Simulect®
(basiliximab)
For Injection
Rx only
Prescribing
Information
WARNING
Only physicians experienced in
immunosuppression therapy and management of organ
transplantation patients should
prescribe Simulect® (basiliximab).
The physician
responsible for Simulect® administration should have
complete information requisite for
the follow-up of the patient.
Patients receiving the drug should be managed in facilities
equipped and staffed with
adequate laboratory and supportive medical resources.
DESCRIPTION
Simulect® (basiliximab) is a chimeric (murine/human)
monoclonal antibody (IgG1κ),
produced
by
recombinant DNA technology, that functions as an immunosuppressive agent,
specifically
binding
to and blocking the interleukin-2 receptor
α-chain (IL-2Rα, also known as CD25
antigen)
on the surface of activated T-lymphocytes.
Based on the amino acid sequence,
the
calculated
molecular weight of the protein is 144 kilodaltons. It is a
glycoprotein obtained
from fermentation of an established
mouse myeloma cell
line genetically engineered
to
express
plasmids containing the human heavy and light chain constant region genes
and
mouse
heavy and light chain variable region genes encoding the RFT5 antibody that
binds
selectively
to the IL-2Rα.
The
active ingredient, basiliximab, is water soluble. The drug product, Simulect®, is
a
sterile
lyophilisate which is available in 6 mL colorless glass vials. Each vial contains 20 mg
basiliximab,
7.21 mg monobasic potassium phosphate, 0.99 mg disodium hydrogen phosphate
(anhydrous),
1.61 mg sodium chloride, 20 mg sucrose, 80 mg mannitol and 40 mg glycine, to
be
reconstituted in 5 mL of Sterile Water for Injection, USP. No preservatives are added.
CLINICAL
PHARMACOLOGY
General
Mechanism of action: Basiliximab functions as an IL-2 receptor
antagonist by binding with
high
affinity (Ka = 1 x 1010 M-1) to the alpha chain of the high affinity IL-2
receptor complex
and inhibiting
IL-2 binding. Basiliximab is specifically targeted
against IL-2Rα, which
is
selectively
expressed on the surface of activated T-lymphocytes. This specific high
affinity
binding
of Simulect® to IL-2Rα competitively inhibits
IL-2-mediated activation of
lymphocytes, a critical pathway in the cellular immune
response involved in allograft
rejection.
While
in the circulation, Simulect® impairs
the response of the immune system to
antigenic
challenges. Whether the ability to
respond to repeated or ongoing challenges with
those
antigens returns to normal after Simulect® is
cleared is unknown (See PRECAUTIONS).
Pharmacokinetics
Adults: Single-dose and multiple-dose pharmacokinetic studies have been conducted in
patients
undergoing first kidney transplantation.
Cumulative doses ranged from 15 mg up to
150
mg. Peak mean ± SD serum concentration
following intravenous infusion of 20 mg over
30
minutes is 7.1 ± 5.1 mg/L. There is a
dose-proportional increase in Cmax and
AUC up to
the
highest tested single dose of 60 mg.
The volume of distribution at steady state is 8.6 ±
4.1
L. The extent and degree of distribution to various body compartments have not
been fully
studied. The terminal half-life is 7.2 ± 3.2 days.
Total body clearance is 41 ± 19 mL/h. No
clinically
relevant influence of body weight or gender on distribution volume or clearance
has
been
observed in adult patients. Elimination
half-life was not influenced by age (20-69 years),
gender
or race (See DOSAGE AND ADMINISTRATION).
Pediatric: The pharmacokinetics of Simulect® have been assessed in 39 pediatric patients
undergoing
renal transplantation. In infants and
children (1-11 years of age, n=25), the
distribution
volume and clearance were reduced by about 50% compared to adult renal
transplantation
patients. The volume of distribution at
steady state was 4.8 ± 2.1 L, half-life
was
9.5 ± 4.5 days and clearance was 17 ±
6 mL/h. Disposition parameters were not
influenced
to a clinically relevant extent by age (1-11 years of age), body weight (9-37
kg) or
body
surface area (0.44-1.20 m2) in this age group. In
adolescents (12-16 years of age, n=14),
disposition was
similar to that
in adult renal
transplantation patients. The
volume of
distribution at
steady state was 7.8 ±
5.1 L, half-life was 9.1 ± 3.9 days and clearance was
31 ±
19 mL/h (See DOSAGE AND ADMINISTRATION).
Pharmacodynamics
Complete and
consistent binding to
IL-2Rα in adults
is maintained as
long as serum
Simulect® levels exceed 0.2 µg/mL. As concentrations fall below this threshold, the IL-2Rα
sites
are no longer fully bound and the number of T-cells expressing unbound IL-2Rα
returns
to
pretherapy values within 1-2 weeks. The relationship between serum concentration and
receptor
saturation was assessed in 13 pediatric patients and was similar to that
characterized
in adult
renal transplantation patients.
In vitro studies using human tissues indicate that
Simulect® binds only to lymphocytes.
The duration
of clinically relevant IL-2
receptor blockade after the recommended
course
of Simulect® is not known.
When basiliximab was added to a regimen of cyclosporine,
USP
(MODIFIED) and corticosteroids in adult patients, the duration of IL-2Rα
saturation was
36 ±
14 days (mean
± SD), similar to that
observed in pediatric
patients (36 ± 14 days)
(See
DOSAGE AND ADMINISTRATION). When basiliximab was added to a triple therapy
regimen
consisting of cyclosporine, USP (MODIFIED), corticosteroids, and azathioprine in
adults,
the duration was 50 ± 20 days and when
added to cyclosporine, USP (MODIFIED),
corticosteroids,
and mycophenolate mofetil in adults, the duration was 59 ± 17
days
(See
PRECAUTIONS-DRUG INTERACTIONS). No significant changes to circulating
lymphocyte
numbers or cell phenotypes were observed by flow cytometry.
CLINICAL
STUDIES
The
safety and efficacy of Simulect® for the prophylaxis of acute organ rejection in adults
following
cadaveric- or living-donor renal transplantation were assessed in four
randomized,
double-blind,
placebo-controlled clinical studies (1184 patients). Of these four, two
studies
[Study
1 (EU/CAN) and Study 2 (US study)] compared two 20 mg doses of Simulect® with
placebo,
each administered intravenously as an infusion, as part of a standard
immunosuppressive
regimen comprised of cyclosporine,
USP (MODIFIED) and
corticosteroids. The
other two controlled
studies compared two 20 mg doses of Simulect®
with
placebo, each administered intravenously as a bolus injection, as part of a
standard triple
immunosuppressive
regimen comprised of cyclosporine, USP (MODIFIED),
corticosteroids
and
either azathioprine or mycophenolate mofetil (Study 3 and Study 4,
respectively). The first
dose
of Simulect® or placebo was administered within 2 hours prior
to transplantation surgery
(Day 0)
and the second dose administered
on Day 4 post-transplantation. The regimen of
Simulect® was chosen to provide 30-45 days of IL-2Rα
saturation.
729 patients
were enrolled in
the two studies using a dual maintenance
immunosuppressive
regimen comprised of cyclosporine, USP (MODIFIED)
and
corticosteroids, of which 363 patients were treated with
Simulect® and 358 patients were
placebo-treated.
Study 1 was conducted at 21 sites in Europe and Canada (EU/CAN Study);
Study 2
was conducted at 21 sites in the USA (US Study). Patients 18-75 years of age
undergoing
first cadaveric (Study 1 and Study 2) or living-donor (Study 2 only) renal
transplantation,
with ≥1 HLA mismatch, were enrolled.1,2
The
primary efficacy endpoint in both studies was the incidence of death, graft
loss or
an
episode of acute rejection during the first 6 months post-transplantation.
Secondary efficacy
endpoints
included the primary efficacy variable measured during the first 12 months
post-transplantation,
the incidence of biopsy-confirmed acute rejection during the first 6 and
12
months post-transplantation, and patient survival and graft survival, each
measured at
12
months post-transplantation. Table 1 summarizes the results of these studies.
Figure 1
displays the
Kaplan-Meier estimates of
the percentage of
patients by treatment
group
experiencing
the primary efficacy endpoint during the first 12 months post-transplantation
for
Study 2. Patients in both studies receiving
Simulect® experienced a significantly lower
incidence
of biopsy-confirmed rejection episodes at both 6 and 12 months
post-
transplantation. There was no difference in the rate of
delayed graft function, patient survival,
or graft
survival between Simulect®-treated
patients and placebo-treated patients in either
study.
There
was no evidence that the clinical benefit of Simulect® was
limited to specific
subpopulations
based on age, gender, race, donor type (cadaveric or living-donor allograft) or
history
of diabetes mellitus.
Two
double-blind, randomized, placebo-controlled studies (Study 3
and Study 4)
assessed
the safety and efficacy of Simulect® for
the prophylaxis of acute renal
transplant
rejection in
adults when used in combination with a triple immunosuppressive regimen.
In
Study 3,
340 patients were concomitantly treated with cyclosporine, USP
(MODIFIED),
corticosteroids
and azathioprine (AZA), of which 168 patients were treated with Simulect®
and 172
patients were treated with placebo. In Study 4, 123
patients were concomitantly
treated
with cyclosporine, USP (MODIFIED), corticosteroids and mycophenolate mofetil
(MMF),
of which 59 patients were treated with Simulect® and
64 patients were treated with
placebo. Patients
18-70 years of age undergoing
first or second cadaveric or living-donor
(related
or unrelated) renal transplantation were enrolled in both studies.
The
results of Study 3 are shown in Table 2.
These results are consistent with the
findings
from Study 1 and Study 2.
In
Study 4, the percentage of patients experiencing biopsy-proven acute
rejection by
6
months was 15% (9 of 59 patients) in the Simulect® group
and 27% (17 of 64 patients) in
the
placebo group. Although numerically
lower, the difference in acute rejection was
not
significant.
In a
multicenter, randomized, double-blind, placebo-controlled trial of Simulect® for
the
prevention of allograft rejection in liver transplant recipients (n=381) receiving
concomitant cyclosporine, USP (MODIFIED) and
steroids, the incidence
of the combined
endpoint
of death, graft loss, or first biopsy-confirmed rejection episode
at either 6 or
12
months was similar between patients randomized to receive Simulect® and those
randomized
to receive placebo.
The
efficacy of Simulect® for the prophylaxis of acute
rejection in recipients of a
second
renal allograft has not been demonstrated.
INDICATIONS AND
USAGE
Simulect® is indicated for the prophylaxis of acute organ
rejection in patients receiving renal
transplantation when
used as part
of an immunosuppressive regimen that includes cyclo-
sporine,
USP (MODIFIED) and corticosteroids.
The
efficacy of Simulect® for the prophylaxis of acute
rejection in recipients of other
solid
organ allografts has not been demonstrated.
CONTRAINDICATIONS
Simulect® is contraindicated in patients with known hypersensitivity to basiliximab or
any
other
component of the formulation. See
composition of Simulect® under DESCRIPTION/
WARNINGS.
General
Simulect® should be administered under qualified medical
supervision. Patients should be
informed
of the potential benefits
of therapy and
the risks associated
with administration of
immunosuppressive
therapy.
While
neither the incidence of lymphoproliferative disorders nor
opportunistic
infections was
higher in Simulect®-treated
patients than in placebo-treated patients,
patients
on
immunosuppressive therapy are at
increased risk for developing these complications and
should
be monitored accordingly.
Hypersensitivity
Severe acute
(onset within 24 hours)
hypersensitivity reactions including anaphylaxis have
been
observed both on initial exposure to Simulect® and/or
following re-exposure after several
months. These
reactions may include
hypotension, tachycardia, cardiac failure, dyspnea,
wheezing,
bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus,
and/or
sneezing. If a severe hypersensitivity reaction occurs, therapy with Simulect® should be
permanently
discontinued. Medications for the treatment of severe hypersensitivity
reactions
including
anaphylaxis should be available for immediate use. Patients previously
administered
Simulect® should only be re-exposed to a subsequent course
of therapy with extreme caution.
The
potential risks of such re-administration, specifically those associated
with
immunosuppression,
are not known.
PRECAUTIONS
General
It
is not known whether Simulect® use will have a
long-term effect on
the ability of
the
immune system
to respond to antigens first encountered during
Simulect®-induced
immunosuppression.
Immunogenicity
Of
renal transplantation patients treated with Simulect® and tested for anti-idiotype antibodies,
4/339
developed an anti-idiotype antibody response, with no deleterious clinical effect upon
the
patient. In none of these cases was there evidence that the presence
of anti-idiotype
antibody
accelerated Simulect® clearance or decreased the period of receptor
saturation. In
Study
2, the incidence of human anti-murine
antibody (HAMA) in
renal transplantation
patients treated
with Simulect® was 2/138 in patients not exposed to muromonab-CD3
and
4/34
in patients who subsequently received muromonab-CD3. The available clinical
data on
the use
of muromonab-CD3 in
patients previously treated
with Simulect® suggest that
subsequent
use of muromonab-CD3 or other murine anti-lymphocytic antibody preparations is
not
precluded.
These data
reflect the percentage of
patients whose test results were considered
positive
for antibodies to Simulect® 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,
concomitant medications, and underlying disease. For these reasons, comparison of the
incidence
of antibodies to Simulect® with the incidence of antibodies
to other products may be
misleading.
Drug
Interactions
No
dose adjustment is necessary when
Simulect® is
added to triple
immunosuppression
regimens
including cyclosporine, corticosteroids, and either azathioprine or mycophenolate
mofetil. Three
clinical trials have
investigated Simulect® use
in combination with
triple
therapy
regimens. Pharmacokinetics were assessed in two of these trials. Total body
clearance
of
Simulect® was reduced by an average 22% and 51% when
azathioprine and mycophenolate
mofetil,
respectively, were added to a regimen consisting of cyclosporine, USP
(MODIFIED)
and corticosteroids. Nonetheless, the range of individual Simulect® clearance values in the
presence of azathioprine (12-57 ml/h) or
mycophenolate mofetil (7-54 ml/h) did not extend
outside
the range observed with dual
therapy (10-78 ml/h). The following medications have
been administered in clinical trials
with Simulect® with no increase in adverse reactions:
ATG/ALG,
azathioprine, corticosteroids, cyclosporine, mycophenolate mofetil,
and
muromonab-CD3.
Carcinogenesis/Mutagenesis/Impairment
of Fertility
No mutagenic
potential of Simulect® was
observed in the in vitro assays
with Salmonella
(Ames)
and V79 Chinese hamster cells. No
long-term or fertility studies in laboratory animals
have
been performed to evaluate the potential of Simulect® to produce carcinogenicity or
fertility
impairment, respectively.
Pregnancy Category B
There
are no adequate and well-controlled studies in pregnant women. No maternal
toxicity,
embryotoxicity,
or teratogenicity was observed in cynomolgus monkeys 100 days post coitum
following
dosing with basiliximab during the organogenesis period; blood levels in
pregnant
monkeys
were 13-fold higher than those seen in human patients. Immunotoxicology studies
have
not been performed in the offspring.
Because IgG molecules are
known to cross
the
placental
barrier, because the IL-2 receptor may play an important role in development of
the
immune
system, and because animal reproduction studies are not always predictive of
human
response,
Simulect® should only be used in pregnant women when
the potential benefit
justifies
the potential risk to the fetus. Women of childbearing potential should use
effective
contraception
before beginning Simulect® therapy, during therapy, and for
4 months after
completion
of Simulect® therapy.
Nursing Mothers
It
is not known whether Simulect® is excreted in human milk.
Because many drugs including
human
antibodies are excreted in human milk, and because of the potential for adverse
reactions,
a decision should be made to discontinue nursing or to discontinue the drug,
taking
into
account the importance of the drug to the mother.
Pediatric Use
No randomized, placebo-controlled studies have
been completed in pediatric patients. In a
safety
and pharmacokinetic study, 41 pediatric patients [1-11 years of age (n=27),
12-16 years
of
age (n=14), median age 8.1 years] were
treated with Simulect® via
intravenous bolus
injection in addition to standard immunosuppressive
agents including cyclosporine, USP
(MODIFIED), corticosteroids, azathioprine, and mycophenolate mofetil. The acute rejection
rate at
six months was
comparable to that
in adults in
the triple therapy
trials. The most
frequently
reported adverse events were hypertension, hypertrichosis, and rhinitis (49%
each),
urinary tract
infections (46%), and fever
(39%). Overall, the adverse event
profile was
consistent
with general clinical experience in the pediatric renal transplantation
population and
with the
profile in the
controlled adult renal
transplantation studies. The
available
pharmacokinetic data
in children and adolescents are described in CLINICAL
PHARMACOLOGY
and DOSAGE AND ADMINISTRATION.
It
is not known whether the immune response
to vaccines, infection,
and other
antigenic stimuli administered or encountered during
Simulect® therapy
is impaired or
whether
such response will remain impaired after Simulect® therapy.
Geriatric Use
Controlled
clinical studies of Simulect® have included a small number of
patients 65 years and
older
(Simulect® 28; placebo 32). From the available data comparing
Simulect® and placebo-
treated patients,
the adverse event
profile in patients ≥65
years of age is not different from
patients
<65 years of age and no age-related dosing adjustment is required. Caution
must be
used
in giving immunosuppressive drugs to elderly patients.
ADVERSE
REACTIONS
Because
clinical trials are conducted under widely varying conditions, adverse reaction
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 from
clinical trials does, however, provide a basis for
identifying the adverse
events
that appear to be related to drug use and for approximating rates.
The
incidence of adverse events for Simulect® was determined
in four randomized,
double-blind,
placebo-controlled clinical trials for the prevention of renal allograft
rejection.
Two of
the studies (Study 1 and Study 2), used a dual
maintenance immunosuppressive
regimen
comprised of cyclosporine, USP (MODIFIED) and corticosteroids, whereas the
other
two
studies (Study 3 and Study 4) used a triple immunosuppressive regimen
comprised of
cyclosporine,
USP (MODIFIED), corticosteroids, and either azathioprine or mycophenolate
mofetil.
Simulect® did not
appear to add to the background of adverse events seen in organ
transplantation patients
as a consequence of their underlying disease and the concurrent
administration
of immunosuppressants and other medications. Adverse events were reported
by
96% of the patients in the placebo-treated group and 96% of the patients
in the
Simulect®-treated group. In the four placebo-controlled
studies, the pattern of adverse events
in
590 patients treated with the recommended dose
of Simulect® was
similar to that
in 594
patients
treated with placebo. Simulect® did not increase the incidence
of serious adverse
events
observed compared with placebo.
The
most frequently reported adverse events were gastrointestinal disorders,
reported
in
69% of Simulect®-treated patients and 67% of placebo-treated
patients.
The incidence
and types of
adverse events were
similar in Simulect®-treated
and
placebo-treated
patients. The following adverse events occurred in ≥10%
of Simulect®-treated
patients: Gastrointestinal System: constipation, nausea, abdominal pain,
vomiting, diarrhea,
dyspepsia; Body as a Whole-General: pain, peripheral edema, fever, viral
infection;
Metabolic and Nutritional: hyperkalemia, hypokalemia, hyperglycemia,
hypercholesterolemia,
hypophosphatemia, hyperuricemia; Urinary System: urinary
tract
infection; Respiratory System: dyspnea, upper respiratory tract infection; Skin and
Appendages: surgical
wound complications, acne; Cardiovascular Disorders-General:
hypertension; Central and Peripheral Nervous System: headache, tremor; Psychiatric:
insomnia;
Red Blood
Cell: anemia.
The
following adverse events, not mentioned above, were reported with an incidence
of ≥3%
and <10% in pooled analysis of patients treated with Simulect® in the four controlled
clinical trials,
or in an analysis of
the two dual
therapy trials: Body as a Whole-General:
accidental
trauma, asthenia, chest pain, increased drug level, infection, face edema,
fatigue,
dependent edema,
generalized edema, leg edema,
malaise, rigors, sepsis; Cardiovascular:
abnormal
heart sounds, aggravated hypertension, angina pectoris, cardiac
failure, chest pain,
hypotension; Endocrine: increased
glucocorticoids; Gastrointestinal: enlarged abdomen,
esophagitis,
flatulence, gastrointestinal disorder, gastroenteritis, GI hemorrhage,
gum
hyperplasia,
melena, moniliasis, ulcerative stomatitis; Heart Rate and Rhythm: arrhythmia,
atrial
fibrillation, tachycardia; Metabolic and Nutritional: acidosis, dehydration, diabetes
mellitus, fluid
overload, hypercalcemia, hyperlipemia, hypertriglyceridemia,
hypocalcemia,
hypoglycemia,
hypomagnesemia, hypoproteinemia, weight
increase; Musculo-Skeletal:
arthralgia,
arthropathy, back pain, bone fracture, cramps,
hernia, myalgia, leg pain; Nervous
System: dizziness,
neuropathy, paraesthesia, hypoesthesia;
Platelet
and Bleeding: hematoma, hemorrhage, purpura, thrombocytopenia,
thrombosis; Psychiatric: agitation,
anxiety,
depression; Red
Blood Cell: polycythemia; Reproductive
Disorders, Male: genital
edema,
impotence; Respiratory: bronchitis, bronchospasm, abnormal chest
sounds, coughing,
pharyngitis, pneumonia, pulmonary disorder,
pulmonary edema, rhinitis,
sinusitis; Skin and
Appendages: cyst, herpes simplex, herpes zoster,
hypertrichosis, pruritus, rash, skin disorder,
skin
ulceration; Urinary: albuminuria, bladder disorder, dysuria,
frequent micturition,
hematuria, increased
non-protein nitrogen, oliguria, abnormal renal function, renal tubular
necrosis,
surgery, ureteral disorder, urinary retention; Vascular Disorders: vascular disorder;
Vision Disorders: cataract, conjunctivitis, abnormal vision; White Blood Cell: leucopenia.
Among
these events, leucopenia and hypertriglyceridemia occurred more frequently in
the two
triple-therapy
studies using azathioprine and mycophenolate mofetil than in the dual-therapy
studies.
Malignancies