, and 36%, and in Cmax by 28%, 52%, and 55% in adults. If possible, prolonged concomitant use of the medicinal product 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.

Tenofovir-mediated interactions

Didanosine. Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended.

Medicinal products eliminated by the kidneys. Since tenofovir is primarily eliminated by the kidneys, concomitant use of tenofovir disoproxil fumarate with medicinal products that impair renal function or compete for active tubular secretion via hOAT1, hOAT3, or MRP4 transporters (e.g., cidofovir) may increase serum concentrations of tenofovir and/or concomitantly administered medicinal products.

Concomitant use of tenofovir disoproxil fumarate with nephrotoxic medicinal products (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2) should be avoided.

Since tacrolimus may affect renal function, careful monitoring of the patient is recommended when it is prescribed together with tenofovir disoproxil fumarate.

Interactions between the combination of dolutegravir, lamivudine, and tenofovir disoproxil and concomitantly administered medicinal products are listed in Table 1 (increases are denoted by ↑, decreases by ↓, no change by ↔, area under the concentration–time curve by AUC, maximum observed concentration by Cmax, concentration at the end of the dosing interval by Cτ).

Table 1

Medicinal products by therapeutic effect	Interaction (changes shown as geometric mean)	Recommendations for concomitant use
ANTIMICROBIALS
Antiretrovirals
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Etravirine without protease inhibitor boosting/ dolutegravir	Dolutegravir ↓ AUC ↓ 71 %; Cmax ↓ 52 %; Cτ ↓ 88 % Etravirine ↔ (induction of UGT1A1 and CYP3A enzymes)	Etravirine reduces dolutegravir plasma concentrations. The recommended dose of dolutegravir for adults is 50 mg twice daily when coadministered with etravirine without protease inhibitor boosting. For pediatric patients, the body weight-based daily dose should be divided into two administrations. When etravirine is used in cases of integrase inhibitor-resistant infections, dolutegravir should be coadministered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.
Lopinavir/ritonavir + etravirine/dolutegravir Lopinavir/ritonavir + tenofovir disoproxil	Dolutegravir ↔ AUC ↑ 11 %; Cmax ↑ 7 %; Cτ ↑ 28 % LPV ↔ RTV ↔ No significant effect on pharmacokinetic parameters of lopinavir/ritonavir Tenofovir: AUC ↑ 32 %; Cmax ↔; Cmin ↑ 51 %	No dose adjustment required
Darunavir/ritonavir + etravirine/dolutegravir	Dolutegravir ↓ AUC ↓ 25 %; Cmax ↓ 12 %; Cτ ↓ 36 % DRV ↔ RTV ↔	No dose adjustment required
Efavirenz/dolutegravir	Dolutegravir ↓ AUC ↓ 57 %; Cmax ↓ 39 %; Cτ ↓ 75% Efavirenz ↔ (historical controls) (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir for adults is 50 mg twice daily when coadministered with efavirenz. For pediatric patients, the body weight-based daily dose should be divided into two administrations. In case of integrase inhibitor-resistant infection, alternative combinations not including efavirenz should be considered.
Nevaripine/dolutegravir	Dolutegravir ↓ (not studied, expected reduction in exposure similar to that with efavirenz due to induction)	The recommended dose of dolutegravir for adults is 50 mg twice daily when coadministered with nevirapine. For pediatric patients, the body weight-based daily dose should be divided into two administrations. In case of integrase inhibitor-resistant infection, alternative combinations not including nevirapine should be considered.
Rilpivirine/ dolutegravir	Dolutegravir ↔ AUC ↑ 12 %; Cmax ↑ 13 %; Cτ ↑ 22 % Rilpivirine ↔	No dose adjustment required
Nucleoside reverse transcriptase inhibitors (NRTIs)
Emtricitabine/ lamivudine		The drug should not be coadministered due to similarity with emtricitabine and lamivudine, hence expected additional toxicity and lack of increased efficacy.
Didanosine/tenofovir disoproxil	Didanosine AUC ↑ 40–60 %	The risk of didanosine-related adverse effects (e.g., pancreatitis, lactic acidosis) is likely increased, and CD4 cell count may significantly decrease with concomitant use. Also, didanosine at a dose of 250 mg taken together with tenofovir disoproxil in several different antiretroviral combination regimens was associated with a high rate of virological failure. Concomitant use of the drug with didanosine is not recommended (see section "Special precautions").
Adefovir dipivoxil/ tenofovir disoproxil	AUC ↔ Cmax ↔	Tenofovir disoproxil should not be coadministered with adefovir dipivoxil (see section "Special precautions").
Entecavir/tenofovir disoproxil	AUC ↔ Cmax ↔	No clinically significant pharmacokinetic interactions were observed when tenofovir disoproxil was coadministered with entecavir.
Protease inhibitors (PIs)
Atazanavir/dolutegravir Atazanavir/tenofovir disoproxil	Dolutegravir ↑ AUC ↑ 91 %; Cmax ↑ 50 %; Cτ ↑ 180 % Atazanavir ↔ (historical controls) (inhibition of UGT1A1 and CYP3A enzymes) Atazanavir: AUC ↓ 25 %; Cmax ↓ 21 %; Cmin ↓ 40 % Tenofovir: AUC ↑ 24 %; Cmax ↑ 14 %; Cmin ↑ 22 %	The dose of dolutegravir should not exceed 50 mg twice daily in combination with atazanavir. When atazanavir is coadministered with the combination of dolutegravir, lamivudine, and tenofovir disoproxil, the dose of atazanavir coadministered with 100 mg ritonavir should be 300 mg once daily (for ritonavir boosting, see information below)
Atazanavir + ritonavir/ dolutegravir Atazanavir + ritonavir/ tenofovir disoproxil	Dolutegravir ↑ AUC ↑ 62 %; Cmax ↑ 34 %; Cτ ↑ 121 % Atazanavir ↔ Ritonavir ↔ (inhibition of UGT1A1 and CYP3A enzymes) Tenofovir: AUC ↑ 37 %; Cmax ↑ 34 %; Cmin ↑ 29 % Atazanavir: AUC ↓ 25 %; Cmax ↓ 28 %; Cmin ↓ 26 %	No dose adjustment required. The dose of dolutegravir should not exceed 50 mg twice daily in combination with atazanavir. Increased exposure to tenofovir may potentiate tenofovir-related adverse events, including renal disorders. Renal function should be closely monitored.
Tipranavir + ritonavir/ dolutegravir	Dolutegravir ↓ AUC ↓ 59 %; Cmax ↓ 47 %; Cτ ↓ 76 % (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir for adults is 50 mg twice daily when coadministered with tipranavir/ritonavir. For pediatric patients, the body weight-based daily dose should be divided into two administrations. In case of integrase inhibitor-resistant infection, alternative combinations not including nevirapine should be considered.
Fosamprenavir + ritonavir/dolutegravir	Dolutegravir ↓ AUC ↓ 35 %; Cmax ↓ 24 %; Cτ ↓ 49 % (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment required in the absence of integrase class resistance. In case of integrase inhibitor-resistant infection, alternative combinations not including fosamprenavir/ritonavir should be considered.
Darunavir + ritonavir/ dolutegravir Darunavir + ritonavir/ tenofovir disoproxil	Dolutegravir ↓ AUC ↓ 22 %; Cmax ↓ 11 %; C24h ↓ 38 % (induction of UGT1A1 and CYP3A enzymes) Darunavir: No significant effect on pharmacokinetic parameters of darunavir/ritonavir Tenofovir: AUC ↑ 22 %; Cmin ↑ 37 %	No dose adjustment required. Increased exposure to tenofovir may potentiate tenofovir-related adverse reactions, including renal disorders. Renal function should be closely monitored.
Lopinavir + ritonavir/ dolutegravir Lopinavir + ritonavir/ tenofovir disoproxil	Dolutegravir ↔ AUC ↓ 4 %; Cmax ↔ 0 %; C24h ↓ 6 % Lopinavir/ritonavir: No significant effect on pharmacokinetic parameters of lopinavir/ritonavir Tenofovir: AUC ↑ 32 %; Cmin ↑ 51 %	No dose adjustment required. Increased exposure to tenofovir may potentiate tenofovir-related adverse reactions, including renal disorders. Renal function should be closely monitored.
Antiviral agents for hepatitis C
Daclatasvir/ dolutegravir Daclatasvir/ tenofovir disoproxil	Dolutegravir ↔ AUC ↑ 33 %; Cmax ↑ 29 %; Cτ ↑ 45 % Tenofovir ↔ AUC ↑ 10 %; Cmax ↓ 5 %; Cmin ↑ 17 % Daclatasvir ↔ ↔ Daclatasvir AUC 1.10 (1.01; 1.21); Cmax 1.06 (0.98; 1.15); Cmin 1.15 (1.02; 1.30) ↔ Tenofovir AUC 1.10 (1.05; 1.15); Cmax 0.95 (0.89; 1.02); Cmin 1.17 (1.10; 1.24)	No dose adjustment required.
Sofosbuvir/tenofovir disoproxil	Tenofovir ↑ Cmax 1.25 (1.08; 1.45); ↔ AUC 0.98 (0.91; 1.05); ↔ Cmin 0.99 (0.91; 1.07) Sofosbuvir ↓ Cmax 0.81 (0.60; 1.10); ↔ AUC 0.94 (0.76; 1.16); Cmin (NA) GS-331007 (major inactive metabolite of sofosbuvir) ↓ Cmax 0.77 (0.70; 0.84); ↔ AUC 0.84 (0.76; 0.92); Cmin (NA)	No dose adjustment of sofosbuvir or the drug is required when coadministered.
Ledipasvir/sofosbuvir + dolutegravir + tenofovir disoproxil (+ emtricitabine)	Sofosbuvir: AUC ↔; Cmax ↔ GS-3310072 AUC ↔; Cmax ↔; Cmin ↔ Ledipasvir: AUC ↔; Cmax ↔; Cmin ↔ Dolutegravir AUC ↔; Cmax ↔; Cmin ↔ Emtricitabine: AUC ↔; Cmax ↔; Cmin ↔ Tenofovir: AUC ↑ 65 %; Cmax ↑ 61 %; Cmin ↑ 115 %	Monitor for tenofovir-related adverse reactions in patients receiving ledipasvir/ sofosbuvir concomitantly with the drug. Renal function should be closely monitored (see section "Special precautions").
Sofosbuvir/velpatasvir + tenofovir disoproxil	Sofosbuvir: AUC ↔; Cmax ↔ GS-3310072: AUC ↔; Cmax ↔ ; Cmin ↑ 42 % Velpatasvir: AUC ↑ 142 %; Cmax ↑ 55 %; Cmin ↑ 301 % Tenofovir: AUC ↔; Cmax ↑ 55 %; Cmin ↑ 39 %	Sofosbuvir/velpatasvir has been shown to increase the effect of tenofovir (inhibition of P-gp). The increase in tenofovir exposure (AUC and Cmax) was approximately 40–80% when coadministered with sofosbuvir/velpatasvir in various HIV treatment regimens. The safety of tenofovir disoproxil when coadministered with sofosbuvir/velpatasvir and a pharmacokinetic booster (e.g., ritonavir or cobicistat) has not been established. Patients receiving tenofovir disoproxil and sofosbuvir/velpatasvir concomitantly should be monitored for tenofovir disoproxil-related adverse reactions (see section "Special precautions").
Sofosbuvir/ velpatasvir/ voxilaprevir + tenofovir disoproxil (+ emtricitabine + darunavir/ritonavir)	Sofosbuvir: AUC ↔; Cmax ↓ 30 %; Cmin N/A GS-3310072: AUC ↔; Cmax↔; Cmin N/A Velpatasvir: AUC ↔; Cmax ↔ ; Cmin ↔ Voxilaprevir: AUC ↑ 143 %; Cmax↑ 72 %; Cmin ↑ 300 % Darunavir: AUC ↔; Cmax ↔; Cmin ↓ 34 % Ritonavir: AUC ↑ 45 %; Cmax↑ 60 %; Cmin ↔ Emtricitabine: AUC ↔; Cmax ↔; Cmin ↔ Tenofovir: AUC ↑ 39 %; Cmax ↑ 48 %; Cmin ↑ 47 %	Sofosbuvir/velpatasvir/voxilaprevir has been shown to increase the effect of tenofovir (inhibition of P-gp). The increase in tenofovir exposure (AUC and Cmax) was approximately 40% when coadministered with sofosbuvir/velpatasvir/voxilaprevir and darunavir + ritonavir + tenofovir disoproxil/emtricitabine. The safety of tenofovir disoproxil when coadministered with sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic booster (e.g., ritonavir or cobicistat) has not been established. Patients receiving tenofovir disoproxil and sofosbuvir/velpatasvir/voxilaprevir concomitantly should be monitored for tenofovir disoproxil-related adverse reactions (see section "Special precautions").
Antibiotics
Rifampicin/ dolutegravir	Dolutegravir ↓ AUC ↓ 54 %; Cmax ↓ 43 %; Cτ ↓ 72 % (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir for adults is 50 mg twice daily when coadministered with rifampicin. For pediatric patients, the body weight-based daily dose should be divided into two administrations. In case of integrase inhibitor-resistant infection, concomitant use of dolutegravir and rifampicin should be avoided.
Rifabutin/dolutegravir	Dolutegravir ↔ AUC ↓ 5 %; Cmax ↑ 16 %; Cτ ↓ 30 % (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment required.
Antifungal agents
Fluconazole Itraconazole Ketoconazole Posaconazole Voriconazole		Theoretically, no interaction with dolutegravir, tenofovir disoproxil, or lamivudine is expected.
Antiepileptic drugs
Carbamazepine/ dolutegravir	Dolutegravir ↓ AUC ↓ 49 %; Cmax ↓ 33 %; Cτ ↓ 73 %	The recommended dose of dolutegravir for adults is 50 mg twice daily when coadministered with carbamazepine. For pediatric patients, the body weight-based daily dose should be divided into two administrations. An alternative to carbamazepine should be used in patients with integrase inhibitor-resistant infection.
Oxcarbazepine/ dolutegravir Phenytoin/dolutegravir Phenobarbital/ dolutegravir	Dolutegravir ↓ (not studied; expected reduction due to induction of UGT1A1 and CYP3A enzymes; expected reduction in exposure similar to that observed with carbamazepine)	The recommended dose of dolutegravir for adults is 50 mg twice daily when coadministered with these metabolic inducers. For pediatric patients, the body weight-based daily dose should be divided into two administrations. For patients with integrase inhibitor resistance, alternative combinations to these metabolic inducers should be considered if possible.
Antiarrhythmic agents
Dofetilide/ dolutegravir	Dofetilide ↑ (not studied, expected increase due to inhibition of OCT2 transporter)	Concomitant use of dolutegravir and dofetilide is contraindicated due to potentially life-threatening risk from high dofetilide concentration.
Potassium channel blockers
Fampridine (also known as dalfampridine)/ dolutegravir	Fampridine ↑	Concomitant use of dolutegravir may cause seizures due to increased plasma concentration of fampridine via inhibition of the OCT2 transporter. Concomitant use has not been studied and is therefore contraindicated.
Antacids and supplements
Antacid containing magnesium or aluminium/ dolutegravir	Dolutegravir ↓ AUC ↓ 74 %; Cmax ↓ 72 % (chelation with polyvalent ions)	Antacids containing magnesium or aluminium should not be coadministered with dolutegravir (administer at least 6 hours before or 2 hours after dolutegravir).
Calcium supplements/ dolutegravir	Dolutegravir ↓ AUC ↓ 39 %; Cmax ↓ 37 %; C24h ↓ 39 % (chelation with polyvalent ions)	Calcium supplements, iron supplements, or multivitamins should not be coadministered with dolutegravir (administer at least 6 hours before or 2 hours after dolutegravir).
Iron supplements/ dolutegravir	Dolutegravir ↓ AUC ↓ 54 %; Cmax ↓ 57 %; C24h ↓ 56 % (chelation with polyvalent ions)
Multivitamins/ dolutegravir	Dolutegravir ↓ AUC ↓ 33 %; Cmax ↓ 35 % C24h ↓ 32 % (chelation with polyvalent ions)
Antidiabetic agents
Metformin/ dolutegravir	With 50 mg dolutegravir once daily: metformin ↑ AUC ↑ 79 %; Cmax ↑ 66 % With 50 mg dolutegravir twice daily: metformin ↑ AUC ↑ 145 %; Cmax ↑ 111 %	Dose adjustment of metformin is required at the initiation and discontinuation of concomitant dolutegravir with metformin to maintain glycemic control. Dose adjustment of metformin should be considered in patients with moderate renal impairment when dolutegravir is prescribed, as the risk of lactic acidosis increases in patients with moderate renal dysfunction due to increased metformin concentration.
Contraceptives
Ethinylestradiol and norelgestromin/ dolutegravir	Dolutegravir ↔ Ethinylestradiol ↔ AUC ↑ 3 %; Cmax ↓ 1 % Norelgestromin ↔ AUC ↓ 2 %; Cmax ↓ 11 %	Dolutegravir had no pharmacodynamic effect on luteinizing hormone, follicle-stimulating hormone, or progesterone. No dose adjustment of oral contraceptives is required when coadministered with dolutegravir.
Corticosteroids
Prednisone/dolutegravir	Dolutegravir ↔ AUC ↑ 11 %; Cmax ↑ 6 %; Cτ ↑ 17 %	No dose adjustment required.
Drug abuse
Methadone/dolutegravir	Dolutegravir ↔ Methadone ↔ AUC ↓ 2 %; Cmax ↔ 0 %; Cτ ↓ 1 %	No dose adjustment required.
Herbal products
St. John's wort/dolutegravir	Dolutegravir ↓ (not studied; expected reduction due to induction of UGT1A1 and CYP3A enzymes; expected reduction in exposure similar to that observed with carbamazepine)	The recommended dose of dolutegravir for adults is 50 mg twice daily when coadministered with St. John's wort. For pediatric patients, the body weight-based daily dose should be divided into two administrations. An alternative to St. John's wort should be used in patients with integrase inhibitor-resistant infection.

Special precautions.

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

HIV transmission

Effective antiviral therapy can substantially reduce the risk of sexual transmission of HIV. However, the risk may not be completely eliminated. Therefore, preventive safety measures should be taken in accordance with national and other authoritative recommendations 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 medications should be discontinued immediately if hypersensitivity reactions develop (severe rash or rash accompanied by elevated liver enzymes, fever, malaise, fatigue, muscle or joint pain, blisters, 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 medications upon the onset of hypersensitivity reactions may lead to a life-threatening allergic reaction.

Immune reconstitution syndrome

In HIV-infected patients with severe immune deficiency at the start of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, 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 to occur during immune recovery. However, the reported onset of these conditions is more variable, and such events may occur many months after initiation of 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 the medicinal product 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. The medicinal product 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 for lamivudine and tenofovir disoproxil, which cannot be achieved with the fixed-dose combination tablet (see sections "Pharmacokinetics" and "Posology and method of administration"). Renal failure, renal dysfunction, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported during clinical use of tenofovir disoproxil (see section "Adverse reactions").

It is recommended to calculate creatinine clearance/estimated glomerular filtration rate (eGFR) in all patients before initiating therapy and, if clinically appropriate, during treatment. If creatinine testing is routinely available, the calculated eGFR at baseline should be used before initiating therapy containing tenofovir disoproxil. If creatinine testing is not routinely available, urine dipstick testing for glycosuria or significant nephrotoxicity of tenofovir disoproxil may be used in patients without risk factors. Creatinine testing is particularly recommended for patients at high risk of developing renal impairment (elderly patients, those with pre-existing kidney disease, long-standing diabetes, uncontrolled hypertension, or receiving protease inhibitors or nephrotoxic drugs) to detect and prevent further progression of renal failure. 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 below 50 ml/min in any patient receiving this medicinal product, renal function should be re-evaluated within one week, including measurement of blood glucose, serum potassium concentration, and urine glucose (see section "Adverse reactions", proximal tubulopathy). Since the dosing interval of individual components of the fixed-dose combination cannot be modified, treatment with this medicinal product must be interrupted in patients with confirmed creatinine clearance < 50 ml/min or serum phosphate levels decreasing to < 1.0 mg/dL (0.32 mmol/L).

Temporary interruption of treatment should also be considered in cases of progressive decline in renal function when no other cause is identified. If discontinuation of one component or dose adjustment of one of the active substances is necessary, individual dolutegravir, lamivudine, and tenofovir disoproxil products should be used.

The medicinal product should be avoided when concomitant or recent use of nephrotoxic drugs is present (e.g., high or repeated doses of non-steroidal anti-inflammatory drugs, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2). If concomitant use of the medicinal product and nephrotoxic drugs is necessary, renal function should be monitored weekly (see section "Interaction with other medicinal products and other forms of interaction").

Tenofovir disoproxil has not been clinically evaluated in patients receiving drugs eliminated via the same renal pathway, including human organic anion transporters (hOAT) 1 and 3 or MRP4 (e.g., cidofovir, a known nephrotoxic drug). These renal transport proteins may be responsible for tubular secretion and partially for renal elimination of tenofovir and cidofovir. Therefore, the pharmacokinetics of drugs secreted via the same renal pathway, including hOAT1 and hOAT3 or MRP4, may be altered when co-administered. Concomitant use of drugs eliminated via the same renal pathway is not recommended except in cases of extreme necessity; however, if such use is necessary, renal function should be monitored weekly (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients

Renal function is more frequently reduced in elderly patients; therefore, caution should be exercised when administering tenofovir disoproxil to such patients.

Bone effects

In a controlled clinical trial in adults comparing tenofovir disoproxil and stavudine (each in combination with lamivudine and efavirenz), bone mineral density (BMD) of the spine decreased and bone biomarkers changed from baseline in both treatment groups, but changes were significantly greater in the tenofovir disoproxil group at week 144. Femoral BMD reduction was significantly higher in this group up to week 96. However, fracture risk was not increased over 144 weeks, and there were no data on clinically significant bone abnormalities.

In other studies, the most pronounced BMD reduction was observed in patients receiving tenofovir disoproxil as part of a regimen containing protease inhibitors boosted with ritonavir or cobicistat.

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

In HIV-1-infected adolescents aged 12 years and older, mean bone growth was lower in the tenofovir disoproxil group compared to the placebo group. No effect on skeletal growth was observed. Bone turnover markers in adolescents receiving tenofovir disoproxil suggest increased bone turnover, consistent with effects seen in adults. Due to the potential impact of tenofovir on bone metabolism, the medicinal product should be used in adolescents under 18 years of age only when the expected benefit outweighs the potential risk (see also section "Adverse reactions").

Bone abnormalities (rarely leading to fractures) may be associated with proximal renal tubulopathy (see section "Adverse reactions"). If bone disorders are suspected, appropriate consultation should be obtained.

Osteonecrosis

Osteonecrosis has been reported, particularly in patients with advanced HIV disease or after prolonged cART. The etiology may be multifactorial and include corticosteroid use, alcohol abuse, severe immunosuppression, and high body mass index. Patients should be advised to seek medical attention if they experience joint pain, joint stiffness, or difficulty moving.

Hepatic function

The safety and efficacy of the medicinal product have not been established in patients with significant pre-existing hepatic disorders. Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during cART and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

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

Healthcare providers should consider current appropriate guidelines for optimal management of HIV infection in patients co-infected with HCV or HBV.

In patients with chronic hepatitis B or C receiving cART, there is an increased risk of severe and potentially fatal hepatic adverse reactions. When concomitant antiviral therapy for hepatitis B or C is administered, the relevant information for these medicinal products should also be considered.

Lamivudine and tenofovir disoproxil are also active against HBV. Therefore, discontinuation of the medicinal product in patients co-infected with HIV and HBV may be associated with severe exacerbation of hepatitis. Patients co-infected with HIV and HBV who discontinue the medicinal product require careful clinical and laboratory monitoring for at least 6 months after stopping treatment. If necessary, resumption of hepatitis B therapy may be warranted. Discontinuation of treatment is not recommended in patients with advanced liver disease or cirrhosis, as hepatitis flare after discontinuation may lead to hepatic decompensation.

Hepatitis flare

Flare during treatment. Spontaneous flares in chronic hepatitis B are relatively common and are characterized by transient increases in serum alanine aminotransferase (ALT) levels. After initiation of antiviral therapy, serum ALT levels may increase in some patients (see section "Adverse reactions"). In patients with compensated liver disease, ALT elevation is usually not accompanied by increased serum bilirubin or hepatic decompensation. Patients with cirrhosis may have a higher risk of hepatic decompensation following hepatitis flare, and therefore, these patients should be closely monitored during therapy.

Flare after discontinuation of treatment. Hepatitis flare has been reported in patients who discontinued hepatitis B therapy. Flares after treatment are usually associated with increased HBV DNA, and most are likely to resolve spontaneously. However, severe flares, including fatal cases, have been reported. Liver function should be monitored regularly, both clinically and by laboratory tests, for at least 6 months after discontinuation of hepatitis B therapy. If necessary, resumption of hepatitis B therapy may be considered. Discontinuation of treatment is not recommended in patients with advanced liver disease or cirrhosis, as hepatitis flare after discontinuation may lead to hepatic decompensation.

Hepatic flares are particularly serious and sometimes fatal in patients with decompensated liver disease.

Antiviral agents for HCV

Concomitant use of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, especially when used together with HIV therapy containing tenofovir disoproxil and a pharmacokinetic booster. Therefore, patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil should be monitored for adverse reactions associated with tenofovir disoproxil.

Concomitant use with other medicinal products

The fixed-dose combination should not be used concomitantly with other medicinal products containing the active components dolutegravir, lamivudine, or tenofovir disoproxil.

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

Concomitant use of tenofovir disoproxil and didanosine is not recommended, as the effect of didanosine is significantly increased after concomitant administration with tenofovir disoproxil (see section "Interaction with other medicinal products and other forms of interaction"). Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported.

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

There are no data on the safety and efficacy of using the fixed-dose combination of dolutegravir, lamivudine, and tenofovir disoproxil in combination with other antiretroviral agents.

Opportunistic infections

Opportunistic infections and other HIV-related complications may continue to occur in patients receiving the medicinal product or any other antiretroviral therapy. Therefore, patients should remain under close clinical supervision by healthcare providers experienced in managing HIV infection.

Body weight and metabolic parameters

During antiretroviral therapy, increases in body weight, lipid levels, and blood glucose may occur. These changes may be partly related to the degree of disease control and lifestyle. Evidence suggests treatment may influence lipid increases in some cases, whereas there is no strong evidence linking body weight gain to a specific treatment. Recommendations for monitoring lipid and blood glucose levels during HIV treatment should be established. Lipid disorders should be managed as clinically necessary.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues may cause mitochondrial damage of varying degrees. Mitochondrial dysfunction has been reported in HIV-negative infants exposed in utero or postnatally to nucleoside analogues; this primarily concerns regimens containing zidovudine. The main adverse reactions are hematological (anemia, neutropenia) and metabolic (hyperlactatemia, hyperlipasemia). These reactions are often transient. Some late-onset neurological disorders (hypertonia, seizures, behavioral disturbances) have been reported. Whether these neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside or nucleotide analogues, even if HIV-negative, should undergo clinical and laboratory evaluation for possible mitochondrial dysfunction if appropriate signs or symptoms are present. These findings do not affect national recommendations for antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Excipients

This medicinal product contains sodium. Caution should be exercised when administering it to patients on a sodium-controlled diet.

The medicinal product contains lactose and should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains mannitol, which may have a mild laxative effect.

Use during pregnancy or breastfeeding.

Pregnancy

Dolutegravir

Preliminary data from an observational study showed an increased incidence of neural tube defects (NTDs) (0.67%) in fetuses when mothers took dolutegravir at conception compared to the corresponding incidence with antiretroviral therapy not containing dolutegravir (0.1%). However, review of more mature study results, data from other countries, population-level risk modeling, and the overall benefits of dolutegravir use in women of reproductive age indicate that the risk of NTDs is lower than initially reported, with a weighted estimated risk of 0.36% (95% CI 0.01–0.62). Although the risk of NTDs remains statistically higher than with other antiretroviral drugs and the background rate, the absolute risk remains very low. Ongoing surveillance is required to definitively confirm or refute the information on increased NTD incidence, and several studies are ongoing.

NTDs occur within the first 4 weeks of fetal development (after which neural tubes close). Available data suggest that any increased risk is associated with dolutegravir exposure during the periconception period, not later in pregnancy.

This same observational study indicates that use of dolutegravir and antiretroviral therapy containing efavirenz (comparator) later in pregnancy yields comparable pregnancy outcomes.

Dolutegravir has been shown to cross the placenta in animals. Reproductive toxicity studies in animals did not reveal adverse developmental outcomes, including NTDs.

Active studies and surveillance of pregnant women exposed to dolutegravir at conception are ongoing. More than 1000 outcomes of dolutegravir exposure in the second and third trimesters do not indicate an increased risk of birth defects.

Women in the first trimester of pregnancy should be informed about the possible increased risk of NTDs in the fetus with dolutegravir use. Antiretroviral therapy regimens may be modified based on individual benefit/risk assessment and local circumstances.

More than 1000 outcomes of dolutegravir exposure in women during the second and third trimesters indicate no increased risk of adverse birth outcomes.

Lamivudine and tenofovir disoproxil

Animal studies do not indicate direct or indirect harmful effects of tenofovir disoproxil or lamivudine on reproductive function. The safety of tenofovir use in pregnant women has not been definitively established. However, a sufficient number of first-trimester exposures to these drugs in women have been monitored to detect at least a twofold increase in the risk of overall congenital defects. Studies have shown no increase in congenital malformations with lamivudine or tenofovir disoproxil use.

Women of reproductive potential

Despite the low absolute risk, there remains a possibility of approximately a threefold increased risk of NTDs in fetuses when women take dolutegravir during the periconception period compared to other HIV drugs, including efavirenz. Women should be informed about the benefits and risks to make an informed choice regarding dolutegravir use or alternative antiretroviral therapy. The choice of an alternative regimen may vary based on individual benefit/risk assessment and local circumstances.

If possible, women of reproductive potential should be tested for pregnancy before starting dolutegravir. Women of reproductive potential taking the medicinal product should be advised to use effective contraception.

Breastfeeding period

Dolutegravir, lamivudine, and tenofovir disoproxil are present in human breast milk. The medicinal product should not be used during breastfeeding.

Fertility

There are no data on the effect of dolutegravir on fertility in men and women. Animal studies show no effect of dolutegravir on fertility in males or females. Animal studies show no harmful effect of dolutegravir, lamivudine, or tenofovir disoproxil on fertility.

Ability to influence reaction speed when driving vehicles or operating machinery.

Patients should be informed that the medicinal product may cause dizziness. The patient's clinical condition and adverse reactions to the medicinal product should be considered when assessing the patient's ability to drive a vehicle or operate machinery.

Method of Administration and Dosage

The medication must be prescribed by a physician experienced in the management of HIV infection.

Dosage

Adults

The dose of the medication is 1 tablet once daily.

Dose Adjustment

If discontinuation of one of the components of the medication or a dose adjustment is required, the individual components—dolutegravir, lamivudine, and tenofovir disoproxil—should be used. Relevant information regarding the use of these medicinal products should be considered.

When it is known or suspected that a patient has HIV-1 infection resistant to integrase inhibitors, additional doses of dolutegravir are required. For additional information, refer to the product information for dolutegravir.

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

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

Children

The medication should not be administered to children with body weight less than 40 kg, as appropriate dose adjustments of this medicinal product cannot be achieved. Separate medicinal products containing lower amounts of dolutegravir, tenofovir disoproxil, or lamivudine are required.

Elderly Patients

The medication 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)

Dose adjustment is not required in patients with mild renal impairment.

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

The medication is not recommended for patients with creatinine clearance < 50 mL/min (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use"), as appropriate dose adjustments are not feasible. These patients should be treated with individual medicinal products containing dolutegravir, lamivudine, and tenofovir disoproxil.

Hepatic Impairment

Dose adjustment is not 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, the medication should be used with caution in these patients.

Discontinuation of Therapy

If treatment with the medication 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 the medication, it 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 tablet should be swallowed whole with water.

The medication can generally be taken with or without food.

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

Children

The medication is indicated for children aged 12 years and older with body weight of at least 40 kg. The medication should not be administered to children with body weight less than 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 this medication. If overdose occurs, supportive therapy with appropriate monitoring should be initiated as needed. Since only a small amount of lamivudine is removed by (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, or automated peritoneal dialysis, it is unknown whether prolonged hemodialysis would be clinically beneficial in lamivudine overdose. Tenofovir disoproxil can be removed by hemodialysis; the average hemodialysis clearance of tenofovir disoproxil is 134 mL/min. Elimination of tenofovir disoproxil by peritoneal dialysis has not been studied. Because dolutegravir is highly protein-bound, it is unlikely to be significantly removed by 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 severe hepatic effects. The most common adverse reactions 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 resulting in fractures). Monitoring of renal function is recommended for patients receiving the medicinal product (see section "Special precautions for use").

Adverse reactions considered possibly related to the use of dolutegravir are listed by system organ class and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated based on available data).

Table 2

From blood and lymphatic system
Uncommon	neutropenia, anemia (rarely severe), thrombocytopenia
Very rare	pure red cell aplasia
Metabolism and nutrition disorders
Very common	hypophosphatemia
Rare	lactic acidosis
Frequency not known	hypokalemia
Respiratory, thoracic and mediastinal disorders
Common	cough, nasal symptoms
Very rare	dyspnea
Immune system disorders
Uncommon	hypersensitivity (see section "Special precautions") immune reconstitution syndrome (see section "Special precautions" and information below)
Psychiatric disorders
Common	insomnia, abnormal dreams, depression, anxiety
Uncommon	suicidal ideation or suicide attempts (particularly in patients with depression or psychiatric disorders), panic attack
Nervous system disorders
Very common	headache
Common	dizziness
Very rare	peripheral neuropathy (paresthesia)
Gastrointestinal disorders
Very common	nausea, diarrhea
Common	vomiting, flatulence, upper abdominal pain, abdominal pain, abdominal discomfort
Rare	pancreatitis, elevated serum amylase levels
Hepatobiliary disorders
Uncommon	hepatitis
Rare	acute hepatic failure
Frequency not known	hepatic steatosis
Skin and subcutaneous tissue disorders
Common	rash, pruritus, hair loss
Musculoskeletal and connective tissue disorders
Uncommon	arthralgia, myalgia
Common	decreased bone mineral density
Frequency not known	rhabdomyolysis, osteomalacia (manifested by bone pain and rarely leading to fractures), muscle weakness, osteonecrosis
Renal and urinary disorders
Rare		Rare acute renal failure, renal failure, proximal renal tubulopathy (including Fanconi syndrome), increased serum creatinine
Very rare		acute tubular necrosis
Frequency not known		nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus
General disorders
Common		fatigue, malaise, fever
Very rare		asthenia
Frequency not known		immune reconstitution syndrome
Investigations
Common		increased levels of ALT and aspartate aminotransferase (AST), creatine kinase

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. The increase in creatinine was 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 several months after initiation of therapy (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 dysfunction (e.g., those with baseline renal risk factors, advanced HIV disease, or receiving concomitant nephrotoxic agents) have an increased risk of incomplete recovery of renal function despite stopping tenofovir disoproxil (see section "Special warnings and precautions for use").

Renal tubulopathy

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

Interaction with didanosine

Concomitant administration 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"). Pancreatitis and lactic acidosis, sometimes fatal, have been rarely reported.

Metabolic parameters

Body weight and levels of lipids and glucose in blood 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-known risk factors, progressive 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 adverse reaction 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, greater deviations in AST and ALT levels were observed 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 start of dolutegravir therapy, particularly in those whose hepatitis B treatment had been discontinued.

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

Hepatitis flare after discontinuation of treatment

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

Special patient populations

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 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 when administering the medicinal product to elderly patients, as they are more likely to have decreased renal function.

Shelf life.

3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

30 or 60 tablets in a plastic container with two desiccant packets.

90 tablets in a plastic container with three desiccant packets.

Prescription status.

Prescription only.

Manufacturer.

LUPIN LIMITED.

Manufacturer's address and location of operations.

Unit-1, Plot No. 6A1, 6A2, Sector-17, Special Economic Zone, Mihan, Nagpur, Maharashtra 441108, India.