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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

Introduction

Antiretroviral; HIV fusion inhibitor.1

Uses for Enfuvirtide

Treatment of HIV Infection

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

Safety and efficacy have not been systematically evaluated in treatment-naive patients (have not previously received antiretroviral therapy).1 12 Experts state the drug is not recommended for initial treatment.5 13

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.16 Used in conjunction with other antiretrovirals.16

Not recommended for routine postexposure prophylaxis, but can be considered with expert consultation.16

Enfuvirtide Dosage and Administration

Administration

Sub-Q Administration

Administer sub-Q into the upper arm, anterior thigh, or abdomen (avoid the navel).1 4 13

Injection sites should be rotated with each injection (i.e., injections should be made at a site different from the preceding injection site).1 4

Injections should not be made into areas where skin shows signs of a previous injection site reaction and 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).1 4 Injections also should not be made directly over blood vessels, near the navel, or into skin abnormalities, moles, scars (including surgical scars), bruises, tattoos, or burn sites.1 4

Refrigerated reconstituted solution should be brought to room temperature before injection.1

May be self-administered if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug.1 4

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 the drug is in contact with the diluent.1 4 Let vial stand until all of the powder goes into solution; reconstitution can take up to 45 minutes.1 Reconstituted solutions of the drug should not be shaken.4

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 13

Adolescents >16 years of age: 90 mg twice daily.1 13

Adults

Treatment of HIV Infection
Sub-Q

90 mg twice daily.1 5

Postexposure Prophylaxis following Occupational Exposure to HIV
Sub-Q

90 mg twice daily.16

Use with expert consultation.16

Initiate postexposure prophylaxis as soon as possible (within hours rather than days) and continue for 4 weeks, if tolerated.16

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 recommendations not available.5

Renal Impairment

Treatment of HIV Infection

Dosage adjustments not needed.1 5

Cautions for Enfuvirtide

Contraindications

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

Warnings/Precautions

Warnings

Local Reactions

Sub-Q administration associated with injection site reactions (e.g., mild to moderate pain/discomfort, induration, erythema, presence of nodules or cysts, pruritus, ecchymosis) in almost all patients.1 2 3

Injection site reactions persist for >7 days in some patients; injection site reactions at ?6 sites reported in 23% of patients in phase 3 clinical studies.1

Infectious Complications

Increased incidence of bacterial pneumonia; 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-Barr? 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

General Precautions

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 complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.1

Administration Using Biojector 2000

Neuralgia and/or paresthesia, sometimes lasting up to 6 months, reported following injection into anatomical sites where large nerve tracts lie close to the skin.1 Bruising and hematomas also reported.1

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

Specific Populations

Pregnancy

Category B.1

Antiretroviral Pregnancy Registry at 800-258-4263.1

Some experts state that safety and pharmacokinetic data insufficient to recommend enfuvirtide in pregnant women.18

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

Pediatric Use

Safety and efficacy not established in children <6 years of age.1 13

Limited efficacy data available in pediatric patients 6–16 years of age.1 6 13

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

Common Adverse Effects

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

Interactions for Enfuvirtide

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

Pharmacokinetic interactions unlikely.1

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Anticoagulants

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

Efavirenz

In vitro evidence of additive or synergistic antiretroviral effects1

Lamivudine

In vitro evidence of additive or synergistic antiretroviral effects1

Indinavir

In vitro evidence of additive or synergistic antiretroviral effects1

Nelfinavir

In vitro evidence of additive or synergistic antiretroviral effects1

Rifampin

Pharmacokinetic interaction unlikely1

Ritonavir

Possible increase in plasma concentrations and AUC of enfuvirtide1

Not considered clinically important1

Saquinavir

Possible increase in AUC of enfuvirtide with ritonavir-boosted saquinavir1

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

In vitro evidence of synergistic antiretroviral effects17

Zidovudine

In vitro evidence of additive or synergistic antiretroviral effects1

Enfuvirtide 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 ?-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

Plasma Protein Binding

92%; bound mainly to albumin and, to a lesser extent, ?-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 SpectrumActions

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

  • Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur.1 HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.1

  • 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 and contacting clinician if such reactions are severe or there are signs of infection such as oozing, increased heat, swelling, redness, or pain.1 4

  • Importance of monitoring for signs and symptoms of pneumonia (cough with fever, rapid breathing, shortness of breath) and contacting clinician if these occur.1 4

  • Importance of discontinuing enfuvirtide and informing clinician if manifestations of a hypersensitivity reaction (combinations of rash, fever, nausea and vomiting, chills, rigors, and/or hypotension) occur.1

  • Advise that dizziness may occur; 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.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan 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)

Roche

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 01, 2009. 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. Roche. Fuzeon (enfuvirtide) prescribing information. Nutley, NJ; 2008 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. [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]

4. Roche. Injection instructions: Fuzeon (enfuvirtide). From the Fuzeon web site. (Assessed 2005 Sep 8.)

5. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (November 3, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

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]

8. Chronimed Statscript Pharmacy. Chronimed to be exclusive U.S. distributor of Fuzeon; contract signed with Roche. From the Chronimed web site. (Assessed 2003 May 12.)

9. Fuzeon progressive distribution program. From the Fuzeon web site. (Assessed 2003 May 12.)

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.

13. Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children of the National Resource Center at the Fran?ois-Xavier Bagnoud Center, Health Resources and Services Administration (HRSA), and National Institutes of Health (NIH). Guidelines for the use of antiretroviral agents in pediatric HIV infection (February 23, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

14. Hammer SM, Saag MS, Schechter M et al. Treatment of adult HIV infection: 2006 recommendations of the International AIDS Society–USA panel. JAMA. 2006; 296:827-43. [PubMed 16905788]

15. Gazzard B, for the BHIVA Guidelines Writing Committee. British HIV association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005). HIV Med. 2005; 6(Suppl 2):1-61.

16. 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.

17. Boehringer Ingelheim. Aptivus (tipranavir) capsules prescribing information. Ridgefield, CT; 2006 Jun 27.

18. Perinatal HIV Guidelines Working Group. US Public Health Service task force recommendations for use of antiretroviral drugs in pregnant HIV-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States (April 29, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

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]

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