Jane S. Ricciuti, RPh, MS


April 22, 2003

In This Article

Antiviral Agents

(enfuvirtide) Injection

Manufacturer: Hoffman-La Roche, Inc

Drug Approval Classification: Original New Drug Application (Approval Date: 03/13/03)

Indication: Fuzeon (enfuvirtide) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection, in adults and children aged 6 years and older, in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts in controlled studies of Fuzeon of 24 weeks' duration. Subjects enrolled were treatment experienced adults; many had advanced disease. There are no studies of Fuzeon in antiretroviral-naive patients. There are no results from controlled trials evaluating the effect of Fuzeon on clinical progression of HIV-1.

Dosing: For adult patients, the recommended dosage of Fuzeon is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh, or abdomen.

For pediatric patients 6 through 16 years of age, the recommended dosage of Fuzeon is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh, or abdomen.

Clinical Summary: Enfuvirtide is the first in a new class of agents that inhibit the fusion of HIV-1 and CD4+ cells. This inhibition blocks the virus's ability to infect certain components of the immune system.

Two randomized, controlled, open-label, multicenter trials were performed to establish efficacy of enfuvirtide in HIV-1 infected patients. Studies T20-301 and T20-302 are currently ongoing. All patients received a background regimen consisting of 3 to 5 antiretroviral agents. Patients were randomized at a 2:1 ratio to enfuvirtide 90 mg twice daily with background regimen or background regimen alone. Table 3 contains outcomes data for both studies.

To fulfill accelerated approval requirements, the following are Hoffman-La Roche's postmarketing commitments outlined in the Fuzeon approval letter:

By December 31, 2003, study reports for the 48-week data of the two ongoing phase 3 studies, T20-301 and T20-302, are to be submitted to the FDA.

  • Clinical and Pharmacology/Toxicology

    Submission of a proposed protocol for the clinical cohort study "Observational Cohort Study on the Incidence of Pneumonia in HIV-1 Infected Patients Treated with Fuzeon." Following FDA review, this study will be initiated shortly after the product launch of enfuvirtide and completed in a time frame specified in the protocol.

  • Conduction of a general-purpose immune suppression screening assay, such as a T-cell dependent antibody-forming assay.

  • Submission to the FDA, results of study T20-305, "Intervention substudy: A Phase 3, Open-label Safety Study of T-20/Ro 29-9800 (HIV-1 fusion inhibitor) in combination with Oral Antiretrovirals, in Patients Who are Unable to Construct a Viable Regimen".

  • Pharmacokinetics

    Provide additional pharmacokinetic data in children less than 6 years old.

  • Evaluate the effect of impaired renal function (creatinine clearance < 35 mL/min) on enfuvirtide pharmacokinetics.

  • Microbiology

    Evaluation of the effect of possible alterations in viral tropism on virulence.

  • In patients who failed virologically in Studies T20-301 and T20-302, submission of a sequence of the entire gp160 sequence of paired isolates to identify the genetic determinants that contribute to the phenotypic resistance.

  • Adverse Effects: The safety of enfuvirtide was assessed in 1153 adult patients and 35 pediatric patients. Only 68 adult patients received the recommended dose for more than 24 weeks. The most frequent adverse event experienced by 98% of patients was a local injection site reaction. Pain and discomfort, induration, and erythema were reported adverse effects associated with local injection site events.

    Other adverse events reported included diarrhea (26.8%), nausea (20.1%), and fatigue (16.1%).

    Pharmacokinetics: Enfuvirtide reaches a Cmax of 4.59 ± 1.5 mcg/mL, an area under the concentration time curve (AUC) of 55.8 ± 12.1 mcg*h/mL, and a Tmax of 8 hours following a single 90-mg subcutaneous injection into the abdomen. Enfuvirtide is approximately 92% bound to plasma proteins (mostly albumin) in HIV-infected plasma over a concentration range of 2 to 10 mcg/mL.

    The pharmacokinetics of enfuvirtide have been studied in 18 pediatric subjects aged 6 through 16 years at a dose of 2 mg/kg. A dose of 2 mg/kg twice daily (maximum 90 mg twice daily) provided enfuvirtide plasma concentrations similar to those obtained in adult patients receiving 90 mg twice daily.

    Pharmacokinetic studies have not been performed in patients with hepatic impairment or renal insufficiency. Geriatric patients have not been studied.

    Plasma concentration data from clinical studies indicate that enfuvirtide clearance is 20% lower in females than males after adjusting for body weight.

    No drug interactions have been identified with enfuvirtide. Enfuvirtide is not an inhibitor of CYP450 enzymes.

    Fuzeon (enfuvirtide) Injection Labeling

    (didanosine) and Videx

    Manufacturer: Bristol-Myers Squibb Company

    Drug Approval Classification: Supplemental New Drug Application (Approval Date: 03/04/03)

    Precautions: The labeling of Videx (didanosine) and Videx EC (didanosine) has been changed to include information on the potential risk associated with the coadministration of didanosine and ribavirin to patients who are coinfected with HIV and HCV.

    Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) is increased when didanosine is coadministered with ribavirin. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, have been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine and ribavirin is not recommended.

    Videx (didanosine) and Videx EC (didanosine) Labeling

    Trade Name (Generic Name)


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