Fuzeon (Enfuvirtide) - Warnings and Precautions

WARNINGS

LOCAL INJECTION SITE REACTIONS

The most common adverse events associated with FUZEON use are local injection site reactions. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Nine percent of patients had local reactions that required analgesics or limited usual activities (see ADVERSE REACTIONS). Reactions are often present at more than one injection site. Patients must be familiar with the FUZEON Injection Instructions in order to know how to inject FUZEON appropriately and how to monitor carefully for signs or symptoms of cellulitis or local infection.

PNEUMONIA

An increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in the Phase 3 clinical trials compared to the control arm (see ADVERSE REACTIONS). It is unclear if the increased incidence of pneumonia is related to FUZEON use. However, because of this finding, patients with HIV infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Risk factors for pneumonia included low initial CD4 cell count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease (see ADVERSE REACTIONS).

HYPERSENSITIVITY REACTIONS

Hypersensitivity reactions have been associated with FUZEON therapy and may recur on re-challenge. Hypersensitivity reactions have included individually and in combination: rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver transaminases. Other adverse events that may be immune mediated and have been reported in subjects receiving FUZEON include primary immune complex reaction, respiratory distress glomerulonephritis, and Guillain-Barre syndrome. Patients developing signs and symptoms suggestive of a systemic hypersensitivity reaction should discontinue FUZEON and should seek medical evaluation immediately. Therapy with FUZEON should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction. Risk factors that may predict the occurrence or severity of hypersensitivity to FUZEON have not been identified (see ADVERSE REACTIONS).

PRECAUTIONS

NON-HIV INFECTED INDIVIDUALS

There is a theoretical risk that FUZEON use may lead to the production of anti-enfuvirtide antibodies which cross react with HIV gp41. This could result in a false positive HIV test with an ELISA assay; a confirmatory western blot test would be expected to be negative. FUZEON has not been studied in non-HIV infected individuals.

INFORMATION FOR PATIENTS

To assure safe and effective use of FUZEON, the following information and instructions should be given to patients:

• Patients should be informed that injection site reactions occur commonly. Patients must be familiar with the FUZEON Injection Instructions for instructions on how to appropriately inject FUZEON and how to carefully monitor for signs or symptoms of cellulitis or local infection. Patients should be instructed when to contact their healthcare provider about these reactions.
• Patients should be made aware that an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in Phase 3 clinical trials compared to the control arm. Patients should be advised to seek medical evaluation immediately if they develop signs or symptoms suggestive of pneumonia (cough with fever, rapid breathing, shortness of breath) (see WARNINGS).
• Patients should be advised of the possibility of a hypersensitivity reaction to FUZEON. Patients should be advised to discontinue therapy and immediately seek medical evaluation if they develop signs/symptoms of hypersensitivity (see WARNINGS).
• FUZEON is not a cure for HIV-1 infection and patients may continue to contract illnesses associated with HIV-1 infection. The long-term effects of FUZEON are unknown at this time. FUZEON therapy has not been shown to reduce the risk of transmitting HIV-1 to others through sexual contact or blood contamination.
• FUZEON must be taken as part of a combination antiretroviral regimen. Use of FUZEON alone may lead to rapid development of virus resistant to FUZEON and possibly other agents of the same class.
• Patients and caregivers must be instructed in the use of aseptic technique when administering FUZEON in order to avoid injection site infections. Appropriate training for FUZEON reconstitution and self-injection must be given by a healthcare provider, including a careful review of the FUZEON Patient Package Insert and FUZEON Injection Instructions. The first injection should be performed under the supervision of an appropriately qualified healthcare provider. It is recommended that the patient and/or caregiver's understanding and use of aseptic self-injection techniques and procedures be periodically re-evaluated.
• Patients should contact their healthcare provider for any questions regarding the administration of FUZEON. Patients should be told not to reuse needles or syringes, and be instructed in safe disposal procedures including the use of a puncture-resistant container for disposal of used needles and syringes. Patients must be instructed on the safe disposal of full containers as per local requirements. Caregivers who experience an accidental needlestick after patient injection should contact a healthcare provider immediately.
• Patients should inform their healthcare provider if they are pregnant, plan to become pregnant or become pregnant while taking this medication.
• Patients should inform their healthcare provider if they are breast-feeding.
• Patients should not change the dose or dosing schedule of FUZEON or any antiretroviral medication without consulting their healthcare provider.
• Patients should contact their healthcare provider immediately if they stop taking FUZEON or any other drug in their antiretroviral regimen.
• Patients should be told that they can obtain more information on the self-administration of FUZEON at www.FUZEON.com or by calling 1-877-4-FUZEON (1-877-438-9366).

Patients should be advised that no studies have been conducted on the ability to drive or operate machinery while taking FUZEON. If patients experience dizziness while taking FUZEON, they should be advised to talk to their healthcare provider before driving or operating machinery.

DRUG INTERACTIONS

CYP450 Metabolized Drugs

Results from in vitro and in vivo studies suggest that enfuvirtide is unlikely to have significant drug interactions with concomitantly administered drugs metabolized by CYP450 enzymes (see CLINICAL PHARMACOLOGY).

Antiretroviral Agents

No drug interactions with other antiretroviral medications have been identified that would warrant alteration of either the enfuvirtide dose or the dose of the other antiretroviral medication.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Carcinogenesis

Long-term animal carcinogenicity studies of enfuvirtide have not been conducted.

Mutagenesis

Enfuvirtide was neither mutagenic nor clastogenic in a series of in vivo and in vitro assays including the Ames bacterial reverse mutation assay, a mammalian cell forward gene mutation assay in AS52 Chinese Hamster ovary cells or an in vivo mouse micronucleus assay.

Impairment of Fertility

Enfuvirtide produced no adverse effects on fertility in male or female rats at doses of up to 30 mg/kg/day administered by subcutaneous injection (1.6 times the maximum recommended adult human daily dose on a m² basis).

PREGNANCY

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 27 times and 3.2 times the adult human dose on a m² basis. The animal studies revealed no evidence of harm to the fetus from enfuvirtide. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

ANTIRETROVIRAL PREGNANCY REGISTRY

To monitor maternal-fetal outcomes of pregnant women exposed to FUZEON and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800- 258-4263.

NURSING MOTHERS

The Centers for Disease Control and Prevention recommends that HIV- infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. It is not known whether enfuvirtide is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving FUZEON.

Studies where radio-labeled³ H-enfuvirtide was administered to lactating rats indicated that radioactivity was present in the milk. It is not known whether the radioactivity in the milk was from radio-labeled enfuvirtide or from radio-labeled metabolites of enfuvirtide (ie, amino acids and peptide fragments).

PEDIATRIC USE

The safety and pharmacokinetics of FUZEON have not been established in pediatric subjects below 6 years of age. Limited efficacy data is available in pediatric subjects 6 years of age and older.

Thirty-five HIV-1 infected pediatric subjects ages 6 through 16 years have received FUZEON in two open-label, single-arm clinical trials. Adverse experiences were similar to those observed in adult patients.

Study T20-204 was an open-label, multicenter trial that evaluated the safety, and antiviral activity of FUZEON in treatment-experienced pediatric subjects. Eleven subjects from 6 to 12 years were enrolled (median age of 9 years). Median baseline CD4 cell count was 509 cells/µL and the median baseline HIV-1 RNA was 4.5 log₁₀ copies/mL.

Ten of the 11 study subjects completed 48 weeks of chronic therapy. By week 48, 6/11 (55%) subjects had >/=1 log₁₀ decline in HIV-1 RNA and 4/11 (36%) subjects were below 400 copies/mL of HIV-1 RNA. The median changes from baseline in HIV-1 RNA and CD4 cell count were -1.48 log₁₀ copies/mL and 122 cells/µL, respectively.

Study T20-310 is an ongoing, open-label, multicenter trial evaluating the pharmacokinetics, safety, and antiviral activity of FUZEON in treatment-experienced pediatric subjects and adolescents. Twenty-four subjects from 6 through 16 years were enrolled (median age of 13 years). Median baseline CD4 cell count was 143 cells/µL and the median baseline HIV-1 RNA was 5.0 log₁₀ copies/mL. The evaluation of the antiviral activity is ongoing.

GERIATRIC USE

Clinical studies of FUZEON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.