Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1614
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Fuzeon (Kit)
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Adults: The recommended dose of FUZEON is 90 mg (1 mL) twice
daily injected subcutaneously into the upper arm, anterior thigh or
abdomen. Each injection should be given at a site different from the
preceding injection site, and only where there is no current injection
site reaction from an earlier dose. 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 section
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. Additional detailed information regarding
the administration of FUZEON is described in the FUZEON Injection Instructions.<br/>Pediatric Patients: Insufficient data are available to establish a dose
recommendation of FUZEON in pediatric patients below the age of 6
years. In pediatric patients 6 years 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. Each injection should be given at a site
different from the preceding injection site and only where there is
no current injection site reaction from an earlier dose. FUZEON should
not be injected into moles, scar tissue, bruises or the navel. Table 7 contains dosing guidelines
for FUZEON based onbody weight. Weight should be monitored periodically
and the FUZEON dose adjusted accordingly.<br/>Directions for Use: For more detailed instructions, see FUZEON Injection Instructions.<br/>Subcutaneous Administration: FUZEON must only be reconstituted with 1.1 mL of
Sterile Water for Injection. After adding sterile water, the vial
should be gently tapped for 10 seconds and then gently rolled between
the hands to avoid foaming and to ensure all particles of drug are
in contact with the liquid and no drug remains on the vial wall. The
vial should then be allowed to stand until the powder goes completely
into solution, which could take up to 45 minutes. Reconstitution time
can be reduced by gently rolling the vial between the hands until
the product is completely dissolved. Before the solution is withdrawn
for administration, the vial should be inspected visually to ensure
that the contents are fully dissolved in solution, and that the solution
is clear, colorless and without bubbles or particulate matter. If
the FUZEON is foamy or jelled, allow more time for it to dissolve.
If there is evidence of particulate matter, the vial must not be used
and should be returned to the pharmacy. FUZEON
contains no preservatives. Once reconstituted, FUZEON should be injected
immediately or kept refrigerated in the original vial until use. Reconstituted
FUZEON must be used within 24 hours. The subsequent dose of FUZEON
can be reconstituted in advance and must be stored in the refrigerator
in the original vial and used within 24 hours. Refrigerated reconstituted
solution should be brought to room temperature before injection and
the vial should be inspected visually again to ensure that the contents
are fully dissolved in solution and that the solution is clear, colorless,
and without bubbles or particulate matter. The reconstituted solution should be injected subcutaneously in the
upper arm, abdomen or anterior thigh. The injection should be given
at a site different from the preceding injection site and only where
there is no current injection site reaction. Also, do not inject 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. A vial is suitable for single use only;
unused portions must be discarded (see FUZEON Injection Instructions). Patients should contact their healthcare provider for
any questions regarding the administration of FUZEON. Information
about the self-administration of FUZEON may also be obtained by calling
the toll-free number 1-877-4-FUZEON (1-877-438-9366) or at the FUZEON
website, www.FUZEON.com. Patients should be taught to recognize the
signs and symptoms of injection site reactions and instructed when
to contact their healthcare provider about these reactions.
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FUZEON (enfuvirtide) is an inhibitor of the fusion
of HIV-1 with CD4cells. Enfuvirtide is a linear 36-amino
acid synthetic peptide with the N-terminus acetylated and the C-terminus
is a carboxamide. It is composed of naturally occurring L-amino acid
residues. Enfuvirtide is a white to off-white
amorphous solid. It has negligible solubility in pure water and the
solubility increases in aqueous buffers (pH 7.5) to 85-142 g/100 mL.
The empirical formula of enfuvirtide is CHNO, and the molecular weight is 4492. It
has the following primary amino acid sequence: CHCO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NHand the following structural formula: The drug product,
FUZEON (enfuvirtide) for Injection, is a white to off-white, sterile,
lyophilized powder. Each single-use vial contains 108 mg of enfuvirtide
for the delivery of 90 mg. Prior to subcutaneous administration, the
contents of the vial are reconstituted with 1.1 mL of Sterile Water
for Injection giving a volume of approximately 1.2 mL to provide the
delivery of 1 mL of the solution. Each 1 mL of the reconstituted solution
contains approximately 90 mg of enfuvirtide with approximate amounts
of the following excipients: 22.55 mg of mannitol, 2.39 mg of sodium
carbonate (anhydrous), and sodium hydroxide and hydrochloric acid
for pH adjustment as needed. The reconstituted solution has an approximate
pH of 9.0.
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Pharmacokinetics: The pharmacokinetic properties of enfuvirtide were
evaluated in HIV-1 infected adult and pediatric patients.<br/>Absorption: Following a 90-mg single subcutaneous injection
of FUZEON into the abdomen in 12 HIV-1 infected subjects, the mean
(��SD) Cwas 4.59��1.5��g/mL, AUC was
55.8��12.1��g���h/mL and the median Twas 8 hours (ranged from 3 to 12 h). The absolute bioavailability
(using a 90-mg intravenous dose as a reference) was 84.3%��15.5%.
Following 90-mg bid dosing of FUZEON subcutaneously in combination
with other antiretroviral agents in 11 HIV-1 infected subjects, the
mean (��SD) steady-state Cwas 5.0��1.7��g/mL,
Cwas 3.3��1.6��g/mL, AUCwas 48.7��19.1��g���h/mL, and the median Twas 4 hours (ranged from 4 to 8 h). Absorption
of the 90-mg dose was comparable when injected into the subcutaneous
tissue of the abdomen, thigh or arm.<br/>Distribution: The mean (��SD) steady-state volume of distribution
after intravenous administration of a 90-mg dose of FUZEON (N=12)
was 5.5��1.1 L. Enfuvirtide is approximately
92% bound to plasma proteins in HIV-infected plasma over a concentration
range of 2 to 10��g/mL. It is bound predominantly to albumin
and to a lower extent to��-1 acid glycoprotein.<br/>Metabolism/Elimination: As a peptide, enfuvirtide is expected to undergo
catabolism to its constituent amino acids, with subsequent recycling
of the amino acids in the body pool. Mass balance
studies to determine elimination pathway(s) of enfuvirtide have not
been performed in humans. In vitro studies
with human microsomes and hepatocytes indicate that enfuvirtide undergoes
hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine
residue, M3. The hydrolysis reaction is not NADPH dependent. The M3
metabolite is detected in human plasma following administration of
enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide
AUC. Following a 90-mg single subcutaneous
dose of enfuvirtide (N=12) the mean��SD elimination half-life
of enfuvirtide is 3.8��0.6 h and the mean��SD apparent
clearance was 24.8��4.1 mL/h/kg. Following 90-mg bid dosing
of FUZEON subcutaneously in combination with other antiretroviral
agents in 11 HIV-1 infected subjects, the mean��SD apparent clearance
was 30.6��10.6 mL/h/kg.<br/>Special Populations:<br/>Drug Interactions:
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FUZEON is contraindicated in patients with known
hypersensitivity to FUZEON or any of its components .
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FUZEON (enfuvirtide) for Injection is a white to
off-white, sterile, lyophilized powder and it is packaged in a single-use
clear glass vial containing 108 mg of enfuvirtide for the delivery
of approximately 90 mg/1 mL when reconstituted with 1.1 mL of Sterile
Water for Injection. FUZEON is available in
a Convenience Kit containing 60 single-use vials of FUZEON (90 mg
strength), 60 vials (2 cartons of 30 each) of Sterile Water for Injection
(1.1 mL per vial), 60 reconstitution syringes (3 cc), 60 administration
syringes (1 cc), alcohol wipes, Package Insert, Patient Package Insert,
and Injection Instruction Guide (NDC 0004-0380-39).<br/>Storage Conditions: Store at 25��C (77��F); excursions permitted
to 15��to 30��C (59��to 86��F) [see USP Controlled
Room Temperature]. Reconstituted solution should
be stored under refrigeration at 2��to 8��C (36��to
46��F) and used within 24 hours. Roche
and FUZEON are trademarks of Hoffmann-La Roche Inc. Biojector is a trademark of Bioject Medical Technologies, Inc. FUZEON has been jointly developed by Trimeris, Inc. and
Hoffmann-La Roche Inc. FUZEON is manufactured by Hoffmann-La Roche
Inc.
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There are no reports of human experience of acute
overdose with FUZEON. The highest dose administered to 12 subjects
in a clinical trial was 180 mg as a single dose subcutaneously. There
is no specific antidote for overdose with FUZEON. Treatment of overdose
should consist of general supportive measures.
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enfuvirtide
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Fuzeon (Kit)
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The overall safety profile of FUZEON is based on
2131 subjects who received at least 1 dose of FUZEON during various
clinical trials. This includes 2051 adults, 658 of whom received the
recommended dose for greater than 48 weeks, and 63 pediatric subjects. Assessment of treatment-emergent adverse events is based
on the pooled data from the two Phase 3 studies T20-301 and T20-302.<br/>Local Injection Site Reactions: Local injection site reactions were the most frequent
adverse events associated with the use of FUZEON. In Phase 3 clinical
studies (T20-301 and T20-302), 98% of subjects had at least one local
injection site reaction (ISR). A total of 7% of subjects discontinued
treatment with FUZEON because of ISRs (4%) or difficulties with injecting
FUZEON (3%) such as injection fatigue and inconvenience. Eighty-five
percent of subjects experienced their first ISR during the initial
week of treatment; ISRs continued to occur throughout treatment with
FUZEON. For most subjects the severity of signs and symptoms associated
with ISRs did not change during the 48 weeks of treatment. The majority
of ISRs were associated with erythema, induration, the presence of
nodules or cysts, and mild to moderate pain at the injection site
(Table 4). In addition, the
average duration of individual ISRs was between three and seven days
in 41% of subjects and more than seven days in 24% of subjects. Also,
the numbers of ISRs per subject at any one time was between six to
14 ISRs in 26% of subjects and more than 14 ISRs in 1.3% of subjects.
Infection at the injection site (including abscess and cellulitis)
was reported in 1.7% of adult subjects.<br/>Biojector 2000 Needle-Free Device: Adverse events associated with the use of the Biojector
2000 needle-free device for administration of FUZEON have included:
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 .<br/>Other Adverse Events: Systemic hypersensitivity reactions have been attributed
to FUZEON (���1%) and in some cases have recurred upon re-challenge
. In the T20-301 and T20-302 studies,
after study week 8, patients on background alone who met protocol
defined criteria for virological failure were permitted to revise
their background regimens and add FUZEON. Exposure on FUZEON+background
was 557 patient-years, and to background alone 162 patient-years.
Due to this difference in exposure, safety results are expressed as
the number of patients with an adverse event per 100 patient-years
of exposure. For FUZEON+background, adverse events are also displayed
by percent of subjects. The events most frequently
reported in subjects receiving FUZEON+background regimen, excluding
injection site reactions, were diarrhea (38 per 100 patient-years
or 31.7%), nausea (27 per 100 patient-years or 22.8%), and fatigue
(24 per 100 patient-years or 20.2%). These events were also commonly
observed in subjects that received background regimen alone: diarrhea
(73 per 100 patient-years), nausea (50 per 100 patient-years), and
fatigue (38 per 100 patient-years). Treatment-emergent
adverse events, regardless of causality and excluding ISRs, from Phase
3 studies are summarized for adult subjects, in Table 5. Any Grade 2 or above events
occurring at���2 percent of subjects and at a higher rate in
subjects treated with FUZEON are summarized in Table 5; events that occurred at a higher
rate in the control arms are not displayed. Rates of adverse events for patients who switched to FUZEON after
virological failure were similar. 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 the Phase 3 clinical trials,
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 CD4lymphocyte count, high initial
viral load, intravenous drug use, smoking, and a prior history of
lung disease. It is unclear if the increased incidence of pneumonia
was 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 .<br/>Less Common Events: The following adverse events have been reported
in 1 or more subjects; however, a causal relationship to FUZEON has
not been established. Immune System Disorders: worsening abacavir
hypersensitivity reaction Renal and Urinary Disorders: glomerulonephritis;
tubular necrosis; renal insufficiency; renal failure (including fatal
cases) Blood
and Lymphatic Disorders: thrombocytopenia; neutropenia;
fever; lymphadenopathy Endocrine and Metabolic: hyperglycemia Infections: sepsis;
herpes simplex Nervous System Disorders: taste disturbance; Guillain-Barre
syndrome (fatal); sixth nerve palsy; peripheral neuropathy Cardiac Disorders: unstable angina pectoris Gastrointestinal Disorders: constipation;
abdominal pain upper General: asthenia Hepatobiliary Disorders: toxic hepatitis;
hepatic steatosis Investigations: increased amylase; increased lipase; increased
AST; increased GGT; increased triglycerides Psychiatric Disorders: insomnia;
depression; anxiety; suicide attempt Respiratory, Thoracic, and Mediastinal Disorders: pneumopathy; respiratory distress; cough Skin and Subcutaneous Tissue Disorders: pruritus<br/>Laboratory Abnormalities: Table 6 shows
the treatment-emergent laboratory abnormalities that occurred in at
least 2 subjects per 100 patient-years and more frequently in those
receiving FUZEON+background regimen than background regimen alone
from studies T20-301 and T20-302.<br/>Adverse Events in Pediatric Patients: FUZEON has been studied in 63 pediatric subjects
5 through 16 years of age with duration of FUZEON exposure ranging
from 1 dose to 134 weeks. Adverse experiences seen during clinical
trials 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.
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FUZEON in combination with other antiretroviral
agents is indicated for the treatment of HIV-1 infection in treatment-experienced
patients with evidence of HIV-1 replication despite ongoing antiretroviral
therapy. This indication is based on results
from two controlled studies of 48 weeks duration. Subjects enrolled
were treatment-experienced adults; many had advanced disease. There
are no studies of FUZEON in antiretroviral naive patients.<br/>Description of Clinical Studies:<br/>Studies in Antiretroviral Experienced Patients: Studies T20-301 and T20-302 were randomized, controlled,
open-label, multicenter trials in HIV-1 infected subjects. Subjects
were required to have either (1) viremia despite 3 to 6 months prior
therapy with a nucleoside reverse transcriptase inhibitor (NRTI),
non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease
inhibitor (PI) or (2) viremia and documented resistance or intolerance
to at least one member in each of the NRTI, NNRTI, and PI classes. All subjects received an individualized background regimen
consisting of 3 to 5 antiretroviral agents selected on the basis of
the subject's prior treatment history and baseline genotypic and phenotypic
viral resistance measurements. Subjects were then randomized at a
2:1 ratio to FUZEON 90 mg bid with background regimen or background
regimen alone. After week 8, patients on either
treatment arm who met protocol defined criteria for virological failure
were permitted to revise their background regimens; those on background
regimen alone were also permitted to add FUZEON. Demographic characteristics for studies T20-301 and T20-302 are shown
in Table 2. Subjects had prior
exposure to a median of 12 antiretrovirals for a median of 7 years. The disposition and efficacy outcomes of studies
T20-301 and T20-302 are shown in Table
3. At 48 weeks, 154 (23%) of subjects in the FUZEON+background
regimen and 27 (8%) in the background regimen alone had HIV RNA levels<50 copies/mL, and 225 (34%) of subjects receiving FUZEON+background
regimen had HIV RNA levels<400 copies/mL compared to 44 (13%)
in the background regimen alone. Subjects achieving HIV RNA levels<50 copies/mL were included in the<400 copies/mL category and
both categories were incorporated in the overall virologic responder
category of achieving HIV RNA at least 1 logbelow baseline. The mean log change in HIV-1 RNA from baseline was -1.4
logcopies/mL in subjects receiving FUZEON+background
and -0.5 in those receiving background alone. The mean change in CD4cell count from baseline to week 48 was +91 cells/mmin the FUZEON+background arm and +45 cells/mmin the background alone arm. Subjects in
the FUZEON+background arm achieved a better virologic and immunologic
outcome than subjects in the background alone arm across all subgroups
based on baseline CD4cell count, baseline HIV-1 RNA,
number of prior ARVs or number of active ARVs in the background regimen.
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Fuzeon
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