A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Amevive Side Effects, and Drug Interactions - Alefacept
Amevive Side Effects, and Drug Interactions - Alefacept
SIDE EFFECTS
The most serious adverse reactions were:
- Lymphopenia (see WARNINGS)
- Malignancies (see WARNINGS)
- Serious Infections requiring hospitalization (see WARNINGS)
- Hypersensitivity Reactions (see PRECAUTIONS, Allergic Reactions)
Commonly observed adverse events seen in the first course of
placebo-controlled clinical trials with at least a 2% higher incidence in the
AMEVIVE®-treated patients compared to placebo-treated patients were: pharyngitis,
dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site
pain, injection site inflammation, and accidental injury. The only adverse event
that occurred at a 5% or higher incidence among AMEVIVE®-treated patients
compared to placebo-treated patients was chills (1% placebo vs. 6% AMEVIVE®),
which occurred predominantly with intravenous administration.
The adverse reactions which most commonly resulted in clinical
intervention were cardiovascular events including coronary artery disorder in
<1% of patients and myocardial infarct in <1% of patients. These events
were not observed in any of the 413 placebo-treated patients. The total number
of patients hospitalized for cardiovascular events in the AMEVIVE®-treated
group was 1.2% (11/876).
The most common events resulting in discontinuation of treatment
with AMEVIVE® were CD4+ T lymphocyte levels below 250 cells/•L (see WARNINGS,
and ADVERSE REACTIONS, Effect on Lymphocyte
Counts), headache (0.2%), and nausea (0.2%).
Because clinical trials are conducted under widely varying
conditions, adverse event rates observed in the clinical trials of a drug cannot
be directly compared to rates in the clinical trials of another drug and may
not reflect the rates observed in practice. The adverse reaction information
does, however, provide a basis for identifying the adverse events that appear
to be related to drug use and a basis for approximating rates.
The data described below reflect exposure to AMEVIVE® in
a total of 1357 psoriasis patients, 85% of whom received 1 to 2 courses of therapy
and the rest received 3 to 6 courses and were followed for up to three years.
Of the 1357 total patients, 876 received their first course in placebo-controlled
studies. The population studied ranged in age from 16 to 84 years, and included
69% men and 31% women. The patients were mostly Caucasian (89%), reflecting
the general psoriatic population. Disease severity at baseline was moderate
to severe psoriasis.
Effect on Lymphocyte Counts
In the intramuscular study (Study 2), 4% of patients temporarily
discontinued treatment and no patients permanently discontinued treatment due
to CD4+ T lymphocyte counts below the specified threshold of 250 cells/µL. In
Study 2, 10%, 28%, and 42% of patients had total lymphocyte, CD4+, and CD8+
T lymphocyte counts below normal, respectively. Twelve weeks after a course
of therapy (12 weekly doses), 2%, 8%, and 21% of patients had total lymphocyte,
CD4+, and CD8+ T cell counts below normal.
In the first course of the intravenous study (Study 1), 10%
of patients temporarily discontinued treatment and 2% permanently discontinued
treatment due to CD4+ T lymphocyte counts below the specified threshold of 250
cells/µL. During the first course of Study 1, 22% of patients had total lymphocyte
counts below normal, 48% had CD4+ T lymphocyte counts below normal and 59% had
CD8+ T lymphocyte counts below normal.
The maximal effect on lymphocytes was observed within 6 to
8 weeks of initiation of treatment. Twelve weeks after a course of therapy (12
weekly doses), 4% of patients had total lymphocyte counts below normal, 19%
had CD4+ T lymphocyte counts below normal, and 36% had CD8+ T lymphocyte counts
below normal.
For patients receiving a second course of AMEVIVE® in Study
1, 17% of patients had total lymphocyte counts below normal, 44% had CD4+ T
lymphocyte counts below normal, and 56% had CD8+ T lymphocyte counts below normal.
Twelve weeks after completing dosing, 3% of patients had total lymphocyte counts
below normal, 17% had CD4+ T lymphocyte counts below normal, and 35% had CD8+
T lymphocyte counts below normal (see WARNINGS,
and PRECAUTIONS, Laboratory Tests).
Malignancies
In the 24-week period constituting the first course of placebo-controlled
studies, 13 malignancies were diagnosed in 11 AMEVIVE®-treated patients.
The incidence of malignancies was 1.3% (11/876) for AMEVIVE®-treated patients
compared to 0.5% (2/413) in the placebo group.
Among 1357 patients who received AMEVIVE®, 25 patients
were diagnosed with 35 treatment-emergent malignancies. The majority of these
malignancies (23 cases) were basal (6) or squamous cell cancers (17) of the
skin. Three cases of lymphoma were observed; one was classified as non-Hodgkin’s
follicle-center cell lymphoma and two were classified as Hodgkin’s disease.
Infections
In the 24-week period constituting the first course of placebo-controlled
studies, serious infections (infections requiring hospitalization) were seen
at a rate of 0.9% (8/876) in AMEVIVE®-treated patients and 0.2% (1/413)
in the placebo group. In patients receiving repeated courses of AMEVIVE®
therapy, the rates of serious infections were 0.7% (5/756) and 1.5% (3/199)
in the second and third course of therapy, respectively. Serious infections
among 1357 AMEVIVE®-treated patients included necrotizing cellulitis, peritonsillar
abscess, post-operative and burn wound infection, toxic shock, pneumonia, appendicitis,
pre-septal cellulitis, cholecystitis, gastroenteritis and herpes simplex infection.
Hypersensitivity Reactions
In clinical studies two patients were reported to experience
angioedema, one of whom was hospitalized. In the 24-week period constituting
the first course of placebo-controlled studies, urticaria was reported in 6
(<1%) AMEVIVE®-treated patients vs. 1 patient in the control group. Urticaria
resulted in discontinuation of therapy in one of the AMEVIVE®-treated patients.
Hepatic Injury
In post-marketing experience there have been
reports of asymptomatic transaminase elevation, fatty infiltration of
the liver, hepatitis, and severe liver failure (see PRECAUTIONS Hepatic Injury).
Injection Site Reactions
In the intramuscular study (Study 2), 16% of AMEVIVE®-treated
patients and 8% of placebo-treated patients reported injection site reactions.
Reactions at the site of injection were generally mild, typically occurred on
single occasions, and included either pain (7%), inflammation (4%), bleeding
(4%), edema (2%), non-specific reaction (2%), mass (1%), or skin hypersensitivity
(<1%). In the clinical trials, a single case of injection site reaction led
to the discontinuation of AMEVIVE®.
Immunogenicity
Approximately 3% (35/1306) of patients receiving AMEVIVE®
developed low-titer antibodies to alefacept. No apparent correlation of antibody
development and clinical response or adverse events was observed. The long-term
immunogenicity of AMEVIVE® is unknown.
The data reflect the percentage of patients whose test results
were considered positive for antibodies to alefacept in an ELISA assay, and
are highly dependent on the sensitivity and specificity of the assay. Additionally,
the observed incidence of antibody positivity in an assay may be influenced
by several factors including sample handling, timing of sample collection, concomitant
medications, and underlying disease. For these reasons, comparison of the incidence
of antibodies to alefacept with the incidence of antibodies to other products
may be misleading.
Other Observed Adverse Reactions from Clinical Trials
Less common events that were observed at a higher rate in AMEVIVE®-treated
patients include rare cases (9) of transaminase elevations to 5 to 10 times
the upper limit of normal.
DRUG INTERACTIONS
No formal interaction studies have been performed. The duration
of the period following treatment with AMEVIVE® before one should consider
starting other immunosuppressive therapy has not been evaluated.
Carcinogenesis, Mutagenesis, and Fertility
In a chronic toxicity study, cynomolgus monkeys were dosed
weekly for 52 weeks with intravenous alefacept at 1 mg/kg/dose or 20 mg/kg/dose.
One animal in the high dose group developed a B-cell lymphoma that was detected
after 28 weeks of dosing. Additional animals in both dose groups developed B-cell
hyperplasia of the spleen and lymph nodes.
All animals in the study were positive for an endemic primate
gammaherpes virus also known as lymphocryptovirus (LCV). Latent LCV infection
is generally asymptomatic, but can lead to B-cell lymphomas when animals are
immune suppressed.
In a separate study, baboons given 3 doses of alefacept at
1 mg/kg every 8 weeks were found to have centroblast proliferation in B-cell
dependent areas in the germinal centers of the spleen following a 116-day washout
period.
The role of AMEVIVE® in the development of the lymphoid
malignancy and the hyperplasia observed in non-human primates and the relevance
to humans is unknown. Immunodeficiency-associated lymphocyte disorders (plasmacytic
hyperplasia, polymorphic proliferation, and B-cell lymphomas) occur in patients
who have congenital or acquired immunodeficiencies including those resulting
from immunosuppressive therapy.
No carcinogenicity or fertility studies were conducted.
Mutagenicity studies were conducted in vitro and in vivo; no
evidence of mutagenicity was observed.
Pregnancy (Category B)
Women of childbearing potential make up a considerable segment
of the patient population affected by psoriasis. Since the effect of AMEVIVE®
on pregnancy and fetal development, including immune system development, is
not known, health care providers are encouraged to enroll patients currently
taking AMEVIVE® who become pregnant into the Biogen Pregnancy Registry by
calling 1-866-AMEVIVE (1-866-263-8483).
Reproductive toxicology studies have been performed in cynomolgus
monkeys at doses up to 5 mg/kg/week (about 62 times the human dose based on
body weight) and have revealed no evidence of impaired fertility or harm to
the fetus due to AMEVIVE®. No abortifacient or teratogenic effects were
observed in cynomolgus monkeys following intravenous bolus injections of AMEVIVE®
administered weekly during the period of organogenesis to gestation. AMEVIVE®
underwent trans-placental passage and produced in utero exposure in the developing
monkeys. In utero, serum levels of exposure in these monkeys were 23% of maternal
serum levels. No evidence of fetal toxicity including adverse effects on immune
system development was observed in any of these animals.
Animal reproduction studies, however, are not always predictive
of human response and there are no adequate and well-controlled studies in pregnant
women. Because the risk to the development of the fetal immune system and postnatal
immune function in humans is unknown, AMEVIVE® should be used during pregnancy
only if clearly needed. If pregnancy occurs while taking AMEVIVE®, continued
use of the drug should be assessed.
Nursing Mothers
It is not known whether AMEVIVE® is excreted in human milk.
Because many drugs are excreted in human milk, and because there exists the
potential for serious adverse reactions in nursing infants from AMEVIVE®,
a decision should be made whether to discontinue nursing while taking the drug
or to discontinue the use of the drug, taking into account the importance of
the drug to the mother.
Geriatric Use
Of the 1357 patients who received AMEVIVE® in clinical
trials, a total of 100 patients were ≥ 65 years of
age and 13 patients were ≥ 75 years of age. No differences
in safety or efficacy were observed between older and younger patients, but
there were not sufficient data to exclude important differences. Because the
incidence of infections and certain malignancies is higher in the elderly population,
in general, caution should be used in treating the elderly.
Pediatric Use
The safety and efficacy of AMEVIVE® in pediatric patients
have not been studied. AMEVIVE® is not indicated for pediatric patients.
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