Enfuvirtide

INDICATIONS

FDA

Indicated for use in combination with other ARV agents for treatment of HIV-1 infection in treatment-experienced pts with evidence of HIV replication despite ongoing ART.

FORMS

brand name	preparation	manufacturer	route	form	dosage^	cost*
Fuzeon	Enfuvirtide (ENF, T20)	Roche	SC	Vial	90 mg	$71.71

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

90 mg (1 mL) SC q12h into upper arm, anterior thigh or abdomen with each injection given at a site different from preceding injection site. Do not inject where large nerves course close to skin, over blood vessels, into moles, scar tissue, tattoos, burn sites, or around umblicus.
- Prior to administration, reconstitute with 1.1 mL of sterile water, giving volume of 1.2 mL.
- Once reconstituted must be refrigerated and used within 24 hrs.

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

[4]

Children < 6 y/o: NOT approved and not recommended to be used.
Children ≥ 6-16 y/o: 2 mg/kg/dose (max 90mg/dose) SQ twice daily into the upper arm, anterior thigh, or abdomen.
Adolescent (> 16 y/o): 90mg (1mL) SQ twice daily into the upper arm, anterior thigh, or abdomen.

PEDIATRIC RENAL DOSING

No renal dosage adjustment necessary.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

90 mg SC q12h

DOSING FOR GLOMERULAR FILTRATION OF 10-50

>35-50 mL/min: No significant change in PK parameters. Usual dose likely.

DOSING IN HEMODIALYSIS

No data, usual dose likely.

DOSING IN PERITONEAL DIALYSIS

No data, usual dose likely.

DOSING IN HEMOFILTRATION

No data, usual dose likely

ADVERSE DRUG REACTIONS

COMMON

Local injection site reaction: including pain (9%), erythema (32%), pruritus (4%), induration (57%), and nodules or cysts (26%), leading to discontinuation in 3%.

OCCASIONAL

Eosinophilia
Bacterial pneumonia (4.68 vs. 0.61 events per 100 pts-yr in treatment and control arms, respectively). Mechanism unknown.
With use of Biojector needle-free device: nerve pain (neuralgia and/or paresthesia) lasting up to 6 months at anatomical sites where large nerves course close to the skin; bruising; hematomas.

DRUG INTERACTIONS

Not inhibitor or inducer CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates. As expected, does not interact with SQV, RTV, or rifampin.
In observational study, TPV Cmin increased by approx. 50% with ENF co-administration. Critical factor such as food-effect and adherence not objectively measured. Limitations of study design could also have affected results.
No significant interaction with PIs, NNRTIs, NRTIs, RAL, and MVC.

RESISTANCE

No cross-resistance with RAL, MVC, NRTIs, NNRTIs, or PIs. In vitro, clinical isolates resistant to NRTI, NNRTI, or PIs retained susceptibility to ENF.
A 21-fold (range,

PHARMACOLOGY

MECHANISM

ENF binds to HR1 site in gp41 subunit of the viral envelope glycoprotein and prevents conformational change required for viral fusion and entry into cells.

PHARMACOKINETIC PARAMETERS

Absorption

Well absorbed from SC site with bioavailability of 84.3% (+/- 15.5%).

Metabolism and Excretion

Undergoes catabolism with 17% converted to an active deaminated form. In vitro, undergoes a non-NADPH dependent hydrolysis.

Protein Binding

92%

Cmax, Cmin, and AUC

Following 90 mg SC, mean Cmax was 5.0 +/-1.7 mcg/mL, Cmin was 3.3+/-1.6 mcg/mL, and AUC was 48.7 +/- 19.1 mcg/mL hr. Cmin 2.2 mcg/mL was associated with virologic suppression (Bonora S et al. CROI 2005 abstract 643)

T1/2

3.8 +/- 0.6 h

Distribution

Vd=5.5 +/- 1.1L. Limited CNS penetration.

DOSING FOR DECREASED HEPATIC FUNCTION

No data. Usual dose likely.

PREGNANCY RISK

Category B: not teratogenic in animal studies. Does not cross placenta (limited data). Inadequate data for use in pregnant women.

BREAST FEEDING COMPATIBILITY

No data. Breastfeeding not recommended in U.S.

COMMENTS

Pro:
- Active against PI-, NNRTI-, and NRTI-resistance virus.
- Good response if background regimen includes ≥2 active ARTs.
- Well studied in ART-experienced pts.
Con:
- SC administration; injection site reactions.
- Time consuming reconstitution process.
- Expensive.
- Requires extensive pt education and training.
- Easier and more convenient alternatives now available for most treatment-experienced pts.

References

Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369(9568):1169-78. [PMID:17416261]
Comment: 61% of DRV/r-treated pts and 15% of control pts achieved >1 log reduction in VL though wk 48. VL <50 achieved in 46% and 10% of DRV/r and control pts, respectively (p<0.003). Darunavir-treated pts who were naive to ENF had a significantly greater VL if they included ENF in their background regimen. 21/36 achieved a VL reduction of at least 1 log, compared with only 4/35 ENF-naive pts who did not receive DRV/r.
Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368(9534):466-75. [PMID:16890833]
Comment: Similar to DRV studies, pts on TPV/r + an OBR that included ENF had a better virologic response rate (VL reduction of 1.67 log vs 0.98 log)
Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med. 2003;348(22):2175-85. [PMID:12637625]
Comment: Pooled data presented to FDA from 2 randomized, controlled, open-label studies (TORO 1 and TORO 2) involving 995 treatment-experienced pts. ENF + an optimized background (OB) regimen superior to OB regimen alone. Pts had baseline VL of 5.2 logs, mean of 12 prior ART agents, and 80-90% had >5 resistance mutations to NRTIs, NNRTIs, or PIs. VL change from baseline to wk 24 was -1.52 log for pts receiving ENF + OB regimen arm compared to -0.73 log in OB arm. As expected, pts with >2 active agents in their OB regimen more likely to achieve undetectable VL.
Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed (07/10/2019) [pages M-171 to M-173]
Comment: DHHS guideline recommendations for use of enfuvirtide in pediatrics.