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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Dolutegravir

(Last updated: February 12, 2014; last reviewed: February 12, 2014)

Dolutegravir (DTG)
Dolutegravir (DTG, Tivicay, GSK1349572)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Tablet: 50 mg
Dosing Recommendations

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.
Children Aged ≥12 Years and Weighing Aat Least 40 kg (Treatment-Naive or Treatment-Experienced/Integrase Strand Transfer Inhibitor [INSTI]-Naive):
  • 50 mg once daily
  • If co-administered with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin, then 50 mg twice daily should be given.
Adult Dose
Adult Population  Recommended Dose 
Treatment-naive or treatment-experienced/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.

Selected Adverse Events
  • Insomnia
  • Headache
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
  • Poor virologic response to 50 mg dolutegravir twice daily may occur if INSTI-resistance Q148 substitution is present along with 2 or more additional INSTI-resistance mutations: L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R.
Metabolism
  • 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. Dolutegravir is not recommended in patients with severe hepatic impairment because of lack of data.
  • 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:

  • Metabolism: Dolutegravir is a UGT1A1 and CYP 3A substrate and may require dosage adjustments when administered with UGT1A1 or CYP 3A-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.

Resistance
The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (http://www.iasusa.org/resistance_mutations/index.html), and the Stanford University HIV Drug Resistance database offers a discussion of integrase strand transfer inhibitor (INSTI) mutations (http://hivdb.stanford.edu/DR/INIResiNote.html). Poor virologic response to 50 mg dolutegravir twice daily may occur if INSTI-resistance Q148 substitution is present along with 2 or more additional INSTI-resistance mutations (see table above for list).

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

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. 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 comparable exposures to those seen in adults receiving 50 mg once daily.1 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 24 weeks, 70% had achieved HIV RNA concentration <50 copies/mL. No safety or tolerability concerns were identified.2 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). An oral pediatric granule formulation will also be studied.

References

  1. Hazra R, Viani R, Acosta E, et al. Pharmacokinetics, safety and efficacy of dolutegravir (DTG; S/GSK1349572) in HIV-1-positive adolescents: preliminary analysis from IMPAACT P1093. Abstract # TUAB0203. Paper presented at: XIX International AIDS Conference; July 22-27, 2012; Washington, DC.
  2. FDA. TIVICAY(dolutegravir) Drug Label. 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf.

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