skip navigation

Skip Nav

Clinical Guidelines Portal

Clinical Guidelines Portal

Table of Contents

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Dolutegravir

(Last updated: March 1, 2016; last reviewed: March 1, 2016)

Dolutegravir (DTG, Tivicay)
Dolutegravir (DTG, Tivicay)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Tablet: 50 mg
Fixed-Dose Combination Tablet:
  • [Triumeq] Abacavir 600 mg plus dolutegravir 50 mg plus lamivudine 300 mg
Dosing Recommendations Selected Adverse Events
Neonate/Infant Dose:
  • Not approved for use in neonates/infants
Children Aged <12 Years:
  • Not approved for use in children aged <12 years. A clinical trial in treatment-experienced children aged <12 years is under way with an experimental dose of 50 mg in children weighing at least 40 kg.

Adolescent (Weighing ≥40 kg) and Adult Dose:
Population Recommended Dose
Treatment-naive or treatment-experienced/integrase strand transfer inhibitor (INSTI)-naive 50 mg once daily
Treatment-naive or treatment-experienced/INSTI-naive when co-administered with the following potent UGT1A/CYP3A inducers: efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or
rifampin
50 mg twice daily
INSTI-experienced with any INSTI-associated resistance substitutions or clinically suspected INSTI resistancea 50 mg twice daily
a Combinations that do not include metabolic inducers should be considered where possible.


Combination Tablet:
[Triumeq] Abacavir plus Dolutegravir plus Lamivudine:
Adolescent (Weighing ≥40 kg) and Adult Dose:
  • 1 tablet once daily
  • Insomnia
  • Headache
  • Hypersensitivity reactions including rash, constitutional symptoms, and organ dysfunction (including liver injury) have been reported rarely.
Special Instructions
  • May be taken without regard to meals
  • Should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications
  • The efficacy of 50 mg dolutegravir twice daily is reduced in patients with certain combinations of INSTI-resistance mutations (see Resistance section below).
Metabolism/Elimination
  • UGT1A1 and cytochrome P450 (CYP) 3A substrate
  • Dosing in patients with hepatic impairment: No dose adjustment is necessary in patients with mild or moderate hepatic impairment. Because of lack of data, dolutegravir is not recommended in patients with severe hepatic impairment.
  • Dolutegravir decreases tubular secretion of creatinine and slightly increases measured serum creatinine, but does not affect glomerular filtration.
  • Dosing in patients with renal impairment: No dose adjustment is required in INSTI-naive patients with mild, moderate, or severe renal impairment or in INSTI-experienced patients with mild or moderate renal impairment.
  • Use dolutegravir with caution in INSTI-experienced patients with severe renal impairment (creatinine clearance <30 mL/min) because dolutegravir concentrations will be decreased (the cause of this decrease is unknown).

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Metabolism: Dolutegravir is a UGT1A1 and CYP3A substrate and may require dosage adjustments when administered with UGT1A1 or CYP3A-modulating medications. Because etravirine significantly reduces plasma concentrations of dolutegravir, dolutegravir should not be administered with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir, which counteracts this effect on dolutegravir concentrations. Dolutegravir should not be administered with nevirapine because of insufficient data.
  • Before dolutegravir is administered, a patient’s medication profile should be carefully reviewed for potential drug interactions.

Major Toxicities

  • More common: Insomnia and headache
  • Less common (more severe): Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, neuropsychiatric symptoms.

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10), and the Stanford University HIV Drug Resistance database offers a discussion of integrase strand transfer inhibitor (INSTI) mutations (http://hivdb.stanford.edu/DR/). The efficacy of 50 mg dolutegravir twice daily is reduced in patients with INSTI-resistance Q148 substitution plus two or more additional INSTI-resistance mutations: T66A, L74I/M, E138A//K/T, G140SA/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.

Pediatric Use

Approval
Dolutegravir is Food and Drug Administration (FDA)-approved in combination with other antiretroviral drugs for children aged ≥12 years, weighing at least 40 kg, and who are treatment-naive or treatment-experienced and INSTI-naive.1

Efficacy and Pharmacokinetics

IMPAACT P1093 is an ongoing open-label trial of HIV-infected children with the plan to enroll down to age 4 weeks. FDA approval of dolutegravir down to age 12 years was based on data from 23 treatment-experienced, INSTI-naive adolescents.2 Intensive pharmacokinetic (PK) evaluations were performed on the first 10 participants (9 weighing ≥40 kg and receiving 50 mg, 1 weighing 37 kg and receiving 35 mg) and revealed exposures comparable to those seen in adults receiving 50 mg once daily. Nine of 10 participants achieved HIV RNA concentration <400 copies/mL at week 4 (optimal background therapy was added 5 to 10 days after dolutegravir was started). An additional 13 participants were then enrolled for evaluation of long-term outcomes. At 48 weeks, 61% had achieved HIV RNA concentration <50 copies/mL. No safety or tolerability concerns were identified. By week 144, 39% and 30% had achieved HIV RNA concentrations <400 and <50 copies/mL, respectively.3 All who experienced virologic failure were nonadherent. In addition, children aged ≥6 to <12 years are undergoing PK and longer-term follow up in P1093, using investigational tablets of lower strengths (or the 50-mg tablet if they weigh at least 40 kg). To date, data from 11 participants have demonstrated a favorable safety profile, adequate PK, and virologic efficacy through 24 weeks.2,4 An oral pediatric granule formulation is also being studied.

References

  1. Dolutegravir (Tivicay) [package insert]. Food and Drug Administration. 2015. Available at https://www.viivhealthcare.com/media/58599/us_tivicay.pdf. Accessed February 17, 2016.
  2. Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV-1 infected adolescents: 48-week results from IMPAACT P1093. Pediatr Infect Dis J. 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26244832.
  3. Viani R, Alvero C, Fenton T, et al. Long-term safety and efficacy of dolutegravir in HIV treatment-experienced adolescents. Presented at: Infectious Disease Week. 2015. San Diego, CA.
  4. Viani R, Carmelita A, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV+ children. Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.

Back to Top