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Enfuvirtide

Class: HIV Entry and Fusion Inhibitors
VA Class: AM800
Chemical Name: N-Acetyl-l-tyrosyl-l-threonyl-l-seryl-l-leucyl-l-isoleucyl-l-histidyl-l-seryl-l-leucyl-l-isoleucyl-l-alpha-glutamyl-l-alpha-glutamyl-l-seryl-l
Molecular Formula: C204H301N51O64
CAS Number: 159519-65-0
Brands: Fuzeon

Medically reviewed by Drugs.com on Jul 27, 2020. Written by ASHP.

Introduction

Antiretroviral; HIV fusion inhibitor.

Uses for Enfuvirtide

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-experienced (previously treated) adults, adolescents, and pediatric patients ≥6 years of age with evidence of HIV-1 replication despite ongoing antiretroviral therapy; used in conjunction with other antiretrovirals.

Safety and efficacy not systematically evaluated in antiretroviral-naive patients (have not previously received antiretroviral therapy).

Not included in any recommended or alternative regimens for initial treatment in antiretroviral-naive adults and adolescents. Not recommended for initial treatment in antiretroviral-naive children.

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

USPHS recommends a 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) as the preferred regimen for PEP following occupational exposures to HIV. Enfuvirtide is one of several alternative agents that may be used in conjunction with other antiretrovirals for PEP, but use only with expert consultation.

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible. Do not delay initiation of PEP while waiting for expert consultation.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission. Used in conjunction with other antiretrovirals.

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF); recommended alternative in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

CDC states enfuvirtide is an alternative antiretroviral that can be used in nPEP regimens, but use in such regimens only with expert consultation.

Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals. Do not delay initiation of nPEP while waiting for expert consultation.

Enfuvirtide Dosage and Administration

Administration

Sub-Q Administration

Administer by sub-Q injection into upper arm, anterior thigh, or abdomen (avoid the navel).

Rotate injection sites with each injection (i.e., inject at a site different from preceding injection sites).

Do not inject into areas where skin shows signs of a previous injection site reaction and do not inject near anatomical areas where large nerve tracts lie close to the skin (e.g., near elbow, knee, groin, inferior or medial section of the buttocks). Do not inject directly over blood vessels, near the navel, or into skin abnormalities, moles, scars (including surgical scars), bruises, tattoos, or burn sites.

Allow refrigerated reconstituted solution to come to room temperature before injection.

May be self-administered if clinician determines that the patient and/or their caregiver is competent to safely administer the drug.

Reconstitution

Add 1.1 mL of sterile water for injection diluent provided by the manufacturer to vial containing 108 mg; tap vial gently with a fingertip for 10 seconds and then gently roll between the hands (avoid foaming) to ensure that drug is in contact with diluent. Let vial stand until all of the powder goes into solution; reconstitution can take up to 45 minutes.

Reconstituted solution contains 90 mg/mL.

Dosage

Must be given in conjunction with other antiretrovirals.

Pediatric Patients

Treatment of HIV Infection
Sub-Q

Children 6–16 years of age: 2 mg/kg (maximum 90 mg) twice daily.

Adolescents >16 years of age: 90 mg twice daily.

Adults

Treatment of HIV Infection
Sub-Q

90 mg twice daily.

Postexposure Prophylaxis following Occupational Exposure to HIV†
Sub-Q

90 mg twice daily. Use in conjunction with other antiretrovirals (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Sub-Q

Children 6–16 years of age: Maximum 90 mg twice daily.

Special Populations

Hepatic Impairment

Dosage adjustments not needed.

Renal Impairment

Treatment of HIV Infection

Dosage adjustments not needed.

Cautions for Enfuvirtide

Contraindications

  • Known hypersensitivity to enfuvirtide or any ingredient in the formulation.

Warnings/Precautions

Local Reactions

Sub-Q enfuvirtide associated with injection site reactions (e.g., mild to moderate pain/discomfort, induration, erythema, presence of nodules or cysts, pruritus, ecchymosis). Infection at injection site (including abscess and cellulitis) occurs rarely. Postmarketing reports of cutaneous amyloidosis at injection site.

Most (98%) of patients in clinical studies had at least 1 local injection site reaction. Such reactions persisted for >7 days in some patients; ongoing injection site reactions at 6–14 sites reported in 26% of patients.

Importance of making each sub-Q injection at different site than preceding injections; importance of not injecting into areas where skin shows signs of a previous injection site reaction. (See Administration under Dosage and Administration.)

Administration Using Biojector 2000

When administered using a Biojector 2000 needle-free device, neuralgia and/or paresthesia, sometimes lasting up to 6 months, reported when injections were given into anatomical sites where large nerve tracts lie close to the skin. Bruising and hematomas also reported when this device used.

Patients receiving anticoagulants and those with hemophilia or other coagulation disorders may be at higher risk for post-injection bleeding.

Pneumonia

Increased incidence of bacterial pneumonia reported in clinical studies; has not been directly attributed to the drug. Risk factors included low initial CD4+ T-cell counts, high initial viral load, IV drug abuse, smoking, and history of lung disease.

Monitor patients (especially those with underlying conditions that may predispose them to pneumonia) carefully for signs and symptoms of pneumonia.

Sensitivity Reactions

Hypersensitivity reactions (e.g., rash, fever, nausea and vomiting, chills, rigors, hypotension, elevated serum liver transaminase concentrations) reported; these hypersensitivity reactions have recurred on rechallenge.

Other adverse events that may be immune mediated include primary immune complex reactions, respiratory distress, glomerulonephritis, and Guillain-Barré syndrome.

If hypersensitivity reaction occurs, discontinue and seek immediate medical evaluation.

Do not reinitiate enfuvirtide in patients who have experienced a hypersensitivity reaction.

Laboratory Test Interferences

Although enfuvirtide has not been studied in non-HIV-infected individuals, the possibility exists that administration of the drug could lead to the production of anti-enfuvirtide antibodies that could cross react with HIV glycoprotein 41(gp41), resulting in a false-positive HIV test using an enzyme-linked immunosorbent assay (ELISA); a confirmatory test (i.e., Western blot) would be expected to be negative.

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium, M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported to occur in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Specific Populations

Pregnancy

Category B.

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Experts state enfuvirtide not recommended for initial treatment regimens in antiretroviral-naive pregnant women. Can be considered for pregnant women when therapy with several other classes of antiretroviral agents has failed; however, safety and pharmacokinetic data insufficient to recommend an appropriate dosage for pregnant women and experts state undertake such use only after consultation with HIV and obstetric specialists.

Lactation

Enfuvirtide or its metabolites distributed into milk in animals; not known whether distributed into human milk.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy not established in children <6 years of age.

Safety and pharmacokinetics evaluated in pediatric patients 6–16 years of age; use in this age group supported by evidence from adequate and well-controlled adult studies. Limited efficacy data available in pediatric patients ≥6 years of age.

Adverse effects in pediatric patients similar to those in adults; however, infections at the injection site (cellulitis, abscess) reported more frequently in adolescents than adults.

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Pharmacokinetics not studied; dosage adjustments not considered necessary.

Renal Impairment

Although clearance reduced in those with severe renal impairment (Clcr ≤35 mL/minute), dosage adjustments not considered necessary.

Common Adverse Effects

Injection site reactions; GI effects (diarrhea, nausea); fatigue.

Interactions for Enfuvirtide

Does not inhibit CYP-450 isoenzymes.

Does not affect metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19, or CYP2E1 substrates.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Based on available data, pharmacokinetic interactions unlikely.

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Anticoagulants

Higher risk for postinjection bleeding when enfuvirtide administered using a Biojector needle-free device

Atazanavir

No in vitro evidence of antagonistic antiretroviral effects

Darunavir

No in vitro evidence of antagonistic antiretroviral effects

Dolutegravir

No in vitro evidence of antagonistic antiretroviral effects

Efavirenz

In vitro evidence of additive to synergistic antiretroviral effects

Etravirine

No in vitro evidence of antagonistic antiretroviral effects

Dosage adjustments not needed

Lamivudine

In vitro evidence of additive to synergistic antiretroviral effects

Indinavir

In vitro evidence of additive to synergistic antiretroviral effects

Maraviroc

No in vitro evidence of antagonistic antiretroviral effects

Recommended maraviroc dosage is 300 mg twice daily when used with enfuvirtide, provided regimen does not include a potent CYP3A inhibitor or inducer

Nelfinavir

In vitro evidence of additive to synergistic antiretroviral effects

Raltegravir

No in vitro evidence of antagonistic antiretroviral effects

Rifampin

Pharmacokinetic interaction unlikely

Ritonavir

Low-dose ritonavir (200 mg twice daily): Increased enfuvirtide concentrations and AUC

Not considered clinically important

Saquinavir

Ritonavir-boosted saquinavir: No clinically important effects on enfuvirtide concentrations or AUC

Test, Enzyme-linked immunosorbent assay (ELISA) for HIV

Possible false-positive in non-HIV-infected individuals given enfuvirtide

Confirmatory test (i.e., Western blot) expected to be negative

Tipranavir

Ritonavir-boosted tipranavir: Increased tipranavir trough concentrations

In vitro evidence of synergistic antiretroviral effects

Ritonavir-boosted tipranavir: Dosage adjustments not recommended

Zidovudine

In vitro evidence of additive to synergistic antiretroviral effects

Enfuvirtide Pharmacokinetics

Absorption

Bioavailability

Almost completely absorbed following sub-Q administration; absolute bioavailability is 84.3%.

Systemic absorption is comparable following injection into the abdomen, thigh, or arm.

Systemic absorption in adults is comparable following sub-Q injection using the Biojector 2000 needle-free device or a 27-gauge ½-inch needle and syringe.

Special Populations

Plasma concentrations in children 6–16 years of age receiving enfuvirtide 2 mg/kg twice daily (maximum 90 mg twice daily) similar to those reported in adults receiving the recommended dosage.

Distribution

Extent

Enfuvirtide or its metabolites distributed into milk in animals; not known whether distributed into human milk.

Plasma Protein Binding

92%; bound mainly to albumin and, to a lesser extent, α-1 acid glycoprotein.

Elimination

Metabolism/Elimination

Expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.

Hemodialysis does not have a clinically important effect on enfuvirtide clearance.

Half-life

3.8 hours.

Special Populations

Pharmacokinetics not evaluated in hepatic impairment.

Clearance not affected in patients with renal impairment with Clcr >35 mL/minute. Clearance reduced by 38% in patients with severe renal impairment (Clcr 11–35 mL/minute) and 14–28% in patients with end-stage renal disease undergoing dialysis.

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).

Store reconstituted solution under refrigeration at 2–8°C; discard 24 hours after reconstitution.

Actions and Spectrum

  • Pharmacologically and structurally different from other currently available antiretrovirals.

  • Active against HIV-1; inactive against HIV-2.

  • Interferes with entry of HIV-1 into target cells by inhibiting fusion of the viral and cellular membranes.

  • HIV-1 with reduced susceptibility to enfuvirtide have been selected in vitro and have emerged during therapy with the drug.

  • Cross-resistance between enfuvirtide and nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), or HIV protease inhibitors (PIs) is highly unlikely since the drugs have different mechanisms of action.

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.

  • Importance of clinicians providing appropriate instruction on use of enfuvirtide to patients and/or their caregivers who are allowed to administer the drug in the home setting.

  • Importance of administering enfuvirtide into the preferred sites (i.e., upper arm, abdomen, anterior thigh). Injections should not be made near anatomical areas where large nerve tracts lie close to the skin (e.g., near the elbow, knee, groin, inferior or medial section of the buttocks), directly over a blood vessel, near the navel, or into skin abnormalities, moles, scars (including surgical scars), bruises, tattoos, or burn sites.

  • Importance of reading the patient package insert from the manufacturer.

  • Importance of monitoring for signs and symptoms of injection site reactions (e.g., cellulitis, local infections) and contacting clinician if such reactions occur.

  • Advise patients that an increased rate of bacterial pneumonia has been reported. Importance of immediately seeking medical evaluation if signs and symptoms of pneumonia (cough with fever, rapid breathing, shortness of breath) occur.

  • Advise patients that hypersensitivity reactions may occur. Importance of discontinuing enfuvirtide and immediately seeking medical evaluation if signs or symptoms of systemic hypersensitivity (e.g., combinations of rash, fever, nausea, vomiting, chills, rigors, and/or hypotension) occur.

  • If dizziness occurs, necessity of exercising caution when driving or operating machinery.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.

  • Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Enfuvirtide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

108 mg (to provide 90 mg)

Fuzeon

Genentech

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 6, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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