Included as part of the PRECAUTIONS section.
Local Injection Site Reactions (ISRs)
The majority of subjects (98%) receiving FUZEON in
randomized, controlled, open-label, multicenter clinical trials had at least
one local injection site reaction; ISRs occurred throughout treatment with
FUZEON. Manifestations may include pain and discomfort, induration, erythema,
nodules and cysts, pruritus, and ecchymosis [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.
Administration With Biojector® 2000
Nerve pain (neuralgia and/or paresthesia) lasting up to 6
months associated with administration at anatomical sites where large nerves
course close to the skin, bruising and hematomas have occurred with use of the
Biojector 2000 needle-free device for administration of FUZEON.
Patients receiving anticoagulants or persons with
hemophilia, or other coagulation disorders, may have a higher risk of
Systemic hypersensitivity reactions have been associated
with FUZEON therapy and may recur on re-challenge. Hypersensitivity reactions
have occurred in <1% of subjects studied and have included combinations of:
rash, fever, nausea and vomiting, chills, rigors, hypotension, and/or 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.
An increased rate of bacterial pneumonia was observed in
subjects treated with FUZEON in the Phase 3 clinical trials compared to the
control arm. The incidence of pneumonia was 2.7% or 3.2 events/100
patient-years in subjects receiving FUZEON+background regimen. On analysis of
all diagnoses of pneumonia (pneumonia, bacterial pneumonia, bronchopneumonia,
and related terms) in T20-301 and T20-302, an increased rate of bacterial
pneumonia was observed in subjects treated with FUZEON compared to the control
arm (6.9%, 6.7 pneumonia events per 100 patient-years versus 0.6 events per 100
patient-years, respectively). Approximately half of the study subjects with
pneumonia required hospitalization. Three subject deaths in the FUZEON arm were
attributed to pneumonia; all three had serious concomitant AIDS-related
illnesses that contributed to their deaths. Risk factors for pneumonia included
low initial CD4 lymphocyte count, high initial viral load, intravenous drug
use, smoking, and a prior history of lung disease.
Because it was unclear whether the higher incidence rate
of pneumonia was related to FUZEON use, an observational study in 1850
HIV-infected patients (740 FUZEON treated patients and 1110 non-FUZEON treated
patients) was conducted to evaluate the risk of pneumonia in patients treated
with FUZEON. A total of 123 patients had a confirmed or probable pneumonia
event in this study (62 in the FUZEON treatment arm with 1962 patient-years of
observation and 61 in the non-FUZEON treatment arm with 3378 patient-years of
observation). The incidence of pneumonia was 3.2 events/100 patient-years in
the FUZEON treatment arm and 1.8 events/100 patient-years in the non-FUZEON treatment
arm. The hazard ratio, adjusting for other baseline risk factors, was 1.34 (95%
C.I. = 0.90 Ã¢â¬“ 2.00). Based on this observational study, it is not possible to
exclude an increased risk of pneumonia in patients treated with FUZEON compared
to non-FUZEON treated patients.
It is unclear if the increased incidence of pneumonia is
related to FUZEON use. However, because of these findings, patients with HIV-1
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
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.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including FUZEON.
During the initial phase of combination antiretroviral treatment, patients
whose immune system responds may develop an inflammatory response to indolent
or residual opportunistic infections (such as Mycobacterium avium infection,
cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP] or
tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as GravesÃ¢â¬™ disease,
polymyositis, and Guillain-BarrÃ© syndrome) have also been reported to occur in
the setting of immune reconstitution, however, the time to onset is more
variable, and can occur many months after initiation of treatment.
Patient Counseling Information
See FDA-Approved Patient Labeling (PATIENT INFORMATION, Instructions for Use)
To assure safe and effective use of FUZEON, the following
information and instructions should be given to patients:
Injection Site Reactions
Inform patients that injection site reactions occur in
almost all patients taking FUZEON. 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.
Instruct patients when to contact their healthcare provider about these
reactions [see WARNINGS AND PRECAUTIONS].
Administration With Biojector® 2000
Inform patients that nerve pain (neuralgia and/or
paresthesia) associated with administration at anatomical sites where large
nerves course close to the skin, bruising and hematomas have occurred with use
of the Biojector 2000 needle-free device for administration of FUZEON [see WARNINGS
Advise patients about the risk of post-injection bleeding
if they are receiving anticoagulants or have coagulation disorders such as
hemophilia [see WARNINGS AND PRECAUTIONS].
Advise patients of the possibility of a systemic
hypersensitivity reaction to FUZEON. Advise patients to discontinue therapy and
immediately seek medical evaluation if they develop signs/symptoms of systemic
hypersensitivity such as combinations of rash, fever, nausea and vomiting,
chills, rigors, and/or hypotension [see WARNINGS AND PRECAUTIONS].
Advise patients that an increased rate of bacterial
pneumonia was observed in subjects treated with FUZEON in clinical trials.
Advise patients to seek medical evaluation immediately if they develop signs or
symptoms suggestive of pneumonia (cough with fever, rapid breathing, shortness
of breath) [see WARNINGS AND PRECAUTIONS].
Pregnancy Exposure Registry
Advise patients that there is a pregnancy exposure
registry that monitors pregnancy outcomes in women exposed to FUZEON during
pregnancy [see Use In Specific Populations].
Instruct mothers with HIV-1 infection not to breastfeed
because HIV-1 can be passed to the baby in breast milk [see Use In Specific
Important Dosing And Administration Instructions
- Inform patients that FUZEON must be taken as part of a
combination antiretroviral regimen and that use of FUZEON alone may lead to
rapid development of virus resistant to FUZEON and possibly other agents of the
- Instruct patients and caregivers 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
caregiverÃ¢â¬™s understanding and use of aseptic injection techniques and
procedures be periodically re-evaluated.
- Instruct patients and caregivers on the preferred
anatomical sites for administration (upper arm, abdomen, anterior thigh).
FUZEON should not be injected near any anatomical areas where large nerves
course close to the skin, such as near the elbow, knee, groin or the inferior
or medial sections of the buttocks, skin abnormalities, including directly over
a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical
scars, tattoos or burn sites.
- Instruct patients and caregivers in the proper techniques
for preparation, injection and disposal of needles and syringes (including not
recapping needles) in order to avoid needle stick injuries. Advise patients not
to reuse needles or syringes, and of safe disposal procedures, including the
use of a puncture-resistant container, for disposal of used needles and
syringes. Instruct patients on the safe disposal of full containers as per
local requirements. Caregivers who experience an accidental needle stick after
patient injection should contact a healthcare provider immediately.
- Inform patients to contact their healthcare provider for
any questions regarding the administration of FUZEON.
- Inform patients not to change the dose or dosing schedule
of FUZEON or any antiretroviral medication without consulting their healthcare
- Inform patients to contact their healthcare provider
immediately if they stop taking FUZEON or any other drug in their
- Inform patients that they can obtain more information on
the self-administration of FUZEON at www.FUZEON.com or by calling
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis And Mutagenesis
Carcinogenicity studies have not been conducted with
Enfuvirtide was not genotoxic in in vivo and in vitro assays
including a bacterial reverse mutation assay, a mammalian cell forward gene
mutation assay in AS52 Chinese Hamster ovary cells, and an in vivo mouse
Impairment Of Fertility
In a fertility and early embryonic development study in
rats, no effects of enfuvirtide on male or female fertility were observed at
enfuvirtide exposures (based on surface area) up to 1.6 times higher than human
exposure at the RHD.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in individuals exposed to FUZEON during pregnancy.
Healthcare providers are encouraged to register patients by calling the
Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Prospective pregnancy data from the APR are not
sufficient to adequately assess the risk of birth defects or fetal outcomes.
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. All pregnancies
have a background risk of birth defect, loss, or other adverse outcomes. The
estimated background rate for major birth defects is 2.7% in the U.S. reference
population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The
estimated rate of miscarriage is not reported in the APR. The estimated
background rate of miscarriage in the U.S. general population is 15Ã¢â¬“20%.
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
exposure at the recommended human dose (RHD) based on surface area (see Data).
In the embryofetal development studies, enfuvirtide was
administered by subcutaneous injection to pregnant rats at doses up to 500
mg/kg/day from gestation days 6 to 17, and to pregnant rabbits at doses up to
30 mg/kg/day from gestation days 6 to 18. No embryofetal toxicities were
observed at doses up to the highest doses tested (27 times and 3.2 times higher
than human exposure at the RHD in rats and rabbits, respectively, based on
In the pre/postnatal development study, enfuvirtide was
administered by subcutaneous injection to pregnant rats at doses up to 30 mg/kg/day
from gestation day 6 to postnatal day 20. No toxicities were observed at doses
up to 30 mg/kg/day (1.6 times higher than human exposure at the RHD based on
The Centers for Disease Control and Prevention recommends
that HIV-1 infected mothers not breastfeed their infants to avoid the risk of
postnatal transmission of HIV-1.
There are no human data available regarding the presence
of enfuvirtide or its metabolites (amino acids and peptide fragments) in human milk,
the effects on the breastfed infant, or the effects on milk production. When
enfuvirtide was administered to lactating rats, enfuvirtide was likely present
in the milk (see Data).
Because of both the potential for (1) HIV-1 transmission
(in HIV-negative infants), (2) developing viral resistance (in HIV-positive
infants) and (3) adverse reactions in breastfed infants similar to those seen
in adults, instruct mothers not to breastfeed if they are receiving FUZEON.
In a lactation study at doses of 200 mg/kg, very low
levels of enfuvirtide or enfuvirtide metabolites (amino acids and peptide
fragments) were excreted in milk following subcutaneous administration to
lactating rats up to 48 hours post-dose on postpartum/lactation days 14 and 18.
Use of FUZEON in pediatric patients weighing at least
11kg is supported by evidence from adequate and well-controlled studies of
FUZEON in adult and by two pediatric studies evaluating the safety,
pharmacokinetics and efficacy of FUZEON in subjects 6 years of age and older:
- T20-204 was an open-label, multicenter trial that
evaluated the safety and antiviral activity of FUZEON in 11,
treatment-experienced pediatric subjects 6 to 12 years (median age of 9 years) [see
CLINICAL PHARMACOLOGY and Clinical Studies].
- T20-310 was an open-label, multicenter trial that
evaluated the pharmacokinetics, safety, and antiviral activity of FUZEON in 52,
treatment-experienced pediatric subjects 5 years and older (median age of 12
years) [see CLINICAL PHARMACOLOGY and Clinical Studies].
Overall, the adverse experiences, including ISRs in the
63 pediatric subjects were similar to those observed in adult subjects,
although infections at site of injection (cellulitis or abscess) were more
frequent in adolescents than in adults, with 4 events occurring in 3 of 28
(11%) subjects [see ADVERSE REACTIONS].
Clinical studies of FUZEON did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. In general, appropriate caution should be
exercised in the administration and monitoring of FUZEON in elderly patients
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
No dosage adjustments of FUZEON are needed in patients
with hepatic impairment [see CLINICAL PHARMACOLOGY].
No dosage adjustments of FUZEON are needed in patients
with renal impairment [see CLINICAL PHARMACOLOGY].