Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Dolutegravir

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Dolutegravir (DTG) is a uridine diphosphate glucuronosyltransferase (UGT) 1A and cytochrome P450 (CYP) 3A substrate and may require dose adjustments when administered with UGT1A-modulating or CYP3A-modulating medications. DTG dosing should be adjusted to twice daily (i.e., twice the usual dose) when coadministered with drugs such as efavirenz and rifampin.^2-4 Because etravirine (ETR) significantly reduces plasma DTG concentrations, DTG should not be administered with ETR without coadministration of atazanavir (ATV)/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir, which counteract this effect on DTG concentrations. DTG should not be administered with nevirapine because of insufficient data on interactions between these drugs. See the product label for a full listing of significant drug–drug interactions.
• Atazanavir (ATV) is an inhibitor of UGT1A1. In a pharmacologic survey of adult patients who were receiving DTG, patients who also received ATV had plasma concentrations of DTG that were twofold to fourfold higher than those of patients who received other antiretroviral (ARV) drugs.⁵
• Before administering DTG, clinicians should carefully review a patient’s medication profile for potential drug interactions.

Major Toxicities

• More common: Insomnia and headache. Excessive weight gain and increased body mass index (BMI) have been reported in adults who received DTG in clinical trials and in some pediatric and adolescent cohorts (see Table 17h. Lypodystrophies and Weight Gain),^6-9 whereas other cohort studies have not identified an association with excessive weight gain.¹⁰
• Less common (more severe): Hypersensitivity reactions characterized by rash, constitutional symptoms, and sometimes organ dysfunction; neuropsychiatric symptoms, especially in patients with a history of psychiatric illness. Multiple post-marketing reports note that neuropsychiatric adverse events (AEs) have occurred following the initiation of DTG-based therapy in adults.^11,12
• Immune reconstitution inflammatory syndrome (IRIS): In retrospective observational studies, severe cases of IRIS that required hospitalization appeared to be more frequent in patients who presented with advanced HIV disease and who initiated treatment with integrase strand transfer inhibitors (INSTIs), particularly DTG.^13,14 This phenomenon is presumed to be linked to the rapid decline in HIV RNA observed in patients receiving INSTI-based therapy.
• Rare: Hepatotoxicity has been reported; two cases of liver injury were presumed to be related to the use of DTG. One of these cases required liver transplantation.^15,16
• Rare: A single case of drug reaction (or rash) with eosinophilia and systemic symptoms (DRESS) has been reported.¹⁷

Resistance

The International Antiviral Society–USA maintains a list of updated resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation. For additional considerations on the impact of nucleoside reverse transcriptase inhibitor (NRTI) resistance and the use of DTG-containing fixed-dose combinations (FDCs), see Recognizing and Managing Antiretroviral Treatment Failure.

The efficacy of DTG is reduced in patients with the INSTI-resistance Q148 substitution plus two or more additional INSTI-resistance mutations, and this reduced efficacy cannot be completely overcome with increased DTG dosing.^18,19

For INSTI-experienced adults with certain INSTI-resistance mutations or clinically suspected INSTI resistance, the Tivicay package insert recommends giving the standard 50-mg dose twice daily rather than once daily. However, modeling and simulation of this potential strategy with the dispersible tablet formulation of DTG in children suggested elevated maximum plasma concentrations (C_max) in comparison to historical data in adults, adolescents, and children would result. Thus, a different dosing strategy was needed for children with certain or clinically suspected INSTI-resistance mutations. The proposed dosing schedule in Table A below was based on simulations with the goal of achieving geometric mean concentration at 12 hours postdose >1.97 µg/mL and area under the curve (AUC) through 12 hours postdose >32.2 µg∙h/mL while avoiding elevated C_max values.²⁰ Additionally, the coformulated dispersible tablet containing abacavir (ABC)/DTG/lamivudine (3TC) cannot be used in combination with a separate dose of single-agent dispersible release DTG because the dosing of the separate formulation is not double the regular dose and the modified dosing strategy would result in underdosing the ABC and 3TC components.

Pediatric Use

Approval

DTG is approved by the U.S. Food and Drug Administration (FDA) for use, in combination with other ARV drugs, in pediatric patients aged at least 4 weeks and weighing ≥3 kg who are treatment naive or treatment experienced but INSTI naive (see Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-‍packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents). DTG dispersible tablets and film-coated tablets in either the single-entity or FDC form can be administered with or without food.^21,22 Pediatric patients weighing ≥20 kg may take the DTG 50-mg film-coated tablets if they are able to swallow tablets.

The combination tablet ABC/DTG/3TC (Triumeq) is approved by the FDA for use in children and adolescents weighing ≥25 kg. Dispersible ABC/DTG/3TC tablets (Triumeq PD) are FDA approved for use in children weighing ≥6 kg to <25 kg.

The combination tablet DTG/3TC (Dovato) is approved by the FDA for adolescents weighing ≥25 kg and aged ≥12 years but is not approved for use in children aged <12 years.

The combination tablet DTG/rilpivirine (RPV) (Juluca) is not approved by the FDA for use in children or adolescents. However, the doses of the component drugs that make up this FDC tablet are approved for use in adolescents and the Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV (the Panel) generally endorses the use of adult formulations for drugs that have been approved for use in children and adolescents. The FDC tablet may be appropriate for use in certain adolescents. See Modifying Antiretroviral Regimens in Children With Sustained Virologic Suppression on Antiretroviral Therapy for additional considerations on the use of this combination.

Formulation Differences: Film-Coated Tablet Compared to Dispersible Tablet

DTG is currently available as either film-coated tablets or dispersible tablets (tablets for oral suspension). The dispersible tablet has 60% to 80% greater bioavailability in adults than the film-coated tablet,²³ so recommended doses using the dispersible tablet cannot be directly compared to those using the film-coated tablets. The drug exposure provided by the 50-mg film-coated tablet is approximately equal to that of DTG 30 mg administered as dispersible tablets.

Efficacy and Pharmacokinetics

Pediatric Patients 4 Weeks to <18 years

Single-Entity Dolutegravir

IMPAACT P1093 is a multinational, open-label trial of DTG in children with HIV. Data from IMPAACT P1093 Cohort 1 (aged 12 years to <18 years) and Cohort 2 (aged 6 years to <12 years) provided support for use of DTG film-coated tablets in pediatric patients weighing ≥14 kg; Cohort 3 (aged 2 to <6 years), Cohort 4 (aged 6 months to <2 years), and Cohort 5 (aged 4 weeks to <6 months) provided evidence supporting the use of DTG 5-mg dispersible tablets. Dosing recommendations that previously included the 25-mg film-coated tablets have been replaced with other formulations.

Results of pharmacokinetic (PK), safety, and efficacy assessments have been reported sequentially for different age and weight cohorts as data became available; similarly, dosing recommendations have been revised sequentially.^24-26 A total of 181 participants were enrolled across these cohorts, of which 96 received dispersible DTG tablets and 85 received nondispersible formulations.²⁶ Seventy-‍five participants received the recommended doses of the film-coated or dispersible tablets based on their weight and age, of which 80% were treatment-experienced and all were INSTI-naive.²⁷ At Week 48, of the 42 participants with available data, 69% achieved HIV RNA <50 copies/mL and 79% achieved HIV RNA <400 copies/mL. The effectiveness observed in the trial was comparable to that of treatment-experienced adult participants.²⁷ The median CD4 T lymphocyte cell (CD4) count (percent) increased from baseline to Week 48 by 141 cells/mm³ (7%). Overall, the safety profile in P1093 participants was comparable to that observed in adults, and both formulations were well tolerated.²⁷ Follow-up data among 16 adolescents in Cohort 1 through 144 weeks showed 43% and 35% of participants achieving and maintaining HIV RNA levels <400 copies/mL and <50 copies/mL, respectively.²⁸ Genotypic testing was available at the time of treatment failure for 6 of the 13 participants; one of these adolescents developed DTG resistance.^26,28

The Once-daily DTG-based ART in Young people vS Standard thErapY (ODYSSEY) trial, conducted by the Pediatric European Network for the Treatment of AIDS (PENTA), enrolled both treatment-naive and treatment-experienced pediatric patients from the European Union, Thailand, and several African countries; this trial initially evaluated doses approved by the European Medicines Agency at the time the trial started. A total of 707 children aged <18 years were enrolled; 311 children started DTG as first-line therapy, and 396 started DTG as second-line therapy.²⁹ DTG-based antiretroviral therapy (ART) as both first-line therapy and second-line therapy in children was superior to standard care through 96 weeks of treatment.³⁰ Results from the younger ODYSSEY cohort of children weighing between 3 kg and 14 kg showed superiority of DTG-based ART compared with other regimens, of which over 70% were protease inhibitor (PI)–based regimens.^30-32 Follow-up data through 192 weeks continued to demonstrate the superiority of DTG-containing ART for virologic suppression compared with first- and second-line ART.³³

Nested PK substudies within ODYSSEY also evaluated simplified pediatric dosing that aligned with World Health Organization (WHO)–recommended weight bands. PK data are available from a cohort of children weighing >25 kg who switched to the DTG 50-mg film-coated tablet, 20 kg to <25 kg who received either the DTG 50-mg film-coated tablet or DTG 30 mg administered as six 5‑mg dispersible tablets,^34,3514 kg to <20 kg who received 25 mg, 3 kg to <6 kg and younger than 6 months received 5 mg DTG, 3 kg to <6 kg and older than 6 months who received 10 mg, 6 kg to <10 kg who received 15 mg, and 10 kg to <14 kg who received 20 mg.³⁵ A total of 19 children weighing <20 kg experienced Grade 3 or higher AEs, including two deaths (one kwashiorkor and one accidental trauma) assessed as unrelated to the study drug. Eleven participants experienced serious AEs, 69% of which were due to infectious diseases.

Combined PK data from P1093 and ODYSSEY across all age/weight cohorts form the basis for the current FDA dose recommendations and are summarized in Table B below. Generally speaking, the AUC and C_max values were comparable or higher than adult values, whereas troughs were slightly lower and more variable, but exposures still fell within acceptable exposure ranges across weight bands. These data support the administration of either DTG 30 mg as dispersible tablets or DTG 50 mg as a film-coated tablet in patients weighing ≥20 kg. In addition, modeling and simulations that included UGT1A1 maturation in infants were used to support the dose of DTG in infants at least 4 weeks of age and weighing at least 3 kg. Dosing in neonates is under investigation.

Separate PK studies and population PK models have continued to support adequate DTG exposures among children and adolescents at the currently recommended doses.^21,36-40 Exploratory investigations also have identified that genetic variants in ATP-binding cassette subfamily G member 2 (ABCG2), nuclear receptor subfamily 1 group I member 2, and UGT1A1 may affect DTG PK in infants and children, which may explain some of the additional variability observed in this population.⁴¹ Genetic variants in ABCG2 and UGT1A1 that were associated with higher DTG exposures showed a trend toward sustained virologic suppression.

Dolutegravir/Abacavir/Lamivudine

The PK, safety, tolerability, and efficacy of dispersible and immediate-release ABC/DTG/3TC FDC tablet formulations were investigated in 57 children weighing 6 kg to <40 kg and aged <12 years among those enrolled in the IMPAACT 2019 study.⁴² Children were dosed across five weight bands in alignment with the WHO ARV dosing recommendations for each component. Children weighing 6 kg to <25 kg received dispersible FDC tablets containing ABC 60 mg/DTG 5 mg/3TC 30 mg (Triumeq PD), and those weighing 25 kg to <40 kg received the immediate-release FDC tablet containing ABC 600 mg/DTG 50 mg/3TC 300 mg (Triumeq). Drug exposures for all three components were comparable to previous studies in children and adults with HIV, including DTG exposures from IMPAACT P1093 and ODYSSEY. Dosing was confirmed based on PK and safety criteria across all weight bands. No Grade 3 or 4 AEs related to the drug components were identified through 24 weeks of treatment, and none of the participants discontinued the study drug because of AEs. At Week 24, 54 of 57 (95%) participants were suppressed to HIV-1 RNA <200 copies/mL, 52 of 57 (91%) were suppressed to HIV-1 RNA <50 copies/mL, and all treatment-experienced patients who switched to ABC/DTG/3TC maintained suppression. Both formulations were also well tolerated, and 10 of 11 participants in the highest weight band were able to swallow the larger immediate-release tablet whole and intact (see Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents). This finding contrasted a separate cohort of 12 adolescents in Spain, where half needed to crush or split the immediate-release tablet because of its size.⁴³ Analyses of safety and efficacy data through 48 weeks in IMPAACT 2019 are ongoing.

Population PK modeling of IMPAACT 2019 data through 48 weeks further demonstrated alignment of PK data collected within this study with existing population PK models for the individual components, further supporting dose confirmation of the dispersible FDC.⁴⁰ These models were then modified with maturation functions specific to each component to evaluate whether a single ABC 60 mg/DTG 5 mg/3TC 30 mg tablet in infants weighing ≥3 kg to <6 kg (aged ≥4 weeks) could achieve comparable drug exposures observed in older children and adults based on dosing simulations, and thus provide comparable safety and efficacy observed in older children and adults.⁴⁴ These models used data from young children across weight bands from IMPAACT 2019 (≥6 kg), P1093 (≥3 kg), ODYSSEY (≥3 kg) clinical trials for DTG, and the PETITE clinical trial for ABC and 3TC.^{26,35,40,42,45,46} Review of the ABC/3TC data from the PETITE study in neonates^45,46 and available ABC, 3TC, and DTG safety data in infants aged <3 months (see below under Pediatric Postmarketing Safety Studies) were used to interpolate safety for infants aged ≥4 weeks to <3 months and suggested no safety concerns for coadministration of ABC/3TC/DTG in young infants. Notably, the doses in the safety evaluation were mostly in alignment with the WHO weight-band dose recommendations of fixed-dose formulations of ABC 120 mg/3TC 60 mg, which were higher than those under evaluation in this modeling and simulation. Based on these findings, the Panel supports the use of the single ABC/3TC/DTG FDC dispersible tablet as an alternative to the separate formulations of ABC, 3TC, and DTG in infants weighing ≥3 kg to <6 kg and aged ≥4 weeks to facilitate treatment adherence.

Retrospective Cohort Studies

Efficacy and safety of DTG-based regimens have been evaluated in multiple observational pediatric cohorts.^47-51 These studies have included a variety of populations, including children, adolescents, and young adults who were ART experienced but INSTI naive and either virologically suppressed or viremic at baseline. Virologic suppression rates between about 80% to 93% have been reported following at least 6 months to 24 months of DTG-containing therapy.^48-53 Discontinuation rates due to toxicity have generally been low (<1%).⁴⁸ Factors associated with a higher likelihood of virologic suppression following the switch included suppressed viral loads at baseline,^47-49,51,52 use of once-daily TDF/3TC/DTG as a single-tablet regimen (compared with ABC/3TC/DTG or ZDV/3TC/DTG),⁴⁸ and good medication adherence. Factors associated with lower odds of virologic suppression included age increases and poorer adherence.^48,50,51 Given the retrospective nature of these analyses, many of which were performed following national rollout programs, direct comparisons among participants who were not suppressed and did not switch to a DTG-containing regimen could not always be performed.⁴⁸

Although observational studies have shown high virologic suppression rates, emerging INSTI mutations specific to DTG have been reported among children being monitored in national treatment programs.⁵³ Thus, continued assessments of sustained long-term virologic suppression (i.e., >24 months) and the development of resistance will be important.^54,55 Additionally, one study noted⁵² more than one-third of children experienced at least two regimen changes during the follow-up period from 2019 to 2021, some of which involved switching from DTG to either a PI or non-nucleoside reverse transcriptase inhibitor (NNRTI). These changes were attributable, in part, to drug shortage, illustrating the importance of continued access and supply of DTG to support rollout initiatives.⁴³

Pediatric Postmarketing Safety Studies

Several studies continue to investigate longer-term safety outcomes in pediatric populations with the expanded use of DTG. Notable outcomes of interest include neuropsychiatric outcomes and growth, weight gain, and metabolic effects over time based on findings in adults.

ODYSSEY reported a small number of neuropsychiatric AEs among 707 children and adolescents randomized to DTG, which was not significantly different from those reported in study participants receiving standard care. However, participants receiving DTG were more likely to have suicidal ideation than those receiving standard care; however, these symptoms were described as transient and did not lead to changes in ART.³¹ A separate systematic review of INSTI use in 3,448 children with perinatal HIV infection identified rates of neuropsychiatric effects from 1% to 16% among those receiving DTG.⁵⁶

Reports of weight gain among adults enrolled in clinical trials prompted similar studies to investigate the metabolic effects of DTG in adolescents. Some studies have identified increases in weight-for-age z-score and BMI-for-age z-score,^7,9,32 as well as trunk fat and trunk/total body fat ratios.⁶ However, others have not identified significant changes^8,10,57 or lower rates of change among those with baseline BMI ≥50th percentile.⁵⁸ Lipid changes also have been evaluated, with one study detailing decreases in total cholesterol and low-density lipoproteins, while serum triglycerides decreased early in the study and subsequently increased.⁶ In another study, adolescents who switched to DTG (n = 30) demonstrated reduced hepatic steatosis and lower total cholesterol and triglycerides compared to those who remained on their initial ART regimens (84% PI-based).⁵⁷ Based on these collective data, weight gain may be observed in adolescents receiving DTG, as observed in adults; the long-term clinical significance of these changes is unclear, and further studies are needed in adolescents and children receiving DTG. See the What to Start section for additional considerations.

Simplification of Treatment

Dolutegravir With Rilpivirine

Two trials in adults (Regimen Switch to Dolutegravir + Rilpivirine from Current Antiretroviral Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults [SWORD-1 and SWORD-2]) supported the approval of a DTG 50-mg/RPV 25­mg FDC tablet as a complete regimen for treatment simplification or maintenance therapy in selected patients. The two identical SWORD trials enrolled 1,024 virologically suppressed patients who had been on stable ART for at least 6 months and who had no history of treatment failure or evidence of resistance mutations. The participants were randomized either to receive DTG/RPV or to continue their suppressive ARV regimen. After 48 weeks of treatment, 95% of patients in both arms maintained HIV RNA levels <50 copies/mL.⁵⁹ After 52 weeks, the participants who had been randomized to continue their suppressive ARV regimen were switched to DTG/RPV. At 148 weeks, 84% of the early-switch patients and 90% of the late-switch patients remained virologically suppressed, and only 11 patients receiving dual therapy met virologic failure criteria. No INSTI-resistance was identified.⁶⁰ During the comparative randomized phase of the study, more AEs were reported and led to discontinuation in the DTG/RPV arm. In a subgroup of the SWORD study, small but statistically significant increases in hip and spine bone mineral density and bone turnover markers were observed in patients whose original ARV regimen contained TDF.⁶¹

Although Juluca is not approved by the FDA for use in adolescents, the doses of the component drugs that make up this FDC tablet are approved for use in adolescents. The Panel generally endorses the use of adult formulations for drugs that have been approved for use in children and adolescents, and these products may be appropriate for use in certain adolescents. The use of DTG/RPV regimens could be useful in patients in whom there is concern for toxicity from NRTIs. However, the Panel notes that adolescents may have difficulties adhering to therapy and suggests considering close monitoring with viral load testing (see the Treatment Simplification section of Management of Children Receiving Antiretroviral Therapy).

Dolutegravir With Lamivudine

The approval of DTG 50 mg/3TC 300 mg as a complete regimen in adults was supported by data from two randomized, double-blind, controlled trials (Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naive HIV Infected Subjects [GEMINI-1 and GEMINI-2]). GEMINI-1 and GEMINI-2 were identical 148-week trials that enrolled a total of 1,433 adults with HIV who had plasma HIV RNA levels between 1,000 copies/mL and ≤500,000 copies/mL at screening and no evidence of major resistance mutations or hepatitis B virus infection. Participants were randomized to receive either DTG plus 3TC or DTG plus 3TC/TDF. During 96 weeks of treatment, 86% of patients who received DTG plus 3TC and 89.5% of patients who received DTG plus 3TC/TDF achieved HIV RNA levels <50 copies/mL. Patients who received DTG plus 3TC had a lower rate of adverse drug reactions (19.6%) than those who received DTG plus 3TC/TDF (25%).⁶²

The combination of DTG/3TC was evaluated as initial ART in adolescents weighing ≥25 kg and aged ≥12 years to <18 years with baseline HIV-1 RNA between 100 copies/mL and ≤500,000 copies/mL through the DANCE study. A total of 32 participants were enrolled, of which 81% and 69% achieved HIV RNA levels <50 copies/mL at Weeks 48 and 96, respectively.⁶³ These results included individuals with missing data due to site closures; thus, sensitivity analyses were performed with the participants excluded. Virologic suppression rates in the sensitivity analyses were 87% (26 of 30) at Week 48 and 88% (22 of 25) at Week 96. Drug exposures for both components were also comparable to historical data in adults and the combination was overall safe and well tolerated.

Both film-coated tablet and dispersible tablet formulations of DTG/3TC are also under active investigation in children aged 2 years to <15 years of age and weighing 6 kg to <40 kg through the D3/Penta21 study.⁶⁴ The doses under evaluation include DTG 15 mg/3TC 90 mg for 6 kg to <10 kg, DTG 20 mg/3TC 120 mg for 10 kg to <14kg, DTG 25 mg/3TC 150 mg for 14 kg to <20 kg, DTG 30 mg/3TC 180 mg or DTG 50 mg/3TC 300 mg film-coated tablet for 20 kg to <25 kg, and DTG 50 mg/3TC 300 mg for ≥25 kg, with DTG 50 mg/3TC 300 mg as the only film-coated formulation. These doses were largely aligned with the WHO weight-band dosing recommendations, except for the DTG 50 mg/3TC 300 mg FCT option in those weighing 20 kg to <25 kg, which is 1.3 times higher than the currently recommended dose from that weight band. Preliminary PK data from nested substudies in 53 children weighing 10 kg to <40 kg demonstrated that all participants achieved DTG trough concentrations (C_trough) above the in vitro protein-adjusted 90% maximal inhibitory concentration (IC₉₀) of 0.064 mg/L and 50 of 53 children exceeded the 90% effective concentration (EC₉₀) of 0.32 mg/L.⁶⁵ Exposures for DTG and 3TC were generally comparable to historical data from ODYSSEY and IMPAACT 2019, respectively.

Dolutegravir With Darunavir/Ritonavir

The combination of once-daily darunavir/ritonavir (DRV/r) with an INSTI is being investigated in a randomized non-inferiority trial among virologically suppressed children aged 6 years to <18 years through the SMILE Penta-17-ANRS 152 clinical trial.⁶⁶ Participants were randomized to either once-daily DRV/r with an INSTI or continuing their standard-of-care regimen consisting of a boosted PI or NNRTI with a NRTI backbone. A total of 318 participants were enrolled between 2016 and 2019, of which 158 were randomized to DRV/r with an INSTI (97% DTG, 3% elvitegravir). DRV/r with an INSTI was non-inferior to standard of care at Week 48 (HIV viral load ≥50 copies/mL in 5% for DRV/r with an INSTI vs. 7.6% in the standard-of-care arm; difference ‍−2.5% [95% CI, −7.6% and 2.5%]). Secondary analyses comparing DRV/r with an INSTI versus standard of care revealed decreases in CD4 counts (−48.3 cells/mm³ [95% CI, −93.4 and −3.2; P = 0.036] and mean high-density lipoprotein change from baseline (−4.1 mg/dL [95% CI, −6.7 and ‍−1.4; P = 0.003]), and increases in weight and BMI (+1.97 kg [95% CI, 1.1 and 2.9; P < 0.001] and +0.66 kg/m² [95% CI, 0.3 and 1.0; P < 0.001], respectively). A nested PK substudy in 153 adolescents aged ≥12 years to <18 years from SMILE also demonstrated that total and unbound DTG concentrations were adequate and well above the protein-adjusted IC₉₀ for DTG.⁶⁷ DTG C_trough were also comparable to those measured in adults receiving 50 mg once daily. Apparent clearance of the unbound drug was influenced by total bilirubin concentrations and Asian ethnicity.

Crushing Film-Coated Tablets for Administration

Dispersible tablets are now considered the preferred formulation for pediatric patients weighing <20 kg, and film-coated tablets should not be used in children weighing <14 kg. In children weighing >14 kg who have difficulty swallowing whole tablets, when the preferred dispersible tablets are not available, the 50-mg tablets either may be split into halves followed by immediate ingestion of both halves of the tablet or crushed and added to a small amount of semisolid food or liquid, all of which must be consumed immediately.¹ In healthy adults, the use of crushed tablets resulted in slightly higher exposures than the use of whole tablets.⁶⁸ No information exists on the impact of splitting or crushing film-coated tablets on palatability. Some case reports describe DTG-containing film-coated tablets being crushed and successfully administered via orogastric tube⁶⁹ or nasogastric tube.⁷⁰ If DTG is administered via enteral tube, care should be taken to disperse the tablets completely and flush the tube to avoid clogging.

References

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