AHFS Class:

• HIV Entry and Fusion Inhibitors 8:18.08.04

Generic Name(s):

• Enfuvirtide

Associated Monographs

• Antiretroviral Agents General Statement

Enfuvirtide, a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) fusion inhibitor.1

Treatment of HIV Infection

Enfuvirtide is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-experienced (previously treated) patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.1

Enfuvirtide, an HIV fusion inhibitor, is not recommended as initial therapy and is usually used as part of an optimized antiretroviral regimen in the management of patients with virologic failure.200,201 Selection of an optimized antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, current and previous drug-resistance test results, and availability of antiretrovirals with a high barrier to resistance.200,201

Clinical Experience

Antiretroviral-experienced Adults

Efficacy of enfuvirtide used in conjunction with other antiretroviral agents has been evaluated in 2 randomized, open-label, multicenter studies in 1013 previously treated adults (study T20-301 [TORO 1] and T20-302 [TORO 2]).1,2,7 Patients included in these studies were adults older than 16 years of age (mean age, 42-43 years), with a median baseline plasma HIV-1 RNA level of 5.1-5.2 log₁₀ copies/mL and median baseline CD4⁺ T-cell counts of 89-97 cells/mm³).1,2,7

Patients had either viremia despite at least 3 (TORO 2) or 6 (TORO 1) months of prior therapy with antiretroviral regimens with an HIV nucleoside reverse transcriptase inhibitor (NRTI), an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), and an HIV protease inhibitor (PI); or viremia and documented resistance or intolerance to at least one drug in each class of antiretroviral agents (i.e., NRTI, NNRTI, PI).1,2,7 All patients received an optimized background regimen consisting of 3-5 antiretroviral agents selected on the basis of the individual's prior antiretroviral treatment and results of baseline genotypic and phenotypic viral resistance testing.2,7 Patients were randomized to receive enfuvirtide (90 mg subcutaneously twice daily) in conjunction with an optimized background regimen or an optimized background regimen alone for 48 weeks.1,2,7 The primary efficacy outcome was change from baseline to week 24 in plasma HIV-1 RNA level, analyzed based on the intent-to-treat population.2,7 Patients treated with enfuvirtide had a substantially greater reduction in viral load compared to baseline versus optimized treatment alone (least-squares mean difference between groups, 0.933 and 0.781 log₁₀ copies/mL in TORO-1 and TORO-2, respectively).2,7 Secondary outcomes of virologic response at week 24, defined as percentage of patients achieving a viral load <50 or <400 copies/mL or reduction from baseline of ≥1 log₁₀ copies/mL, also favored enfuvirtide.2,7

Pooled analysis at 48 weeks indicated that enfuvirtide added to an optimized antiretroviral regimen resulted in greater decreases in plasma HIV-1 RNA levels (-1.4 log₁₀ copies/mL) than the optimized background regimen alone (-0.5 log₁₀ copies/mL); a reduction in plasma HIV-1 RNA levels of ≥1 log₁₀ copies/mL below baseline was achieved in 46% of those receiving enfuvirtide in conjunction with the optimized regimen compared with 18% of those receiving the optimized regimen alone.1 At 48 weeks, 34 and 23% of adults receiving enfuvirtide in conjunction with an optimized antiretroviral regimen and 13 and 8% of those receiving the optimized regimen alone had plasma HIV-1 RNA levels <400 or 50 copies/mL, respectively.1 Increases in CD4⁺ T-cell counts were greater in patients receiving enfuvirtide in conjunction with an optimized antiretroviral regimen (+91 cells/mm³) than in those receiving an optimized regimen alone (+45 cells/mm³).1

Enfuvirtide used in conjunction with 2 or more other antiretroviral agents selected on the basis of the individual's prior antiretroviral treatment and results of baseline genotypic and phenotypic viral resistance testing also has been evaluated in an uncontrolled, open-label, phase 2 study (study T20-205).3 A total of 71 patients who had been enrolled in previous trials with enfuvirtide were given enfuvirtide 5 mg subcutaneously twice daily along with conventional agents for 48 weeks.3 At 48 weeks, 32.9% of adults had a virologic response, defined as a decline >1 log₁₀ copies/mL from baseline in HIV-1 RNA or a viral load of <400 copies/mL, based on intent-to-treat analysis.3

Antiretroviral-experienced Pediatric Patients

Limited data are available on the efficacy of enfuvirtide in pediatric patients 6 years of age or older.1,6,201 In one open-label study (T20-204), 14 previously treated pediatric patients were given enfuvirtide for 48 weeks (with an option to extend to 96 weeks) in addition to optimized antiretroviral therapy; outcomes were evaluable in 11 of the 14 patients.1,6 At baseline, the median age of the evaluable patients was 9 years, (range, 6-12 years), median HIV-1 RNA was 4.6 log₁₀ copies/mL, and median CD4+ T-cell count was 495 cells/mm³.1

At 48 weeks, antiretroviral therapy that included enfuvirtide was associated with a reduction in plasma HIV-1 RNA levels of ≥1 log₁₀ copies/mL in 6 of 11 (55%) evaluable patients and plasma HIV-1 RNA levels <400 copies/mL in 4 of 11 (36%) (as-treated population).1,6 Two patients achieved HIV-1 RNA levels <50 copies/mL.6 The median change from baseline in plasma HIV-1 RNA levels was <1.48 log₁₀ copies/mL and the median change from baseline in CD4+ T-cell counts was +122 cells/mm³ (as-treated population).1

In addition, efficacy, safety, and pharmacokinetics of enfuvirtide were evaluated in an open-label, nonrandomized, noncomparative study (T20-310) in 52 previously treated pediatric patients.1,301 Patients were treated with enfuvirtide 2 mg/kg (maximum 90 mg) subcutaneously twice daily for at least 48 weeks, with an extension phase of 48 weeks, along with an optimized regimen of at least 3 antiretroviral agents.1,301 At baseline, the median age, was 12 years (range, 5-16 years), median baseline plasma HIV-1 RNA was 5 log₁₀copies/mL, and median baseline CD4+ T-cell count was 117 cells/mm³.1 Approximately 62% of patients completed 48 weeks of therapy.1 At week 48 of enfuvirtide therapy, 33% of children had a reduction in plasma HIV-1 RNA levels of at least 1 log₁₀ copies/mL, and 21 and 10% of children had plasma HIV-1 RNA levels below 400 and 50 copies/mL, respectively (intent-to-treat population).1 The median change from baseline in plasma HIV-1 RNA levels was <1.17 log₁₀copies/mL and the median change from baseline in CD4+ T-cell counts was +106 cells/mm³ (as-treated population).1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a third active ARV drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201 Selection of an initial antiretrovial regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

In the 2023 HHS adult HIV treatment guideline, enfuvirtide is listed among other drugs with novel mechanisms of action that can be considered in patients who have not previously received these drugs as part of a fully active regimen for treatment of HIV infection with virologic failure.200 It is recommended that a new antiretroviral regimen following virologic failure include 2 fully active drugs with at least one having a high resistance barrier or 3 fully active drugs, if a high resistance barrier antiretroviral is not available.200 Although some agents (certain NRTIs, PI, and second-generation INSTIs) may have partial activity in the presence of drug-resistance mutation, enfuvirtide should be discontinued if resistance is identified or expected.200

In the 2023 HHS pediatric HIV treatment guideline, enfuvirtide is listed as an option to constitute part of a fully active regimen for treatment of HIV infection with virologic failure.201 It is recommended that a new antiretroviral regimen include at least 2, preferably 3, fully active agents for viral suppression.201 Enfuvirtide may be considered for addition to a regimen after failure of regimens that included NRTI(s), NNRTI(s), and PI(s) and if there is minimal NRTI viral activity.201

In the 2023 HHS perinatal HIV treatment guideline, enfuvirtide is not recommended as initial therapy before or during pregnancy.202 Enfuvirtide is not recommended in other settings of pregnancy or in nonpregnant people who are trying to conceive, except under special circumstances.202 Enfuvirtide can be continued as part of a fully suppressive, well-tolerated existing antiretroviral regimen if pregnancy occurs during treatment.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Enfuvirtide is only recommended for use in postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals after expert consultation.199

Clinical Perspective

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include 2 NRTIs (dual NRTIs) plus an INSTI, NNRTI, or PI.199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), and zidovudine and emtricitabine.199 These experts also state that enfuvirtide is one of several alternative agents that may be used in conjunction with other antiretrovirals in PEP regimens, but only with expert consultation.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Enfuvirtide is only recommended for use in postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) after sexual, injection drug use, or other nonoccupational exposures in individuals after expert consultation.198

Clinical Persepctive

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada®).198 The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada®).198

The CDC guideline states that enfuvirtide is an alternative antiretroviral that can be used in nPEP regimens, but only with expert consultation.198 Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guideline is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

General

Pretreatment Screening

• Evaluate patient use of anticoagulants or presence of coagulation disorders.1 Risk of post-injection bleeding is higher in these patients.1

Patient Monitoring

• Monitor for injection site reactions including signs or symptoms of cellulitis or local infection.1
• Monitor for signs and symptoms of pneumonia.1

Reconstitution and Administration

Enfuvirtide is available as a single-dose lyophilized powder and administered by subcutaneous injection.1 It is available as a vial or as a kit containing enfuvirtide vials, diluent (sterile water for injection), and reconstitution and administration syringes.1

Enfuvirtide is intended for use under the guidance and supervision of a clinician;1 the drug may be self-administered if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug subcutaneously after appropriate training and with medical follow-up as necessary.1

Reconstitute enfuvirtide lyophilized powder for injection prior to administration.1 Observe strict aseptic technique since the drug and diluent contain no preservative.1 The drug is reconstituted by adding 1 mL of sterile water for injection diluent to the contents of a vial labeled as containing 108 mg of enfuvirtide.1 Gently tap the vial with a fingertip for 10 seconds and gently roll between the hands to avoid foaming and ensure that the drug is in contact with the diluent.1 The vial should then stand until all of the powder goes into solution; reconstitution can take up to 45 minutes.1 The resultant solution contains 90 mg of enfuvirtide per mL.1

Enfuvirtide solutions should be clear and colorless.1 Visually inspect for particulate matter, bubbles, and discoloration; if particulate matter is present, do not use the product.1

Store enfuvirtide at 25°C (excursions permitted between 15-30°C).1 Once reconstituted, administer enfuvirtide immediately or store in the original vial at 2-8°C for up to 24 hours.1 Bring reconstituted solutions of enfuvirtide that have been refrigerated to room temperature before administration and inspect to ensure that the contents are fully dissolved and the solution is clear, colorless, and without bubbles or particulates.1

Administer subcutaneous injections of enfuvirtide into the upper arm, anterior thigh, or abdomen (avoid the navel).1 Rotate injection sites with each injection (i.e., injections should be made at a site different from the preceding injection site).1 Do not inject into areas where the skin shows signs of a previous injection site reaction and 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).1 Do not inject directly over blood vessels, near the navel, or into skin abnormalities, moles, scars (including surgical scars), bruises, tattoos, or burn sites.1 If it is determined that the patient and/or caregiver is competent to safely administer enfuvirtide, provide a copy of the patient information from the manufacturer and provide careful instructions on the proper administration of the drug, including aseptic technique.1 Caution patients and/or their caregivers against reuse of syringes and needles, carefully instruct on the proper, safe disposal of needles and syringes, and supply a puncture-resistant container for disposal of such equipment after use.1

Dosage

Adult Dosage

Treatment of HIV Infection

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, the usual dosage of enfuvirtide is 90 mg twice daily in combination with other antiretroviral agents.1

Pediatric Dosage

Treatment of HIV Infection

For the treatment of HIV-1 infection in pediatric patients weighing at least 11 kg, the usual dosage of enfuvirtide is 2 mg/kg (maximum 90 mg) twice daily in combination with other antiretroviral agents.1 Dosing recommendations by weight are provided in the Table.

Special Populations

Hepatic Impairment

The manufacturer states that no dosage adjustments are needed for patients with hepatic impairment.1

Renal Impairment

The manufacturer states that no dosage adjustments are needed for patients with renal impairment.1

Geriatric Use

The manufacturer makes no recommendations for dosage adjustments in geriatric patients.1

Contraindications

Known hypersensitivity to enfuvirtide or any ingredient in the formulation.1

Warnings/Precautions

Local Injection Site Reactions

Subcutaneous injection of enfuvirtide is associated with reactions at the site of administration, including mild to moderate pain/discomfort, induration, erythema, presence of nodules or cysts, pruritus, and ecchymosis.1,2,3 There have been postmarketing reports of cutaneous amyloidosis at the injection site.1 These reactions occurred throughout the course of treatment and are often present at more than one injection site.1

In clinical studies, most patients (98%) had at least one local injection site reaction.1 The first injection site reaction occurred during the initial week of therapy in 86% of patients,1 and such reactions continued to occur throughout enfuvirtide treatment.1 Individual injection site reactions persisted for 3-7 days in 41% and longer than 7 days in 24% of patients;1 ongoing reactions were present at any one time at 6-14 injection sites in 26% and at more than 14 injection sites in 1.3% of patients.1 The severity of these reactions generally did not change over the study period.1 Infection at the injection site (including abscess and cellulitis) occurred in 1.7% of patients.1

Inject subcutaneously at a site different from the preceding injection site; do not inject into areas where the skin shows signs of a previous injection site reaction.1

Administration with Biojector® 2000

When administered using a Biojector^® 2000 needle-free device, neuralgia and/or paresthesia, sometimes lasting up to 6 months, was reported when injections were given into anatomical sites where large nerve tracts lie close to the skin.1 Bruising and hematomas also have occurred when this device was used.1

Post-Injection Bleeding

Patients receiving anticoagulants and those with hemophilia or other coagulation disorders may be at higher risk for post-injection bleeding.1

Hypersensitivity Reactions

Hypersensitivity reactions, including rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver transaminase concentrations, have been reported in less than 1% of patients receiving enfuvirtide; these hypersensitivity reactions have recurred on rechallenge.1,2

Other adverse events reported in patients receiving enfuvirtide that may be immune-mediated include primary immune complex reactions, respiratory distress, glomerulonephritis, and Guillain-Barré syndrome.1,2

Discontinue enfuvirtide and seek medical evaluation immediately in patients experiencing signs and symptoms suggestive of a systemic hypersensitivity reaction.1 Do not reinitiate enfuvirtide therapy in patients who have experienced systemic signs and symptoms consistent with a hypersensitivity reaction while receiving the drug.1

Pneumonia

An increased incidence of bacterial pneumonia was reported in patients receiving enfuvirtide in phase 3 clinical studies.1 When all diagnoses of pneumonia (pneumonia, bacterial pneumonia, bronchopneumonia, and related terms) were analyzed, the rate of bacterial pneumonia in patients receiving enfuvirtide was higher than in control patients (6.7 pneumonia events per 100 patient-years versus 0.6 events per 100 patient-years, respectively).1 Approximately 50% of study patients with pneumonia required hospitalization, and 3 deaths in study patients receiving enfuvirtide were attributed to pneumonia.1 Risk factors for pneumonia included low initial CD4⁺ T-cell count, high initial viral load, IV drug abuse, smoking, and history of lung disease.1

In an observational study of HIV-infected patients conducted to evaluate the risk of pneumonia in patients treated with enfuvirtide, the incidence of pneumonia was 3.2 events per 100 patient-years in the enfuvirtide group and 1.8 events per 100 patient-years in the group that did not receive the drug.1 After adjusting for other baseline risk factors, the hazard ratio was 1.34.1 Based on this observational study, it is not possible to exclude an increased risk of pneumonia in patients treated with enfuvirtide.1

Although the increased incidence of pneumonia has not been directly attributed to the drug, carefully monitor HIV-infected patients receiving enfuvirtide (especially those with underlying conditions that may predispose them to pneumonia) for signs and symptoms of pneumonia.1

Non-HIV Infected Individuals

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.1

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.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to antiretroviral medicines during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263.1

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or fetal outcomes.1 A limited number of reports on the use of enfuvirtide during pregnancy has been submitted to the APR and the number of exposures to enfuvirtide is insufficient to make a risk assessment compared to a reference population.1

In animal reproduction studies, no adverse developmental effects were observed with subcutaneous administration of enfuvirtide at exposures greater than or equal to approximately 2 times higher than human exposures at the recommended human dose based on surface area.1

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that enfuvirtide is not recommended for initial treatment regimens in antiretroviral-naive pregnant women.202 These experts state that use of enfuvirtide can be considered for pregnant women when therapy with several other classes of antiretroviral agents has failed; however, because safety and pharmacokinetic data are insufficient to recommend an appropriate dosage for pregnant women, such use should be undertaken only after consultation with HIV and obstetric specialists.202

Lactation

The Centers for Disease Control and Prevention (CDC) recommends that HIV-1 infected mothers not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1.1 Recommendations from the panel on HIV treatment states that the risk of postnatal HIV transmission to the infant is eliminated with use of properly prepared formula or pasteurized donor human milk.202 Breastfeeding transmission risk is reduced to <1% but not eliminated in women who achieve and maintain viral suppression through ART during pregnancy and postpartum.202

There are no human data available regarding the presence of enfuvirtide or its metabolites (amino acids, peptide fragments) in human milk, the effects on the breastfed infant, or the effects on milk production.1 When administered to lactating rats, enfuvirtide was likely present in milk.1 Because of both the potential for HIV-1 transmission (in HIV-negative infants), developing viral resistance (in HIV-positive infants), and adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are taking enfuvirtide.1

Pediatric Use

Use of enfuvirtide in pediatric patients weighing at least 11 kg is supported by evidence from adequate and well-controlled studies in adults and by 2 pediatric studies evaluating its safety , pharmacokinetics, and efficacy in pediatric patients.1 Both pediatric studies (T20-204 and T20-310) were open-label, multicenter trials of treatment-experienced pediatric patients.1 Study T20-204 evaluated safety and antiviral activity of enfuvirtide and included 11 evaluable patients 6-12 years old (median age, 9 years).1 Study T20-310 evaluated pharmacokinetics, safety, and antiviral activity in 52 patients 5 years and older (median age, 12 years).1

Adverse effects, including injection-site reactions, reported in the 63 pediatric patients were similar to those reported in adults; however, infections at the injection site (cellulitis, abscess) occurred more frequently in adolescents (4 events occurring in 3 of 28 [11%] patients) than in adults.1

Geriatric Use

Experience in those 65 years of age or older is insufficient to determine whether they respond differently than younger adults.1 Enfuvirtide should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Hepatic Impairment

Pharmacokinetics of enfuvirtide have not been studied in patients with hepatic impairment; dosage adjustments are not considered necessary.1

Renal Impairment

No clinically significant changes in pharmacokinetics have been observed based on any degree of renal impairment or hemodialysis.1 Dosage adjustments are not considered necessary.1

Common Adverse Effects

The most common adverse reactions are local injection site reactions, diarrhea, nausea, and fatigue.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that enfuvirtide does not inhibit cytochrome P-450 (CYP) isoenzymes.1 Results of an in vivo human metabolism study indicate that the recommmended dose of enfuvirtide 90 mg twice daily did not affect metabolism of CYP3A4, 2D6, 1A2, 2C19, or 2E1 substrates.1

Based on available data, co-administration of enfuvirtide and other drugs that are inducers or inhibitors of CYP450 is not expected to alter the pharmacokinetics of enfuvirtide.1 No dosage adjustments are needed when enfuvirtide is co-administered with other antiretroviral and non-antiretroviral drugs.1

Anticoagulants

There may be a higher risk for postinjection bleeding in patients receiving anticoagulants if enfuvirtide is administered using a Biojector^® needle-free device.1

Antiretroviral Agents

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz

No in vitro evidence of antagonism to antiretroviral effects of efavirenz.1

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

No in vitro evidence of antagonism to antiretroviral effects of HIV NRTIs (e.g., lamivudine, zidovudine).1

HIV Protease Inhibitors (PIs)

No in vitro evidence of antagonism to antiretroviral effects of HIV PIs (indinavir, nelfinavir).1

Ritonavir

Pharmacokinetic interaction with ritonavir (24% increase in peak plasma concentration and 22% increase in area under the concentration-time curve [AUC] of enfuvirtide);1 not considered clinically important.1

Saquinavir

Concomitant use of ritonavir-boosted saquinavir and enfuvirtide does not result in clinically important effects on enfuvirtide plasma concentrations or AUC.1

Rifampin

Rifampin had no clinically important effects on enfurvitide plasma concentrations or AUC.1

Description

Enfuvirtide, a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) fusion inhibitor.1 Enfuvirtide is a synthetic 36-amino acid peptide that interferes with entry of HIV type 1 (HIV-1) into target cells by inhibiting fusion of the viral and cellular membranes.1 Enfuvirtide binds to heptad repeat 1 (HR1) in the envelope glycoprotein 41 (gp41) of HIV-1 that is involved in fusion of the virus with the membrane of the host CD4+ T-cell.1 Binding of enfuvirtide to gp41 blocks conformational changes in the HIV-1 glycoprotein that are required for fusion of the viral and cell membranes, thereby preventing entry of the viral genome into the healthy CD4+ T-cell.1

In vitro studies indicate that enfuvirtide is active against HIV-1,1 but is inactive against HIV-2.1 HIV-1 strains with reduced susceptibility to enfuvirtide can be produced in vitro and strains with reduced susceptibility to enfuvirtide have emerged during therapy with the drug.1,10 These strains have contained mutations in the HR1 domain of gp41 within the region of amino acids 36-45.1,10 HR1 substitutions associated with resistance to enfuvirtide include G36D/E/S/V, I37V, V38A/E/G/M, Q39R, Q40H, N42D/Q/T, N43D/H/K/Q/S, L44M, and, L45M.1 Combinations of HR1 resistance-associated substitutions can lead to greater reductions in susceptibility.1 Substitutions or polymorphisms in other regions of gp41 have been associated with resistance (e.g., HR2 domain N216K, E137K, and S138A substitutions) and these may affect susceptibility to enfuvirtide.1

In cell culture, HIV-1 clinical isolates resistant to NNRTIs, NRTIs, and PIs were susceptible to enfuvirtide.1

The pharmacokinetics of enfuvirtide have been evaluated in a limited number of HIV-infected adults and pediatric patients.1,11,12 Enfuvirtide is almost completely absorbed following subcutaneous injection (absolute bioavailability: 84.3%),11 and systemic absorption is comparable following subcutaneous injection of a 90-mg dose into the abdomen, thigh, or arm.1 Systemic absorption is comparable following subcutaneous injection using the Biojector^® 2000 needle-free device or a 27-gauge ½-inch needle and syringe.19 Because enfuvirtide is a peptide, it is expected to undergo catabolism to its constituent amino acids.1 In vitro studies indicate that enfuvirtide undergoes hydrolysis (not NADPH dependent) to form a deaminated metabolite.1 Following a single 90-mg subcutaneous dose, the mean elimination half-life of enfuvirtide is 3.8 hours.1

Advice to Patients

• Advise patients of the critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1
• Inform patients of the importance of using in conjunction with other antiretrovirals—not for monotherapy.1
• Advise patients that antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1
• Provide appropriate instruction on use of enfuvirtide to patients and/or their caregivers who are allowed to administer the drug in the home setting.1
• Advise patient and/or caregiver of the importance of administering enfuvirtide into the preferred sites (i.e., upper arm, abdomen, or anterior thigh).1 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.1
• Advise patients of the importance of monitoring for signs and symptoms of injection site reactions (e.g., cellulitis, local infections) and contacting clinician if such reactions occur.1
• Advise patients that an increased rate of bacterial pneumonia has been reported.1 Importance of immediately seeking medical evaluation if signs and symptoms of pneumonia (cough with fever, rapid breathing, shortness of breath) occur.1
• Advise patients that hypersensitivity reactions may occur.1 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.1
• Advise patients that if dizziness occurs, necessity of exercising caution when driving or operating machinery.1
• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses.1
• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1
• Importance of informing patients of other precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Genentech USA. Fuzeon^® (enfuvirtide) for injection prescribing information. South San Francisco, CA; 2019 Dec.

2. Lalezaru 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; 348:2175-85. [PubMed 12637625]

3. Lalezari JP, Eron JJ, Carlson M et al. A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy. AIDS . 2003; 17:691-8. [PubMed 12646792]

6. 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 . 2002; 21:653-9. [PubMed 12237598]

7. Lazzarin A, Clotet B, Cooper D et al for the TORO2 study group. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med . 2003; 348:2186-95. [PubMed 12773645]

10. Joly V, Jidar K, Tatay M, et al. Enfuvirtide: from basic investigations to current clinical use.. Expert Opin Pharmacother. 2010;11(16):2701-13. . ; [PubMed 12019106]

11. Zhang X, Nieforth K, Lang JM et al. Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: inverse Gaussian density absorption and 2-compartment disposition. Clin Pharmacol Ther . 2002; 72:10-9. [PubMed 12152000]

12. Zhang X, Lin T, Bertasso A, et al. Population pharmacokinetics of enfuvirtide in HIV-1-infected pediatric patients over 48 weeks of treatment. J Clin Pharmacol. 2007;47(4):510-517.

19. True AL, Chiu YY, Demasi RA et al. Pharmacokinetic bioequivalence of enfuvirtide using a needle-free device versus standard needle administration. Pharmacother . 2006; 26: 1679-86.

198. Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - United States, 2016. From HHS AIDS Information (AIDSinfo) website.

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol . 2013; 34:875-92. [PubMed 23917901]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2023). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

203. Bristol-Myers Squibb. Reyataz^® (atazanavir sulfate) capsules and oral powder prescribing information. Princeton, NJ; 2020 Sep.

204. Janssen Therapeutics. Prezista^® (darunavir) oral suspension and film-coated tablets prescribing information. Titusville, NJ; 2022 Oct.

211. Boehringer Ingelheim. Aptivus^® (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2020 Jun.

214. Janssen. Intelence^® (etravirine) tablets prescribing information. Raritan, NJ; 2023 Mar.

224. ViiV Healthcare. Selzentry^® (maraviroc) tablets and oral solution prescribing information. Research Triangle Park, NC; 2022 Sept.

225. Merck Sharp and Dohme. Isentress^® (raltegravir) film-coated tablets, chewable tablets, and for oral suspension and Isentress^® HD (raltegravir) film-coated tablets prescribing information. Whitehouse Station, NJ; 2022 May.

236. ViiV Healthcare. Tivicay^® (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2022 Oct.

301. 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. 2007;26(9):799-805.