Acriptega

Acriptega

Manufacturer:

Viatris

Distributor:

Atlanta Medicare

Marketer:

Atlanta Medicare
Full Prescribing Info
Contents
Dolutegravir, lamivudine, tenofovir disoproxil fumarate.
Description
Each film coated tablet contains: Dolutegravir (as Dolutegravir Sodium) 50 mg, Lamivudine 300 mg, Tenofovir Disoproxil Fumarate (equivalent to 245 mg of Tenofovir Disoproxil) 300 mg.
Inactive Ingredients/Excipients: Core tablet: Mannitol, Microcrystalline cellulose, Povidone, Sodium Starch Glycolate, Lactose Monohydrate, Croscarmellose Sodium, Magnesium Stearate.
Film coat: Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc.
Action
Pharmacotherapeutic Group: Not assigned, combinations. ATC Code: Not assigned.
Pharmacology: Pharmacodynamics: Lamivudine/Tenofovir Disoproxil Fumarate: Mechanism of action and Pharmacodynamic Effects: Lamivudine, the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside 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), resulting in DNA chain termination. Both substances are active against HIV-1 and HIV-2, as well as against hepatitis B virus.
Resistance: In many cases when a lamivudine-containing treatment regimen fails, the M184V mutation will be selected for at an early stage. M184V causes high-level resistance to lamivudine (>300-fold reduced susceptibility). Virus with M184V replicates less well than does wild type virus. M184V causes high-level resistance to lamivudine (>300-fold reduced susceptibility).
In vitro data tend to suggest that the continuation of lamivudine in an antiretroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established.
Cross-resistance conferred by the M184V mutation is limited within the nucleoside/nucleotide inhibitor class of antiretroviral agents. M184V confers full cross-resistance against emtricitabine. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V mutant shows a <4-fold decrease in susceptibility to didanosine; the clinical significance of this is unknown.
The K65R mutation is selected in vitro when HIV-1 is cultured in the presence of increasing tenofovir concentrations. It may also emerge in vivo upon virological failure of a treatment regimen including tenofovir. K65R reduces tenofovir susceptibility in vitro approximately 2-fold, and has been associated with a lack of response to tenofovir-containing regimens.
Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir against strains of HIV-1 with thymidine analogue mutations (TAMs), which are not selected for by tenofovir. Patients whose HIV expressed 3 or more TAMs that included either the M41L or L210W mutation showed reduced response to tenofovir.
Clinical Efficacy: When tenofovir disoproxil fumarate and lamivudine were combined with efavirenz in treatment-naïve patients with HIV-1, the proportion of patients (ITT) with HIV-RNA <50 copies/ml were 76.3% and 67.8% at 48 and 144 weeks, respectively.
No specific studies with the combination tenofovir disoproxil fumarate, Lamivudine and dolutegravir have been conducted in adolescents.
Dolutegravir: Mechanism of action: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.
Pharmacodynamic Effects: Antiviral activity in cell culture: The IC50 for dolutegravir in various labstrains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference 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 value 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).
Antiviral activity in combination with other antiviral agents: No antagonistic effects in vitro were seen with dolutegravir and other antiretrovirals tested: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc and raltegravir. In addition, no antagonistic effects were seen for dolutegravir and adefovir, and ribavirin had no apparent effect on dolutegravir activity.
Effect of human serum: In 100% human serum, the mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 ug/mL.
Resistance: Resistance in vitro: Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIV-1 IIIB during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F, resulting in a maximal fold change in susceptibility of 4 (range 2-4). These mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432, mutations E92Q (FC 3) and G193E (also FC 3) were selected. The E92Q mutation has been selected in patients with pre-existing raltegravir resistance who were then treated with dolutegravir (listed as a secondary mutation for dolutegravir).
In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all five isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two ART experienced, INI naive individual patients with subtypes B and C in the clinical program, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (FC 10), but was not detected in patients receiving dolutegravir in the Phase III program.
Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q and T66I) do not affect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to these primary mutations in experiments with site directed mutants, dolutegravir susceptibility is still unchanged (FC <2 vs wild type virus), except in the case of Q148-mutations, where a FC of 5-10 or higher is seen with combinations of certain secondary mutations. The effect by the Q148-mutations (H/R/K) was also verified in passage experiments with site directed mutants. In serial passage with strain NL432, starting with site directed mutants harbouring N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). In contrast, starting with mutants harbouring mutation Q148H (FC 1), a variety of secondary mutations were seen with a consequent increase of FC to values >10.
A clinically relevant phenotypic cut-off value (FC vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome.
Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed for susceptibility to dolutegravir. Dolutegravir has a less than or equal to 10 FC against 94% of the 705 clinical isolates.
Resistance in vivo: In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase class, or to the NRTI class was seen (n=1118 follow-up of 48-96 weeks).
In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks treated with dolutegravir, which was given in combination with an investigator selected background regimen (BR). Of these four, two subjects had a unique R263K integrase substitution, with a maximum FC of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum FC of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase experienced or infected with integrase resistant virus by transmission. The R263K mutation was also selected in vitro (see above).
In the presence of integrase class-resistance (VIKING-3 study) the following mutations were selected in 32 patients with protocol defined virological failure (PDVF) through Week 24 and with paired genotypes (all treated with 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), and N155H (n=1) and E157E/Q (n=1). Treatment emergent integrase resistance typically appeared in patients with a history of the Q148-mutation (baseline or historic). Five further subjects experienced PDVF between weeks 24 and 48, and 2 of these 5 had treatment emergent mutations. Treatment-emergent mutations or mixtures of mutations observed were L74I (n=1), N155H (n=2).
The VIKING-4 study examined dolutegravir (plus optimized background therapy) in subjects with primary genotypic resistance to INIs at Screening in 30 subjects. Treatment-emergent mutations observed were consistent with those observed in the VIKING-3 study.
Effects on electrocardiogram: No relevant effects were seen on the QTc interval, with doses exceeding the clinical dose by approximately three fold.
Clinical Efficacy and Safety: Previously untreated patients: The efficacy of dolutegravir in HIV-infected, therapy naïve subjects is based on the analyses of 96-week data from two randomized, international, double-blind, active-controlled trials, SPRING-2 (ING113086) and SINGLE (ING114467). This is supported by 96 week data from an open-label, randomized and activecontrolled study FLAMINGO (ING114915) and additional data from the open-label phase of SINGLE to 144 weeks.
In SPRING-2, 822 adults were randomized and received at least one dose of either dolutegravir 50 mg once daily or raltegravir (RAL) 400 mg twice daily, both administered with either ABC/3TC or TDF/FTC. At baseline, median patient age was 36 years, 14% were female, 15% non-white, 11% had hepatitis B and/or C co-infection and 2% were CDC Class C, these characteristics were similar between treatment groups.
In SINGLE, 833 subjects were randomized and received at least one dose of either dolutegravir 50 mg once daily with fixed-dose abacavir-lamivudine (DTG + ABC/3TC) or fixed-dose efavirenz-tenofovir emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% nonwhite, 7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics were similar between treatment groups.
The primary endpoint and other week 48 outcomes (including outcomes by key baseline covariates) for SPRING-2 and SINGLE are shown in Table 1. (See Table 1.)

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At week 48, dolutegravir was non-inferior to raltegravir in the SPRING-2 study, and in the SINGLE study dolutegravir + ABC/3TC was superior to efavirenz/TDF/FTC (p=0.003), Table 1 above. In SINGLE, the median time to viral suppression was shorter in the dolutegravir treated patients (28 vs 84 days, (p<0.0001, analysis pre-specified and adjusted for multiplicity).
At week 96, results were consistent with those seen at week 48. In SPRING-2, dolutegravir was still noninferior to raltegravir (viral suppression in 81% vs 76% of patients), and with a median change in CD4 count of 276 vs 264 cells/mm3, respectively. In SINGLE, dolutegravir + ABC/3TC was still superior to EFV/TDF/FTC (viral suppression in 80% vs 72%, treatment difference 8.0% (2.3, 13.8), p=0.006, and with an adjusted mean change in CD4 count of 325 vs 281 cells/ mm3, respectively. At 144 weeks in the open label phase of SINGLE, virologic suppression was maintained, the dolutegravir + ABC/3TC arm (71%) was superior to the EFV/TDF/FTC arm (63%), treatment difference was 8.3% (2.0, 14.6).
In FLAMINGO (ING114915), an open-label, randomised and active-controlled study, 484 HIV-1 infected antiretroviral naïve adults received one dose of either dolutegravir 50 mg once daily (n=242) or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily (n=242), both administered with either ABC/3TC or TDF/FTC. At baseline, median patient age was 34 years, 15% were female, 28% non-white, 10% had hepatitis B and/or C co-infection, and 3% were CDC Class C; these characteristics were similar between treatment groups. Virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir group (90%) was superior to the DRV/r group (83%) at 48 weeks. The adjusted difference in proportion and 95% CI were 7.1% (0.9, 13.2), p=0.025. At 96 weeks, virologic suppression in the dolutegravir group (80%) was superior to the DRV/r group (68%), (adjusted treatment difference [DTG-(DRV+RTV)]: 12.4%; 95% CI: [4.7, 20.2].
Treatment emergent resistance in previously untreated patients failing therapy: Through 96 weeks in SPRING-2 and FLAMINGO and 144 weeks in SINGLE, no cases of treatment emergent primary resistance to the integrase- or NRTI-class were seen in the dolutegravir-containing arms. For the comparator arms, the same lack of treatment emergent resistance was also the case for patients treated with darunavir/r in FLAMINGO. In SPRING-2, four patients in the RAL-arm failed with major NRTI mutations and one with raltegravir resistance; in SINGLE, six patients in the EFV/TDF/FTC-arm failed with mutations associated with NNRTI resistance, and one developed a major NRTI mutation.
Patients with prior treatment failure, but not exposed to the integrase class: In the international multicentre, double-blind SAILING study (ING111762), 719 HIV-1 infected, antiretroviral therapy (ART)-experienced adults were randomized and received either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily with investigator selected background regimen consisting of up to 2 agents (including at least one fully active agent). At baseline, median patient age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or C co-infection, and 46% were CDC Class C. All patients had at least two class ART resistance, and 49% of subjects had at least 3-class ART resistance at baseline.
Week 48 outcomes (including outcomes by key baseline covariates) for SAILING are shown in Table 2.

Click on icon to see table/diagram/image

In the SAILING study, virologic suppression (HIV-1 RNA <50 copies/mL) in the Dolutegravir arm (71%) was statistically superior to the raltegravir arm (64%), at Week 48 (p=0.03).
Statistically fewer subjects failed therapy with treatment-emergent integrase resistance on Dolutegravir (4/354, 1%) than on raltegravir (17/361, 5%) (p=0.003) (refer to section 'Resistance in vivo' above for details).
Paediatric population: In a Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of Dolutegravir will be evaluated in combination regimens in HIV-1 infected adolescents.
At 24 weeks, 16 of 23 (70%) adolescents (12 to less than 18 years of age) treated with Dolutegravir once daily (35 mg n=4, 50 mg n=19) plus OBR achieved viral load <50 copies/mL. Four subjects had virologic failure none of which had INI resistance at the time of virologic failure.
Pharmacokinetics: Lamivudine: Absorption and Bioavailability: Lamivudine is rapidly absorbed following oral administration. Bioavailability is between 80 and 85%. Following single dose administration of one tablet of Efavirenz/Lamivudine/Tenofovir Disoproxil Fumarate 600 mg/300 mg/300 mg Tablets in healthy volunteers, the mean (±SD) lamivudine Cmax value was 2483 (±706) ng/ml and the corresponding value for AUC was 13457 (±3717) ng.h/ml. The mean (±SD) lamivudine tmax value was 1.92 (±0.93) hours.
Co-administration of lamivudine with food results in a delay of tmax and a lower Cmax (decreased by 47%). However, the extent (based on the AUC) of lamivudine absorbed is not influenced.
Distribution: Intravenous studies with lamivudine showed that the mean apparent volume of distribution is 1.3 l/kg. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin (< 36% serum albumin in vitro).
Metabolism: Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominantly cleared unchanged by renal excretion. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%) and low plasma protein binding.
Elimination: The observed lamivudine half-life of elimination is 5 to 7 hours. The half-life of intracellular lamivudine triphosphate has been estimated to approximately 22 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70%), including tubular secretion through the organic cationic transport system.
Special Populations: Renal impairment: Studies in patients with renal impairment show that lamivudine elimination is affected by renal dysfunction. Dose reduction is recommended for patients with creatinine clearance ≤50 ml/min (see Dosage & Administration).
Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate is a water-soluble ester prodrug, which is rapidly converted in vivo to tenofovir and formaldehyde. Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, tenofovir diphosphate.
Absorption:
Following oral administration of tenofovir disoproxil fumarate to HIV infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients was approximately 25%. Administration of tenofovir disoproxil fumarate with a high fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately 14%.
Following single dose administration of one tablet of Efavirenz/Lamivudine/Tenofovir Disoproxil Fumarate 600 mg/300 mg/300 mg Tablets in healthy volunteers, the mean (±SD) tenofovir Cmax value was 277 (±79) ng/ml and the corresponding value for AUC was 2358 (±627) ng.h/ml. The mean (±SD) tenofovir tmax value was 1.17 (±0.57) hours.
Distribution : Following intravenous administration, the steady-state volume of distribution of tenofovir was estimated to be approximately 800 ml/kg. In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/ml.
Elimination: Tenofovir is primarily excreted by the kidney, both by filtration and an active tubular transport system with approximately 70-80% of the dose excreted unchanged in urine following intravenous administration. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration the terminal half-life of tenofovir is approximately 12 to 18 hours.
Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the multidrug resistant protein 4 (MRP 4). In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes.
Age and gender: Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect. Tenofovir exposure achieved in adolescent patients receiving oral daily doses of tenofovir 300 mg was similar to exposures achieved in adults receiving once-daily doses of tenofovir 300 mg. Pharmacokinetic studies have not been performed in children or in the elderly (over 65 years). Pharmacokinetics have not been specifically studied in different ethnic groups.
Renal impairment: Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil fumarate 300 mg to 40 non-HIV, non-HBV infected patients with varying degrees of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and severe with CrCl = 10-29 ml/min). Compared with patients with normal renal function, the mean (%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to respectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients with mild, moderate and severe renal impairment. The dosing recommendations in patients with renal impairment, with increased dosing interval, are expected to result in higher peak plasma concentrations and lower Cmin levels in patients with renal impairment compared with patients with normal renal function. The clinical implications of this are unknown.
In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, between dialysis tenofovir concentrations substantially increased over 48 hours achieving a mean Cmax of 1,032 ng/ml and a mean AUC0-48h of 42,857 ng·h/ml. It is recommended that the dosing interval for tenofovir disoproxil fumarate 300 mg is modified in patients with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis (see Dosage & Administration).
The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance < 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not been studied.
Hepatic impairment: A single 300 mg dose of tenofovir disoproxil fumarate was administered to non-HIV, non-HBV infected patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetic parameters were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng·h/ml, respectively, in normal subjects compared with 289 (46.0%) ng/ml and 2,31 (43.5%) ng·h/ml in subjects with moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with severe hepatic impairment.
Intracellular pharmacokinetics: Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs).
Dolutegravir: Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is low to moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC and Cmax ranged from ~20 to 40% and Cτ from 30 to 65% across studies. The between-subject PK variability of dolutegravir was higher in HIV-infected subjects than healthy subjects. Within-subject variability (CVw%) is lower than between-subject variability.
Absorption: Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for tablet formulation. Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. These increases may be clinically relevant in the presence of certain integrase class resistance. Therefore, Dolutegravir is recommended to be taken with food by patients infected with HIV with integrase class resistance (see Dosage & Administration).
The absolute bioavailability of dolutegravir has not been established.
Distribution: Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data. The apparent volume of distribution is 17 L to 20 L in HIV-infected patients, based on a population pharmacokinetic analysis. Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma is increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment.
Dolutegravir is present in cerebrospinal fluid (CSF). In 13 treatment-naïve subjects on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the IC50).
Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% and 17% in rectal tissue of those in corresponding plasma at steady state.
Biotransformation: Dolutegravir is primarily metabolized through glucuronidation via UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).
Drug interaction: In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Based on this data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters (see Interactions).
In vitro, dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.
Elimination: Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1L/hr in HIV-infected patients based on a population pharmacokinetic analysis.
Linearity/non-linearity: The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of tablet formulations, in general, dolutegravir exhibited nonlinear pharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; however increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg for the tablet formulation. With 50 mg twice daily, the exposure over 24 hours was approximately doubled compared to 50 mg once daily.
Pharmacokinetic/pharmacodynamic relationship(s): In a randomized, dose-ranging trial, HIV-1-infected subjects treated with dolutegravir monotherapy (ING111521) demonstrated rapid and dose-dependent antiviral activity, with mean decline in HIV-1 RNA of 2.5 log10 at day 11 for 50 mg dose. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group.
PK/PD modelling using pooled data from clinical studies in integrase resistant patients suggest that increasing the dose from 50 mg twice daily to 100 mg twice daily may increase the effectiveness of dolutegravir in patients with integrase resistance and limited treatment options due to advanced multi class resistance. The proportion of responders (HIV-1 RNA <50 c/mL) at week 24 was predicted to increase around 4-18% in the subjects with Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I. Although these simulated results have not been confirmed in clinical trials, this high dose may be considered in the presence of the Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I in patients with overall limited treatment options due to advanced multi class resistance. There is no clinical data on the safety or efficacy of the 100 mg twice daily dose. Co-treatment with atazanavir increases the exposure of dolutegravir markedly, and should not be used in combination with this high dose, since safety with the resulting dolutegravir exposure has not been established.
Special patient populations: Children: The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to <18 years of age) showed that Dolutegravir 50 mg once daily oral dosage resulted in dolutegravir exposure comparable to that observed in adults who received Dolutegravir 50 mg orally once daily.
Elderly: Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure. Pharmacokinetic data for dolutegravir in subjects >65 years of age are limited.
Renal impairment: Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min) and matched healthy controls. The exposure to dolutegravir was decreased by approximately 40% in subjects with severe renal impairment. The mechanism for the decrease is unknown. No dosage adjustment is considered necessary for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis.
Hepatic impairment: Dolutegravir is primarily metabolized and eliminated by the liver. A single dose of 50 mg of dolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5- to 2-fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairment compared to healthy controls. No dosage adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of Dolutegravir has not been studied.
Polymorphisms in drug metabolising enzymes: There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n=41).
Gender: Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed no clinically relevant effect of gender on the exposure of dolutegravir.
Race: Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese subjects appear similar to observed parameters in Western (US) subjects.
Co-infection with Hepatitis B or C: Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited data on subjects with hepatitis B co-infection.
Toxicology: Preclinical Safety Data: Administration of lamivudine in animal toxicity studies at high doses was not associated with any major organ toxicity. Lamivudine was not mutagenic in bacterial tests but showed activity in an in vitro cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vitro at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed in in vivo tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment.
The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential relevant for humans.
Tenofovir: Preclinical studies conducted in rats, dogs and monkeys revealed target organ effects in gastrointestinal tract, kidney, bone and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (rats and dogs). Findings in the rat and monkey studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in bone mineral density. However, no conclusion could be drawn on the mechanism(s) underlying these toxicities.
Reproductive studies were conducted in rats and rabbits. There were no effects on mating or fertility parameters or on any pregnancy or foetal parameter. There were no gross foetal alterations of soft or skeletal tissues. Tenofovir disoproxil fumarate reduced the viability index and weight of pups in peri-post natal toxicity studies.
Genotoxicity studies have shown that tenofovir disoproxil fumarate was negative in the in vivo mouse bone marrow micronucleus assay but was positive for inducing forward mutations in the in vitro L5178Y mouse lymphoma cell assay in the presence or absence of S9 metabolic activation. Tenofovir disoproxil fumarate was positive in the Ames test (strain TA 1535) in two out of three studies, once in the presence of S9 mix (6.2- to 6.8-fold increase) and once without S9 mix. Tenofovir disoproxil fumarate was also weakly positive in an in vivo/in vitro unscheduled DNA synthesis test in primary rat hepatocytes.
Tenofovir disoproxil fumarate did not show any carcinogenic potential in a long-term oral carcinogenicity study in rats. A long-term oral carcinogenicity study in mice showed a low incidence of duodenal tumours, considered likely related to high local concentrations of tenofovir disoproxil fumarate in the gastrointestinal tract at a dose of 600 mg/kg/day. While the mechanism of tumour formation is uncertain, the findings are unlikely to be of relevance to humans.
Dolutegravir: Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay. Dolutegravir was not carcinogenic in long term studies in the mouse and rat.
Dolutegravir did not affect male or female fertility in rats at doses up to 1000 mg/kg/day, the highest dose tested (24 times the 50 mg twice daily human clinical exposure based on AUC).
Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (27 times the 50 mg twice daily human clinical exposure based on AUC).
Oral administration of dolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity (0.40 times the 50 mg twice daily human clinical exposure based on AUC). In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.40 times the 50 mg twice daily human clinical exposure based on AUC).
The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oral dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primary effect of dolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemic exposures approximately 21 and 0.82 times the 50 mg twice daily human clinical exposure based on AUC, respectively. Because gastrointestinal (GI) intolerance is considered to be due to local active substance administration, mg/kg or mg/m2 metrics are appropriate determinates of safety cover for this toxicity. GI intolerance in monkeys occurred at 15 times the human mg/kg equivalent dose (based on a 50 kg human), and 5 times the human mg/m2 equivalent dose for a clinical dose of 50 mg twice daily.
Indications/Uses
Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is a fixed dose combination of Lamivudine, Tenofovir Disoproxil Fumarate and Dolutegravir.
It is indicated for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age weighing at least 40 kg (see Precautions and Pharmacology: Pharmacodynamics under Actions).
The choice of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets to treat antiretroviral experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or the treatment history of the patient. Consideration should be given to official treatment guidelines for HIV-1 infection (e.g. by WHO).
No data are available to support the combination of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets and other antiretroviral agents.
Dosage/Direction for Use
Therapy should be prescribed by a physician experienced in the management of HIV-1 infection.
Posology: Adults and adolescents (from 12 years of age and weighing ≥ 40 kg): The recommended dose of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets in adults and adolescents is one tablet once daily.
Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should not be administered to adults or adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose reduced.
Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments. Separate preparations of Lamivudine, Tenofovir Disoproxil Fumarate and Dolutegravir are available in cases where discontinuation or dose adjustment of one of the active substances is indicated. In these cases the physician should refer to the individual product information for these medicinal products.
Pregnancy Testing before Initiation of Dolutegravir: Perform pregnancy testing before initiation of dolutegravir in adolescents and adults of childbearing potential.
Method of administration: It is recommended that Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets be swallowed whole with water.
Children: Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is not recommended for use in children below 12 years of age due to a lack of data on safety and efficacy.
Elderly: There are limited data available on the use of Dolutegravir in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see Pharmacology: Pharmacokinetics under Actions). Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should be administered with caution to elderly patients (see Precautions).
Dose adjustments: Where discontinuation of therapy with one of the components of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is indicated or where dose modification is necessary, separate preparations of tenofovir disoproxil fumarate, lamivudine and Dolutegravir are available. Please refer to the Summary of Product Characteristics for these medicinal products.
Renal impairment: Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is not recommended for patients with moderate or severe renal impairment (creatinine clearance (CrCl) < 50 ml/min). Patients with moderate or severe renal impairment require dose interval adjustment of lamivudine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: The pharmacokinetics of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets have not been studied in patients with hepatic impairment. Patients should be monitored carefully for adverse reactions.
If Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is discontinued in patients co-infected with HIV and HBV, these patients should be closely monitored for evidence of exacerbation of hepatitis (see Precautions).
Overdosage
Lamivudine/Tenofovir Disoproxil Fumarate: If overdose occurs the patient must be monitored for evidence of toxicity (see Adverse Reactions and Pharmacology: Toxicology under Actions), and standard supportive treatment applied as necessary.
Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/min. The elimination of tenofovir by peritoneal dialysis has not been studied.
Because a negligible amount of lamivudine was removed via (4-hour) haemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous haemodialysis would provide clinical benefit in a lamivudine overdose event.
Dolutegravir: There is currently limited experience with overdosage in dolutegravir.
Limited experience of single higher doses (up to 250 mg in healthy subjects) revealed no specific symptoms or signs, apart from those listed as adverse reactions.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of dolutegravir. If overdose occurs, the patient should be treated supportively with appropriate monitoring, as necessary. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
Contraindications
Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is contraindicated in patients with clinically significant hypersensitivity to tenofovir, lamivudine, dolutegravir or to any of the excipients contained in the formulation.
Co-administration with dofetilide (see Interactions).
Special Precautions
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Embryo-Fetal Toxicity: Preliminary data from an observational study showed that dolutegravir was associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy. As there is limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of dolutegravir at the time of conception through the first trimester of pregnancy.
If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on dolutegravir, if possible, switch to an alternative regimen.
Perform pregnancy testing before initiation of dolutegravir in adolescents and adults of childbearing potential to exclude use of dolutegravir during the first trimester of pregnancy.
Advise adolescents and adults of childbearing potential to consistently use effective contraception.
General: As a fixed combination, Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should not be administered concomitantly with other medicinal products containing any of the same active components, Dolutegravir, lamivudine or tenofovir disoproxil fumarate. Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should not be administered concomitantly with other cytidine analogues such as emtricitabine. (see Interactions). Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should not be administered concomitantly with adefovir dipivoxil.
Transmission of HIV: Treatment with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets has not been shown to eliminate the risk of transmission of HIV infection by sexual contact or by blood transfer, although the risk may be reduced. Patients should continue to use appropriate precautions to prevent transmission of HIV.
Liver disease: The safety and pharmacokinetics of Dolutegravir has not been investigated in patients with severe liver disease. Therefore Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should only be used in this group of patients if the benefits are considered to outweigh the risks, and with close safety monitoring.
Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection: Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.
Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with HBV.
Lamivudine and tenofovir disoproxil fumarate are also active against HBV. Therefore, discontinuation of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets must be closely monitored with both clinical and laboratory follow-up for at least four months after stopping treatment with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets. If appropriate, resumption of specific anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see Adverse Reactions).
Integrase class resistance of particular concern: The decision to use Dolutegravir in the presence of integrase class resistance should take into account that the activity of Dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I (see Pharmacology: Pharmacodynamics under Actions). To what extent Dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain (see Pharmacology: Pharmacokinetics under Actions).
Hypersensitivity reactions: Hypersensitivity reactions have been reported with Dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect agents should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with Dolutegravir or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction.
Renal function: Tenofovir is primarily excreted by the kidneys through a combination of glomerular filtration and active tubular secretion. Thus, clearance is decreased in patients with impaired renal function. There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function (< 80 ml/min). In such patients, Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should only be used if the potential benefits of treatment are considered to outweigh the potential risks.
In patients with moderate to severe renal impairment, the plasma half-life of lamivudine is increased due to decreased clearance. Decreased doses are recommended for patients with creatinine clearance <50 ml/min.
The use of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is not recommended in patients with creatinine clearance < 50 ml/min, since appropriate dose reductions cannot be achieved with the combination tablet (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see Interactions). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets. Routine monitoring of calculated creatinine clearance and serum phosphate should be performed in patients at risk for renal impairment.
In patients receiving tenofovir disoproxil fumarate renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations, if serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance decreases below 50 ml/min (see Proximal tubulopathy under Adverse Reactions).
Consideration should also be given to interrupting treatment with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets in patients whose creatinine clearance falls below 50 ml/min or whose serum phosphate decreases below 1.0 mg/dl (0.32 mmol/l).
Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should be avoided with concurrent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored weekly.
Bone effects: In a controlled clinical study decreases in bone mineral density of spine and changes in bone biomarkers from baseline were observed in both treatment groups, but were significantly greater in the tenofovir disoproxil fumarate treatment group than in the comparator group treated with stavudine (each in combination with lamivudine and efavirenz) at 144 weeks. Decreases in bone mineral density of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.
Tenofovir was studied in HIV-1 infected paediatric subjects 12 years of age and older. Under normal circumstances, bone mineral density increases rapidly in this age group. In this study, the mean rate of bone gain was less in the tenofovir-treated group compared to the placebo group. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in tenofovir-treated paediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults. Due to the possible effects of tenofovir on bone metabolism, Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should only be used in adolescents under the age of 18 if the benefits are considered to exceed the risk (see also Adverse Reactions).
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see Adverse Reactions). If bone abnormalities are suspected then appropriate consultation should be obtained.
Lactic acidosis: Lactic acidosis is a rare but severe, potentially life-threatening complication associated with use of nucleoside reverse transcriptase inhibitors (NRTI). Several other agents of this class are known to cause lactic acidosis. Preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, considered a putative class effect of nucleoside analogues, is very low for tenofovir disoproxil fumarate and lamivudine. However, this risk cannot be excluded. Lactic acidosis may occur after a few to several months of NRTI treatment. Patients with hyperlactataemia may be asymptomatic, critically ill, or may have non-specific symptoms such as dyspnoea, fatigue, nausea, vomiting, diarrhoea and abdominal pain. Risk factors for NRTI-related lactic acidosis include female gender and obesity. Patients at increased risk should be closely monitored clinically. Screening for hyperlactataemia in asymptomatic patients treated with NRTIs, however, is not recommended. Symptomatic patients usually have levels > 5 mmol/l and require discontinuation of all NRTIs. Lactic acid levels > 10 mmol/l usually are a medical emergency.
Lipodystrophy and metabolic disorders: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV-infected patients. Whereas for some other antiretrovirals there is considerable evidence for this adverse reaction, the evidence for tenofovir, lamivudine and Dolutegravir as causative agents is weak; indeed switching from a thymidine analogue (e.g. stavudine) to tenofovir has been shown to increase limb fat in patients with lipoatrophy. A higher risk of lipodystrophy has been associated e.g. with older age of the patient, longer duration of antiretroviral therapy and related metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Measurement of fasting serum lipids and blood glucose as well as appropriate management of lipid disorders should be considered (see Adverse Reactions).
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see Adverse Reactions).
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated, in vitro and in vivo, to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Pancreatitis: Treatment with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur (see Adverse Reactions).
Opportunistic infections: Patients receiving antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians or health care providers experienced in the treatment of HIV infection.
Drug interactions: Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g. magnesium/aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John's wort and certain antiepileptic drugs) (see Interactions).
Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control (see Interactions). Metformin is eliminated renally and therefore it is of importance to monitor renal function when co-treated with dolutegravir. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45-59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.
Co-administration of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets and didanosine is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate (see Interactions).
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Excipients: Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets contain 136.00 mg of lactose per maximum recommended daily dose. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on the Ability to Drive and Use Machine: There have been no studies to investigate the effect of dolutegravir on driving performance or the ability to operate machines. However, patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical4 status of the patient and the adverse reaction profile of dolutegravir should be borne in mind when considering the patient's ability to drive or operate machinery.
Use in the Elderly: Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate
Use In Pregnancy & Lactation
Pregnancy: Lamivudine/Tenofovir Disoproxil Fumarate: Animal studies do not indicate direct or indirect harmful effects of tenofovir disoproxil fumarate with respect to pregnancy, foetal development, parturition or postnatal development (see Pharmacology: Toxicology under Actions). In humans, the safety of tenofovir in pregnancy has not been fully established. Sufficient numbers of first trimester exposures have been monitored, however, to detect at least a twofold increase in the risk of overall birth defects. No increase in birth defects was seen (www.apregistry.com).
No increased risk of birth defects has been reported for lamivudine (www.apregistry.com). However, risks to the fetus cannot be ruled out.
Dolutegravir: Risk Summary: Preliminary data from an observational study has identified a possible increased risk of neural tube defects when Dolutegravir is administered at the time of conception compared with non-dolutegravir-containing antiretroviral regimens. As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk. In addition, 2 of the 4 birth defects (encephalocele and iniencephaly), which have been observed with dolutegravir use, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester. Due to the limited understanding of the types of reported neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of Dolutegravir at the time of conception through the first trimester of pregnancy. No neural tube defects have been reported in infants born to mothers who have started Dolutegravir after the first trimester of pregnancy (see Data).
If there are plans to become pregnant or if pregnancy is confirmed while on Dolutegravir during the first trimester, if possible, switch to an alternative regimen. Advise pregnant adolescents and adults of the potential risk to the embryo exposed to Dolutegravir from the time of conception through the first trimester of pregnancy.
There are insufficient human data on the use of Dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD) of Dolutegravir (see Data).
Human Data: As of May 2018, in an ongoing birth outcome surveillance study in Botswana, there have been 4 cases of neural tube defects reported out of 426 births (0.94%) to mothers who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.12% (14/11,300) in the non-dolutegravir arm and 0.09% (61/66,057) in the HIV-uninfected arm. Four cases reported with dolutegravir included one case each of encephalocele, anencephaly, myelomeningocele, and iniencephaly. No infant born to a woman who started dolutegravir during pregnancy had a neural tube defect (n = 2,812).
Data analyzed to date from other sources including the APR, clinical trials, and post marketing data are insufficient to address the risk of neural tube defects with dolutegravir.
Animal Data: Dolutegravir was administered orally at up to 1,000 mg per kg daily to pregnant rats and rabbits on gestation Days 6 to 17 and 6 to 18, respectively, and to rats on gestation Day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at up to the highest dose tested.). During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the MRHD and in rats were approximately 27 times the exposure in humans at the MRHD. In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 27 times human exposure at the MRHD). ).
Breast-feeding: Lamivudine/Tenofovir Disoproxil Fumarate: In animal studies it has been shown that tenofovir is excreted into milk. It is not known whether tenofovir is excreted in human milk. Lamivudine is excreted into the breast milk of lactating mothers.
Current recommendations on HIV and breastfeeding (e.g. those from the WHO) should be consulted before advising patients on this matter. Preferred options may vary depending on the local circumstances.
Dolutegravir: Risk Summary: It is not known whether Dolutegravir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, dolutegravir was present in milk (see Data).
Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving Dolutegravir.
Data: Animal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg per kg on lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours postdose.
Fertility: Dolutegravir: Females and Males of Reproductive Potential: Pregnancy Testing: Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of Dolutegravir.
Contraception: Adolescents and adults of childbearing potential should avoid use of Dolutegravir at the time of conception through the first trimester of pregnancy because of the potential risk of neural tube defects. Advise adolescents and adults of childbearing potential who are taking Dolutegravir to consistently use effective contraception.
Adverse Reactions
Lamivudine/Tenofovir Disoproxil Fumarate: Adverse events considered at least possibly related to treatment with lamivudine are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), unknown (frequency cannot be estimated from the available data).
Blood and lymphatic systems disorders: Uncommon: neutropenia, anaemia (occasionally severe), thrombocytopenia.
Very rare: pure red cell aplasia.
Metabolism and nutrition disorders: Very common: hypophosphataemia.
Rare: lactic acidosis.
Unknown: hypokalaemia.
Nervous system disorders: Very common: dizziness.
Common: headache and insomnia.
Very rare: peripheral neuropathy (paraesthesia).
Respiratory, thoracic and mediastinal disorders: Common: cough, nasal symptoms.
Very rare: dyspnoea.
Gastrointestinal disorders: Very common: diarrhoea, nausea, vomiting.
Common: abdominal pain/cramps, flatulence.
Rare: pancreatitis, elevated serum amylases.
Hepatobiliary disorders: Uncommon: transient elevation in liver enzymes.
Rare: hepatitis.
Unknown: hepatic steatosis.
Skin and subcutaneous tissue disorders: Common: Rash, hair loss.
Musculoskeletal and connective tissue disorders: Common: arthralgia, muscle disorder.
Unknown: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), muscular weakness, myopathy, osteonecrosis.
Renal and urinary disorders: Rare: acute renal failure, renal failure, proximal renal tubulopathy (including Fanconi syndrome), increased serum creatinine.
Very rare: acute tubular necrosis.
Unknown: nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus.
General disorders and administration site disorders: Common: fatigue, malaise, fever.
Very rare: asthenia.
Unknown: immune reconstitution syndrome.
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalaemia, muscular weakness, myopathy and hypophosphataemia. These events are not considered to be causally associated with tenofovir disoproxil fumarate therapy in the absence of proximal renal tubulopathy.
In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of HBV therapy (see Precautions).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see Precautions).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Dolutegravir: Summary of the safety profile: The safety profile is based on pooled data from Phase IIb and Phase III clinical studies in 1222 previously untreated patients, 357 previously treated patients unexposed to integrase inhibitors and 264 patients with prior treatment failure that included an integrase inhibitor (including integrase class resistance). The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see Precautions). The most commonly seen treatment emergent adverse reactions were nausea (13%), diarrhoea (18%) and headache (13%).
The safety profile was similar across the different treatment populations mentioned above.
Tabulated list of adverse reactions: The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). (See Table 3.)

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Description of selected adverse reactions: Changes in laboratory biochemistries: Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. A mean change from baseline of 9.96 μmol/L was observed after 48 weeks of treatment. Creatinine increases were comparable by various background regimens. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.
Co-infection with Hepatitis B or C: In Phase III studies patients with hepatitis B and/or C co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see Precautions).
Immune response syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see Precautions).
Paediatric population: Based on limited available data in adolescents (12 to less than 18 years of age and weighing at least 40 kg), there were no additional types of adverse reactions beyond those observed in the adult population.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
Interactions relevant to lamivudine: Co-administration with trimethoprim / sulfamethoxazole results in a 40% increase in lamivudine area under the concentration curve. No dose adjustment of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.
Interactions relevant to tenofovir: Didanosine: Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see Precautions and Table 4).
Renally eliminated medicinal products: Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.
Tenofovir disoproxil fumarate should be avoided with concurrent use of a nephrotoxic medicinal product, such as aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see Precautions).
Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil fumarate.
Other interactions: Interactions between Lamivudine/Tenofovir Disoproxil Fumarate 300mg/300mg and HIV protease inhibitors, as well as antiviral agents other than protease inhibitors, are listed in Table below (increased exposure is indicated as "↑", decreased exposure as "↓", no change as "↔", twice daily as "b.i.d.", and once daily as "q.d."). (See Table 4.)

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Studies conducted with other medicinal products: There were no clinically significant pharmacokinetic interactions when Lamivudine/Tenofovir Disoproxil Fumarate 300mg/300mg Tablets is coadministered with indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/ethinyl oestradiol.
Food effect: Tenofovir disoproxil fumarate must be taken with food, as food enhances the bioavailability of tenofovir (see Pharmacology: Pharmacodynamics under Actions).
Interactions relevant to dolutegravir: Effect of other agents on the pharmacokinetics of dolutegravir: All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance.
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Tables 5a, 5b and 5c).
Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Tables 5a, 5b and 5c). The absorption of dolutegravir is reduced by certain anti-acid agents (see Tables 5an, 5b and 5c).
Effect of dolutegravir on the pharmacokinetics of other agents: In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see Pharmacology: Pharmacokinetics under Actions).
In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 or MATE-1 (e.g. dofetilide, metformin) (see Tables 5a, 5b and 5c, and Contraindications).
In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medical products in which excretion is dependent upon OAT3.
Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Tables 5a, 5b and 5c.
Interaction table dolutegravir: Interactions between dolutegravir and co-administered medicinal products are listed in Tables 5a, 5b and 5c (increase is indicated as "↑", decrease as "↓", no change as "↔", area under the concentration versus time curve as "AUC", maximum observed concentration as "Cmax", concentration at end of dosing interval as "Cτ").

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Paediatric population: Interaction studies have only been performed in adults.
Caution For Usage
Instructions for use and handling and disposal: No special requirements.
Incompatibilities: Not applicable.
Storage
Special precautions for storage: Do not store above 30°C. Store in the original container.
Shelf life: 24 months.
MIMS Class
ATC Classification
J05AR27 - lamivudine, tenofovir disoproxil and dolutegravir ; Belongs to the class of antivirals for treatment of HIV infections, combinations.
Presentation/Packing
FC tab (white to off-white, film coated, capsule shaped, biconvex, beveled edge tablet debossed with M on one side and LTD on the other side of the tablet) 30's.
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