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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Entry and Fusion Inhibitors

Enfuvirtide

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

Enfuvirtide (ENF, T-20, Fuzeon)
Enfuvirtide (ENF, T-20, Fuzeon)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Lyophilized Powder for Injection
:
  • 108 mg vial of enfuvirtide. Reconstitution with 1.1 mL sterile water will deliver 90 mg/mL.
Convenience Kit:
  • 60 single-use vials of enfuvirtide (90-mg strength), 60 vials of sterile water for injection, 60 reconstitution syringes (3 mL), 60 administration syringes (1 mL), alcohol wipes
Dosage Recommendations
Pediatric/Adolescent Dose (Aged 6–16 Years):
Children Aged <6 Years:
  • Not approved for use in children aged <6 years
Children Aged ≥6 Years:
  • 2 mg/kg (maximum dose, 90 mg [1 mL]) twice daily injected subcutaneously (SQ) into the upper arm, anterior thigh, or abdomen

Adolescent (Aged >16 Years)/Adult Dose:
  • 90 mg (1 mL) twice daily injected SQ into the upper arm, anterior thigh, or abdomen


Selected Adverse Events
  • Local injection site reactions (e.g., pain, erythema, induration, nodules and cysts, pruritus, ecchymosis) in up to 98% of patients.
  • Increased rate of bacterial pneumonia (unclear association)
  • Hypersensitivity reaction (HSR)—symptoms may include rash, fever, nausea, vomiting, chills, rigors, hypotension, or elevated serum transaminases. Re-challenge is not recommended.
Special Instructions
  • Carefully instruct patient or caregiver in proper technique for drug reconstitution and administration of SQ injections. Enfuvirtide injection instructions are provided with convenience kits.
  • Allow reconstituted vial to stand until the powder goes completely into solution, which could take up to 45 minutes. Do not shake.
  • Once reconstituted, inject enfuvirtide immediately or keep refrigerated in the original vial until use. Reconstituted enfuvirtide must be used within 24 hours.
  • Enfuvirtide must be given SQ; severity of reactions increases if given intramuscularly.
  • Give each injection at a site different from the preceding injection site; do not inject into moles, scar tissue, bruises, or the navel. Both the patient/caregiver and health care provider should carefully monitor for signs and symptoms of local infection or cellulitis.
  • To minimize local reactions apply ice or heat after injection or gently massage injection site to better disperse the dose. There are reports of injection-associated neuralgia and paresthesia when alternative delivery systems, such as needle-free injection devices, are used.
  • Advise patient/caregiver of the possibility of a HSR; instruct them to discontinue treatment and seek immediate medical attention if the patient develops signs and symptoms consistent with a HSR.
Metabolism
  • Catabolism to constituent amino acids.

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

  • There are no known significant drug interactions with enfuvirtide.

Major Toxicities

  • More common: Almost all patients (87%–98%) experience local injection site reactions including pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Reactions are usually mild to moderate in severity but can be more severe. Average duration of local injection site reaction is 3 to 7 days, but was >7 days in 24% of patients.
  • Less common (more severe): Increased rate of bacterial pneumonia (unclear association).1 Pediatric studies have lacked the statistical power to answer questions concerning enfuvirtide use and increased risk of pneumonia.
  • Rare: Hypersensitivity reactions (HSRs) (<1%) including fever, nausea and vomiting, chills, rigors, hypotension, and elevated liver transaminases; immune-mediated reactions including primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Patients experiencing HSRs should seek immediate medical attention. Therapy should not be restarted in patients with signs and symptoms consistent with HSRs.
  • Pediatric specific: Local site cellulitis requiring antimicrobial therapy (up to 11% in certain subgroups of patients in pediatric studies).2

Resistance

The International Antiviral 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/pages/GRIP/enfuvirtide.html).

Pediatric Use 

Approval
Although enfuvirtide is Food and Drug Administration (FDA)-approved for use in children, it is not commonly used because of its high cost, need for twice-daily subcutaneous (SQ) injections, and high rate of injection site reactions. Use in deep salvage regimens3 has also declined with the availability of integrase inhibitors and other entry inhibitors (such as maraviroc).

Pharmacokinetics
A single-dose pharmacokinetic (PK) evaluation study of enfuvirtide, given SQ to 14 HIV-infected children aged 4 to 12 years (PACTG 1005), identified that enfuvirtide 60 mg/m2 of body surface area per dose resulted in a target trough concentration that approximated the “equivalent” of a 90-mg dose delivered SQ to an adult (1000 mg/mL).4 In a second pediatric study of 25 children aged 5 to 16 years, a 2-mg/kg dose (maximum 90 mg) of enfuvirtide given twice daily, yielded drug concentrations similar to 60 mg/m2 of body surface area dose independent of age group, body weight, body surface area, and sexual maturation.5 The Food and Drug Administration (FDA)-recommended dose of enfuvirtide for children aged 6 to 16 years is 2 mg/kg (maximum 90 mg) administered SQ twice daily. Further data are needed for dosing in children aged <6 years. 

Efficacy
The safety and antiretroviral (ARV) activity of twice-daily SQ enfuvirtide administration at 60 mg/m2 per dose plus optimized background therapy (OBT) was evaluated over 96 weeks in 14 children aged 4 to 12 years who had failed to achieve viral suppression on multiple prior ARV regimens (PACTG 1005). At 24 weeks 71% of the children had a >1.0log reduction in viral load; 43% and 21% had HIV RNA levels suppressed to <400 copies/mL and <50 copies/mL, respectively. However, only 36% of children maintained virologic suppression (>1.0log decrease in HIV RNA) at Week 96. Most children had local injection site reactions.6 Significant improvements in CD4 T lymphocyte (CD4) percentages and height z scores were observed in children receiving enfuvirtide for 48 and 96 weeks.

T20-310, a Phase I/II study of enfuvirtide (2.0 mg/kg SQ, maximum 90 mg, twice daily) plus OBT, enrolled 52 treatment-experienced children aged 3 years to 16 years for 48 weeks. Only 64% of the children completed 48 weeks of therapy. The median decrease in HIV RNA was -1.17 log10 copies/mL (n = 32) and increase in CD4 count was 106 cells/mm3 (n = 25). At Week 8, treatment responses as measured by several plasma HIV RNA parameters were superior in younger children (aged <11 years) compared with adolescents. Median increases in CD4 cell count were 257 cells/mm3 in children and 84 cells/mm3 in adolescents. Local skin reactions were common in all age groups (87% of study participants). The observed differential responses between children and adolescents probably reflect unique challenges to adherence with the prescribed regimen.2

References

  1. Kousignian I, Launay O, Mayaud C, et al. Does enfuvirtide increase the risk of bacterial pneumonia in patients receiving combination antiretroviral therapy? J Antimicrob Chemother. Jan 2010;65(1):138-144. Available at http://www.ncbi.nlm.nih.gov/pubmed/19903719.
  2. Wiznia A, Church J, Emmanuel P, et al. Safety and efficacy of enfuvirtide for 48 weeks as part of an optimized antiretroviral regimen in pediatric human immunodeficiency virus 1-infected patients. Pediatr Infect Dis J. Sep 2007;26(9):799-805. Available at http://www.ncbi.nlm.nih.gov/pubmed/17721374.
  3. Feiterna-Sperling C, Walter H, Wahn V, Kleinkauf N. A 12-year-old boy with multidrug-resistant human immunodeficiency virus type 1 successfully treated with HAART including ritonavir-boosted tipranavir oral solution and enfuvirtide. Eur J Med Res. Jan 28 2009;14(1):44-46. Available at http://www.ncbi.nlm.nih.gov/pubmed/19258211.
  4. Church JA, Cunningham C, Hughes M, et al. Safety and antiretroviral activity of chronic subcutaneous administration of T-20 in human immunodeficiency virus 1-infected children. Pediatr Infect Dis J. Jul 2002;21(7):653-659. Available at http://www.ncbi.nlm.nih.gov/pubmed/12237598.
  5. Bellibas SE, Siddique Z, Dorr A, et al. Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy. Pediatr Infect Dis J. 2004;23(12):1137-1141. Available at http://www.ncbi.nlm.nih.gov/pubmed/15626952.
  6. Church JA, Hughes M, Chen J, et al. Long term tolerability and safety of enfuvirtide for human immunodeficiency virus 1-infected children. Pediatr Infect Dis J. Aug 2004;23(8):713-718. Available at http://www.ncbi.nlm.nih.gov/pubmed/15295220.

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