Fuzeon

Generic Name: 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

Introduction

Antiretroviral; HIV fusion inhibitor.1

Uses for Fuzeon

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-experienced (previously treated) patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy; used in conjunction with other antiretrovirals.1

Safety and efficacy not systematically evaluated in antiretroviral-naive patients (have not previously received antiretroviral therapy).1 12 Not recommended for initial treatment in antiretroviral-naive adults, adolescents, or children.200 201

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Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for transmission of the virus.199 Used in conjunction with other antiretrovirals.199

Not recommended for routine postexposure prophylaxis, but can be considered with expert consultation.199

Fuzeon Dosage and Administration

Administration

Sub-Q Administration

Administer sub-Q into upper arm, anterior thigh, or abdomen (avoid the navel).1 201

Rotate injection sites with each injection (i.e., inject at a site different from preceding injection sites).1

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).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

Allow refrigerated reconstituted solution to come to room temperature before injection.1

May be self-administered if clinician determines that the patient and/or their caregiver is competent to safely administer the drug.1

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.1 Let vial stand until all of the powder goes into solution; reconstitution can take up to 45 minutes.1

Reconstituted solution contains 90 mg/mL.1

Dosage

Must be given in conjunction with other antiretrovirals.1

Pediatric Patients

Treatment of HIV Infection
Sub-Q

Children 6–16 years of age: 2 mg/kg (maximum 90 mg) twice daily.1 201

Adolescents >16 years of age: 90 mg twice daily.1 201

Adults

Treatment of HIV Infection
Sub-Q

90 mg twice daily.1 200

Postexposure Prophylaxis following Occupational Exposure to HIV
Sub-Q

90 mg twice daily.199

Use with expert consultation.199

Initiate postexposure prophylaxis as soon as possible (within hours rather than days) and continue for 4 weeks, if tolerated.199

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Sub-Q

Children 6–16 years of age: Maximum 90 mg twice daily.1

Special Populations

Hepatic Impairment

Dosage adjustments not needed.1 200

Renal Impairment

Treatment of HIV Infection

Dosage adjustments not needed.1 200

Cautions for Fuzeon

Contraindications

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

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).1 2 3 Infection at injection site (including abscess and cellulitis) occurs rarely.1

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

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.1 (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.1 Bruising and hematomas also reported when this device used.1

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

Pneumonia

Increased incidence of bacterial pneumonia reported in clinical studies; has not been directly attributed to the drug.1 Risk factors included low initial CD4+ T-cell counts, high initial viral load, IV drug abuse, smoking, and history of lung disease.1

Monitor patients (especially those with underlying conditions that may predispose them to pneumonia) carefully for signs and symptoms of pneumonia.1

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.1 2

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

If hypersensitivity reaction occurs, discontinue and seek immediate medical evaluation.1

Do not reinitiate enfuvirtide in patients who have experienced a hypersensitivity reaction.1

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.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 jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.1

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.1

Specific Populations

Pregnancy

Category B.1

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Experts state that safety and pharmacokinetic data insufficient to recommend enfuvirtide in antiretroviral-naive pregnant women.202 However, in consultation with HIV and obstetric specialists, use can be considered in pregnant women who have failed therapy with several other classes of antiretroviral agents.202

Lactation

Enfuvirtide or its metabolites distributed into milk in animals; not known whether distributed into human milk.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Pediatric Use

Safety and efficacy not established in children <6 years of age.1 201

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.1 Limited efficacy data available in pediatric patients ≥6 years of age.1 6 201

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.1

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Hepatic Impairment

Pharmacokinetics not studied;1 dosage adjustments not considered necessary.1 200

Renal Impairment

Although clearance reduced in those with severe renal impairment (Clcr ≤35 mL/minute),1 dosage adjustments not considered necessary.1 200

Common Adverse Effects

Injection site reactions; GI effects (diarrhea, nausea); fatigue.1

Interactions for Fuzeon

Does not inhibit CYP-450 isoenzymes.1

Does not affect metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19, or CYP2E1 substrates.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Based on available data, pharmacokinetic interactions unlikely.1 Clinically important drug interactions not identified to date.200

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Anticoagulants

Higher risk for postinjection bleeding when enfuvirtide administered using a Biojector needle-free device1

Atazanavir

No in vitro evidence of antagonistic antiretroviral effects203

Darunavir

No in vitro evidence of antagonistic antiretroviral effects204

Efavirenz

In vitro evidence of additive to synergistic antiretroviral effects1

Etravirine

No in vitro evidence of antagonistic antiretroviral effects214

Dosage adjustments not needed214

Lamivudine

In vitro evidence of additive to synergistic antiretroviral effects1

Indinavir

In vitro evidence of additive to synergistic antiretroviral effects1

Maraviroc

In vitro evidence of additive to synergistic antiretroviral effects224

Recommended maraviroc dosage is 300 mg twice daily when used with enfuvirtide, provided regimen does not include a potent CYP3A inhibitor or inducer224

Nelfinavir

In vitro evidence of additive to synergistic antiretroviral effects1

Raltegravir

In vitro evidence of additive to synergistic antiretroviral effects225

Rifampin

Pharmacokinetic interaction unlikely1

Ritonavir

Low-dose ritonavir (200 mg twice daily): Increased enfuvirtide concentrations and AUC1

Not considered clinically important1

Saquinavir

Ritonavir-boosted saquinavir: Increased enfuvirtide AUC1

Not considered clinically important1

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

Possible false-positive in non-HIV-infected individuals given enfuvirtide1

Confirmatory test (i.e., Western blot) expected to be negative1

Tipranavir

Ritonavir-boosted tipranavir: Increased tipranavir trough concentrations211

In vitro evidence of synergistic antiretroviral effects211

Ritonavir-boosted tipranavir: Dosage adjustments not recommended211

Zidovudine

In vitro evidence of additive to synergistic antiretroviral effects1

Fuzeon Pharmacokinetics

Absorption

Bioavailability

Almost completely absorbed following sub-Q administration; absolute bioavailability is 84.3%.1

Systemic absorption is comparable following injection into the abdomen, thigh, or arm.1

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.19

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.1

Distribution

Extent

Enfuvirtide or its metabolites distributed into milk in animals; not known whether distributed into human milk.1

Plasma Protein Binding

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

Elimination

Metabolism/Elimination

Expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.1

Hemodialysis does not have a clinically important effect on enfuvirtide clearance.1

Half-life

3.8 hours.1

Special Populations

Pharmacokinetics not evaluated in hepatic impairment.1

Clearance not affected in patients with renal impairment with Clcr >35 mL/minute.1 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.1

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).1

Store reconstituted solution under refrigeration at 2–8°C; discard 24 hours after reconstitution.1

Actions and Spectrum

  • Pharmacologically and structurally different from other currently available antiretrovirals.1

  • Active against HIV-1; inactive against HIV-2.1

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

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

  • 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.12

Advice to Patients

  • 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.1 200

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.1

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1

  • 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.200 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.1 200

  • 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.1

  • Importance of administering enfuvirtide into the preferred sites (i.e., upper arm, abdomen, 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

  • Importance of reading the patient package insert from the manufacturer.1

  • 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

  • If dizziness occurs, necessity of exercising caution when driving or operating machinery.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.1

  • Importance of women informing clinicians 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 advising patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Enfuvirtide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

108 mg (to provide 90 mg)

Fuzeon (with sterile water for injection diluent)

Genentech

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 17, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. Genentech USA. Fuzeon (enfuvirtide) for injection prescribing information. South San Francisco, CA; 2012 Aug.

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. [IDIS 498400] [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. [IDIS 487366] [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. [IDIS 498401] [PubMed 12773645]

10. Wei X, Decker JM, Liu H et al. Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother. 2002; 46:1896-1905. [IDIS 481643] [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. [IDIS 484779] [PubMed 12152000]

12. Roche. Nutley, NJ: Personal communication.

19. True AL, Chiu YY, Demasi RA et al. Pharmacokinetic bioequivalence of enfuvirtide using a needle-free device versus standard needle administration. Pharmacotherapy. 2006; 26: 1679-86. [PubMed 17125431]

199. Center for Disease Control and Prevention. Updated U.S. public health service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep. 2005; 54(No. RR-9):1-17.

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 (April 18, 2012). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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 (August 11, 2011). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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 (July 31, 2012). Updates may be available at HHS AIDS Information (AIDSinfo) website.

203. Bristol-Myers Squibb. Reyatz (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2012 Mar.

204. Janssen. Prezista (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2012 Jun.

211. Boehringer Ingelheim. Aptivus (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2012 Apr.

214. Janssen. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2012 Aug.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2012 Aug.

225. Merck Sharp and Dohme. Isentress (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

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