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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Raltegravir

(Last updated:2/12/2014; last reviewed:2/12/2014)

Raltegravir (RAL, Isentress)

Raltegravir (RAL, Isentress)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Formulations

Tablets: 400 mg (film-coated poloxamer tablet)
Chewable Tablets: 100 mg (scored) and 25 mg
For Oral Suspension: Single-use packet of 100 mg (expected fall 2014)

Note: Film-coated tablets, chewable tablets, and oral suspension are not interchangeable.

Dosing Recommendations

Neonate Dose:
  • Not approved for use in neonates. Note: Metabolism by UGT1A1 is immature in neonates. Neonatal dose will be studied in full-term infants in IMPAACT P1110. 
Infant/Pediatric Dose

Oral Suspension Dosing Tablea
Children at least 4 weeks of age and weighing 3 kg to < 20 kg:
Body Weight (kg)  Volume (Dose) of Suspension to be Administered
3 to <4
1 mL (20 mg) twice daily
4 to <6
1.5 mL (30 mg) twice daily
6 to <8
2 mL (40 mg) twice daily
8 to <11
3 mL (60 mg) twice daily
11 to <14
4 mL (80 mg) twice daily
14 to <20
5 mL (100 mg) twice daily
a The weight-based dosing recommendation for the oral suspension is based on approximately 6 mg/kg/dose twice daily.

Note
: Maximum dose of oral suspension is 5 ml (100 mgd) twice daily.

Children Aged 2 to <12 Years:
  • <25 kg: Chewable tablet twice daily (maximum of 300 mg twice daily). See table below for chewable tablet dose.
  • ≥25 kg: 400-mg film-coated tablet twice daily or chewable tablets twice daily. See table for chewable tablet dose.
Chewable Tablet Dosing Table
Dosing
a of chewable tablets in children aged 2 to <12 years:
Body Weight (kg) Dose Number of Chewable Tablets 
10 to <14   75 mg twice daily 3 X 25 mg twice daily
14 to <20  100 mg twice daily 1 X 100 mg twice daily
20 to <28 150 mg twice daily 1.5 X 100 mgb twice daily
28 to <40  200 mg twice daily 2 X 100 mg twice daily
≥40  300 mg twice daily 3 X 100 mg twice daily
a The weight-based dosing recommendation for the chewable tablet is based on approximately 6 mg/kg/dose twice daily.
b The 100-mg chewable tablet can be divided into equal halves.

Note: Maximum dose of chewable tablets is 300 mg twice daily.

Adolescent (Aged ≥12 Years)/Adult Dose:
  • 400-mg film-coated tablet twice daily

Selected Adverse Events

  • Rash, including Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis
  • Nausea, diarrhea
  • Headache
  • Insomnia
  • Fever
  • Creatine phosphokinase elevation, muscle weakness, and rhabdomyolysis

Special Instructions

  • Can be given without regard to food.
  • Chewable tablets may be chewed or swallowed whole.
  • Film-coated tablets, chewable tablets, and oral suspension are not interchangeable. Chewable tablets and oral suspension have better bioavailability than the film-coated tablets.
  • Chewable tablets should be stored in the original package with desiccant to protect from moisture.
  • Chewable tablets contain phenylalanine. Therefore, patients with phenylketonuria should make the necessary dietary adjustments.
  • Oral suspension is provided with a kit which includes 2 mixing cups, 2 dosing syringes, and 60 foil packets. Detailed instructions are provided in Instructions for Use document. Each foil, single-use packet contains 100 mg of raltegravir, which will be suspended in 5 mL of water for final concentration of 20 mg/mL. Dose should be administered within 30 minutes of mixing; unused solution should be discarded as directed in Instructions for Use document.

Metabolism

  • Uridine diphosphate glucotransferase (UGT1A1)-mediated glucuronidation.
  • Dosing of raltegravir in patients with hepatic impairment: No dosage adjustment is necessary for patients with mild-to-moderate hepatic insufficiency. No dosing information is available for patients with severe hepatic impairment.
  • Dosing of raltegravir in patients with renal impairment: No dosage adjustment necessary.

Drug Interactions (See also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents)

  • Metabolism: The major route of raltegravir elimination is mediated through glucuronidation by uridine diphosphate glucotransferase (UGT1A1). 
  • Inducers of UGT1A1 such as rifampin and tipranavir may result in reduced plasma concentrations of raltegravir whereas inhibitors of UGT1A1 such as atazanavir may increase plasma concentrations of raltegravir. 
  • In adults, an increased dose of raltegravir is recommended when co-administered with rifampin. The appropriate dose adjustment is not known in children.
  • Efavirenz and etravirine may decrease raltegravir concentrations. 
  • Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions with raltegravir.
  • Raltegravir plasma concentrations may be reduced when administered with antacids containing divalent metal cations such as magnesium hydroxide, aluminum hydroxide, or calcium carbonate. Co-administration or administration of raltegravir within 2 hours of aluminum and/or magnesium hydroxide-containing antacids resulted in significantly reduced raltegravir plasma levels and is not recommended.  

Major Toxicities

  • More common: Nausea, headache, dizziness, diarrhea, fatigue, itching, and insomnia
  • Less common: Abdominal pain, vomiting. Patients with chronic active hepatitis B and/or hepatitis C are more likely to experience worsening aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin than are patients who are not coinfected. 
  • Rare: Moderate to severe increase in creatine phosphokinase. Myopathy and rhabdomyolysis: Use raltegravir with caution in patients receiving medications associated with these toxicities. Anxiety, depression, especially in those with prior history. Rash including Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis have been reported. Thrombocytopenia.

Resistance

The International AIDS Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/INIResiNote.html). 

Pediatric Use

Approval
Raltegravir is FDA-approved for use in infants and children aged ≥ 4 weeks and weight ≥3 kg. Current pediatric approval and dosing recommendations are based upon evaluations in 122 patients aged ≥ 4 weeks to 18 years enrolled in IMPAACT P1066.

Efficacy and Pharmacokinetics

Children Aged 2 to 18 Years
IMPAACT P1066 is a Phase I/II open label multicenter study to evaluate the pharmacokinetic (PK) profile, safety, tolerability, and efficacy of various formulations of raltegravir in combination antiretroviral treatment (cART)-experienced, HIV-infected children and adolescents aged 2 to 18 years in combination with an optimized background cART regimen.2 Subjects receive either the 400-mg, film-coated tablet formulation twice daily (patients aged 6–18 years and weighing at least 25 kg) or the chewable tablet formulation at a dose of 6 mg/kg twice daily (aged 2 to <12 years). In IMPAACT P1066, the initial dose-finding stage includes intensive PK evaluation in various age cohorts: (aged 12 to <19 years, 6 to <12 years, 2 to <6 years). Dose selection is based upon achieving target PK parameters similar to those seen in adults: PK targets are geometric mean (GM) area under the curve of 14–25 µMxh and GM 12-hour concentration >33 nM. Additional subjects are then enrolled in each age cohort to evaluate long-term efficacy, tolerability, and safety. Ninety-three (97%) subjects completed 24 weeks of treatment with 54% achieving HIV RNA <50 copies/mL with a mean CD4 T lymphocyte (CD4) count (percent [%]) increase of 119 cells/mm3 (3.8%). Ninety-one subjects completed 48 weeks of treatment with 57% achieving HIV RNA <50 copies/mL with a mean CD4 count (percent [%]) increase of 156 cells/mm3 (4.6%).2 In subjects who experienced virologic failure, development of drug resistance and/or poor adherence were contributing factors. The frequency, type, and severity of drug-related adverse reactions through week 48 were comparable to those observed in adult studies. Observed adverse reactions considered drug-related included one patient with grade 3 psychomotor hyperactivity, abnormal behavior, and insomnia; one patient with a grade 2 allergic rash; and one patient with grade 3 ALT and grade 4 AST laboratory elevations. There were no discontinuations due to adverse events and no drug-related deaths.

In 19 HIV-infected children and adolescents with multidrug-resistant virus in the HIV Spanish Pediatric Cohort (CoRISe), good virologic response and improved CD4 counts were observed when raltegravir was included in an optimized regimen.3 Additional experience from the French expanded access program in treatment-experienced adolescents support the good virologic and immunologic results observed in P1066.4,5

Infants/Toddlers Aged At Least 4 Weeks to <2 Years
IMPAACT P1066 studied 26 infants and toddlers aged 4 weeks to <2 years who were administered the oral suspension in combination with an optimized background regimen. All subjects had received prior antiretrovirals as part of prevention of perinatal transmission and/or treatment of HIV infection, and 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL. Twenty-three (88%) completed 48 weeks of treatment with 44% achieving HIV RNA <50 copies/mL with a mean CD4 cell count (percent [%]) increase of 492 cells/mm3 (7.8%).1 PK parameters were similar to those achieved for the older cohorts in P1066.

Neonates Aged <4 Weeks 
There are no data on the safety and dosing of raltegravir in neonates aged <4 weeks. Raltegravir is metabolized by UGT1A1, the same enzyme responsible for the elimination of bilirubin. UGT enzyme activity is low at birth and it is likely that raltegravir elimination is prolonged in neonates. In addition, bilirubin and raltegravir may compete for UGT and albumin binding sites.6

Washout PK of raltegravir in neonates born to HIV-infected pregnant women was studied in P1097.7 The neonatal plasma half-life was highly variable, ranging from 9.3 to 184 hours, suggesting potential roles for developmental aspects of neonatal UGT1A1 enzyme activity, redistribution, and/or enterohepatic recirculation of raltegravir. IMPAACT P1110 is a phase I trial that will evaluate the safety and PK of raltegravir in HIV-1 exposed neonates at high risk of acquiring HIV-1 infection. 

Formulations

The PK of raltegravir were compared in HIV-infected adult patients receiving intact whole 400-mg tablets and patients who chewed the 400-mg film-coated tablets because of swallowing difficulties. Drug absorption was significantly higher in the group who chewed the tablets, although palatability was rated as poor.8 

The raltegravir chewable tablet and oral suspension have higher oral bioavailability than the film-coated tablet based on a comparative study in healthy adult volunteers.9 Interpatient and intrapatient variability for PK parameters of raltegravir are considerable, especially with the film-coated tablets.1,10 Because of the differences in the bioavailability of the chewable and film-coated tablets, the dosing recommendations are different and these products are not interchangeable

References

  1. FDA. Isentress Prescribing Information. 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022145s028,203045s005lbl.pdf. Accessed December 20, 2013.
  2. Nachman S, Zheng N, Acosta EP, et al. Pharmacokinetics, Safety, and 48-Week Efficacy of Oral Raltegravir in HIV-1-Infected Children Aged 2 Through 18 Years. Clin Infect Dis. Nov 23 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/24145879.
  3. Briz V, Leon-Leal JA, Palladino C, et al. Potent and sustained antiviral response of raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and adolescents. Pediatr Infect Dis J. Mar 2012;31(3):273-277. Available at http://www.ncbi.nlm.nih.gov/pubmed/22330165.
  4. Thuret I, Tamalet C, Reliquet V. Raltegravir in Children and Adolescents: The French Expanded Access Program. Paper Presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2009.
  5. Thuret I, Chaix ML, Tamalet C, et al. Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS. Nov 13 2009;23(17):2364-2366. Available at http://www.ncbi.nlm.nih.gov/pubmed/19823069.
  6. Clarke DF, Wong RJ, Wenning L, Stevenson DK, Mirochnick M. Raltegravir in vitro effect on bilirubin binding. Pediatr Infect Dis J. Sep 2013;32(9):978-980. Available at http://www.ncbi.nlm.nih.gov/pubmed/23470680.
  7. Clarke DF, Acosta EP, Rizk M, et al. Raltegravir Pharmacokinetics and Safety in Neonates: IMPAACT P1097. Paper presnted at: Conference on Retroviruses and Opportunistic Infections (CROI); 2013; Atlanta, GA.
  8. Cattaneo D, Baldelli S, Cerea M, et al. Comparison of the in vivo pharmacokinetics and in vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or by chewing. Antimicrob Agents Chemother. Dec 2012;56(12):6132-6136. Available at http://www.ncbi.nlm.nih.gov/pubmed/22964253.
  9. Brainard D, Gendrano N, Jin B, et al. A pharmacokinetic comparison of adult and pediatric formulations of RAL in healthy adults. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA.
  10. Siccardi M, D'Avolio A, Rodriguez-Novoa S, et al. Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting. Ther Drug Monit. Apr 2012;34(2):232-235. Available at http://www.ncbi.nlm.nih.gov/pubmed/22406652.