Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/196
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BEXXAR (Kit)
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Recommended Dose: The BEXXAR therapeutic
regimen consists of four components administered in two discrete steps:
the dosimetric step, followed 7-14 days later by a therapeutic step. Note: The safety of
the BEXXAR therapeutic regimen was established only in the setting
of patients receiving thyroid blocking agents and premedication to
ameliorate/prevent infusion reactions (see Concomitant Medications). Dosimetric step Therapeutic
step Note: Do not administer the therapeutic step if biodistribution is altered
(see Assessment of Biodistribution of Iodine
I 131 Tositumomab).<br/>Concomitant Medications: The safety of
the BEXXAR therapeutic regimen was established in studies in which
all patients received the following concurrent medications: Patients should not
receive the dosimetric dose of Iodine I 131 Tositumomab if they have
not yet received at least three doses of SSKI, three doses of Lugol's
solution, or one dose of 130 mg potassium iodide tablet (at least
24 hours prior to the dosimetric dose). The BEXXAR therapeutic regimen is administered
via an IV tubing set with an in-line 0.22 micron filter. THE SAME IV TUBING SET AND FILTER MUST BE USED THROUGHOUT
THE ENTIRE DOSIMETRIC OR THERAPEUTIC STEP. A CHANGE IN FILTER CAN
RESULT IN LOSS OF DRUG. Figure1 shows an overview of the dosing schedule. PREPARATION OF THE
BEXXAR THERAPEUTIC REGIMEN GENERAL Read all directions thoroughly and assemble all
materials before preparing the dose for administration. The Iodine I
131 Tositumomab dosimetric and therapeutic doses should be measured
by a suitable radioactivity calibration system immediately prior to
administration. The dose calibrator must be operated in accordance
with the manufacturer's specifications and quality control
for the measurement of Iodine-131. All supplies for preparation and administration
of the BEXXAR therapeutic regimen should be sterile. Use
appropriate aseptic technique and radiation precautions for the preparation
of the components of the BEXXAR therapeutic regimen. Waterproof gloves should be utilized in the preparation and administration
of the product. Iodine I 131 Tositumomab doses should be prepared,
assayed, and administered by personnel who are licensed to handle
and/or administer radionuclides. Appropriate shielding should be used
during preparation and administration of the product. Restrictions on patient contact with others and release
from the hospital must follow all applicable federal, state, and institutional
regulations. Preparation for the Dosimetric Step Tositumomab Dose Required materials not supplied: A. One 50 mL syringe with attached 18-gauge
needle (to withdraw 450 mg of Tositumomab from two vials each containing
225 mg Tositumomab) B. One 50 mL bag of
sterile 0.9% Sodium Chloride for Injection, USP C. One 50 mL syringe for drawing up 32 mL of saline for disposal
from the 50 mL bag of sterile 0.9% Sodium Chloride for Injection,
USP Method: Note: Tositumomab
solution may contain particulates that are generally white in nature.
The product should appear clear to opalescent, colorless to slightly
yellow. Preparation
of Iodine I 131 Tositumomab Dosimetric Dose Required materials not supplied: A. Lead shielding for preparation vial
and syringe pump B. One 30 mL syringe with
18-gauge needle to withdraw the calculated volume of Iodine I 131
Tositumomab from the Iodine I 131 Tositumomab vial. One 60 mL syringe
with 18-gauge needle to withdraw the volume from the preparation vial
for administration C. One 20 mL syringe
with attached needle, filled with 0.9% Sodium Chloride for Injection,
USP D. One 3 mL syringe with attached needle
to withdraw Tositumomab from 35 mg vial E.
One sterile, 30 or 50 mL preparation vial F.
Two lead pots, both kept at room temperature. One pot is used to thaw
the labeled antibody and the second pot is used to hold the preparation
vial Method: Administration
of the Dosimetric Step Required materials not supplied: For questions
about required materials call the BEXXAR Service Center at 1-877-423-9927. A. IV Filter set (0.22 micron filter),
15 inch with injection site (port) and luer lock B. One Primary IV infusion set C. One
100 mL bag of sterile 0.9% Sodium Chloride for Injection, USP D. Two Secondary IV infusion sets E. One IV Extension set, 30 inch luer lock F. One 3-way stopcock G. One 50 mL
bag of sterile 0.9% Sodium Chloride for Injection, USP H. One Infusion pump for Tositumomab infusion I. One Syringe Pump for Iodine I 131 Tositumomab infusion J. Lead shielding for use in the administration of
the dosimetric dose Tositumomab Infusion: (See Figure
1 in the���Workbook for Dosimetry
Methodology and Administration Set-Up���for diagrammatic
illustration of the configuration of the infusion set components.) Iodine I 131 Tositumomab
Dosimetric Infusion: (See Figure
2 in the���Workbook for Dosimetry
Methodology and Administration Set-Up���for diagrammatic
illustration of the configuration of the infusion set components.) Determination of Dose
for the Therapeutic Step (see Calculation of Iodine-131 Activity for
Therapeutic Dose): The method for determining and calculating
the patient-specific dose of Iodine-131 activity (mCi) to be administered
in the therapeutic step is described below. The derived values obtained
in steps 3 and 4 and calculation of the therapeutic dose as described
in step 6 may be determined manually [see���Workbook for Dosimetry Methodology and Administration Set-Up���] or calculated automatically using the GlaxoSmithKline proprietary
software program [BEXXAR Patient Management Templates]. To receive
training and to obtain the���BEXXAR Patient Management Templates���call the BEXXAR Service Center at 1-877-423-9927. For assistance with
either manual or automated calculations call the BEXXAR Service Center
at 1-877-423-9927. The following equation is used to calculate
the activity of Iodine-131 required for delivery of the desired total
body dose of radiation. Preparation for the Therapeutic
Step Tositumomab
Dose Required materials not supplied: A. One 50 mL syringe with attached 18-gauge needle (to withdraw
450 mg of Tositumomab from two vials each containing 225 mg Tositumomab) B. One 50 mL bag of sterile 0.9% Sodium Chloride for
Injection, USP C. One 50 mL syringe for
drawing up 32 mL of saline for disposal from the 50 mL bag of sterile
0.9% Sodium Chloride for Injection, USP Method: Note: Tositumomab
solution may contain particulates that are generally white in nature.
The product should appear clear to opalescent, colorless to slightly
yellow. Preparation
of Iodine I 131 Tositumomab Therapeutic Dose Required materials not
supplied: A.Lead shielding for
preparation vial and syringe pump B.One
or two 30 mL syringes with 18-gauge needles to withdraw the calculated
volume of Iodine I 131 Tositumomab from the Iodine I 131 Tositumomab
vial(s). One or two 60 mL syringes with 18-gauge needles to withdraw
the volume from the preparation vial for administration C. One 20 mL syringe with attached needle filled with
0.9% Sodium Chloride for Injection, USP D. One
3 mL sterile syringe with attached needle to draw up Tositumomab from
the 35 mg vial E. One sterile, 30 or 50 mL preparation
vial F.Two lead pots both kept at room temperature.
One pot is used to thaw the labeled antibody, and the second pot is
used to hold the preparation vial Method: Administration
of the Therapeutic Step Note: Restrictions on patient contact
with others and release from the hospital must follow all applicable
federal, state, and institutional regulations. Required materials not supplied: For
questions about required materials call the BEXXAR Service Center
at 1-877-423-9927. A. One IV Filter
set (0.22 micron, filter), 15 inch with injection site (port) and
luer lock B. One Primary IV infusion set C. One 100 mL bag of sterile 0.9% Sodium Chloride for
Injection, USP D. Two Secondary IV infusion
sets E. One IV extension set, 30 inch luer
lock F. One 3-way stopcock G. One 50 mL bag of sterile 0.9% Sodium Chloride for Injection, USP H. One Infusion pump for Tositumomab infusion I. One Syringe Pump for Iodine I 131 Tositumomab infusion J. Lead shielding for use in the administration of the
therapeutic dose Tositumomab
Infusion: (See Figure 1 in the���Workbook for Dosimetry Methodology and Administration
Set-Up���for diagrammatic illustration of the configuration
of the infusion set components.) Iodine I 131 Tositumomab
Therapeutic Infusion: (See Figure
2 in the���Workbook for Dosimetry
Methodology and Administration Set-Up���for diagrammatic
illustration of the configuration of the infusion set components.) DOSIMETRY The following sections describe the procedures for
image acquisition for collection of dosimetry data, interpretation
of biodistribution images, calculation of residence time, and calculation
of activity hours. Please read all sections carefully. IMAGE ACQUISITION AND INTERPRETATION Gamma Camera and Dose Calibrator Procedures Manufacturer-specific quality control
procedures should be followed for the gamma camera/computer system,
the collimator, and the dose calibrator. Less than 20% variance between
maximum and minimum pixel count values in the useful field of view
is acceptable on Iodine-131 intrinsic flood fields and variability<10% is preferable. Iodine-131-specific camera uniformity corrections
are strongly recommended, rather than applying lower energy correction
to the Iodine-131 window. Camera extrinsic uniformity should be assessed
at least monthly usingTc orCo as a source
with imaging at the appropriate window. Additional
(non-routine) quality control procedures are required. To assure the
accuracy and precision of the patient total body counts, the gamma
camera must undergo validation and daily quality control on each day
it is used to collect patient images. Use
the same setup and region of interest (ROI) for calibration, determination
of background, and whole body patient studies. Gamma Camera Set-Up The same camera,
collimator, scanning speed, energy window, and setup must be used
for all studies. The gamma camera must be capable of whole body imaging
and have a large or extra large field of view with a digital interface.
It must be equipped with a parallel-hole collimator rated to at least364 keV by the manufacturer with a septal penetration for Iodine-131
of<7%. The camera and computer must be
set up for scanning as follows: Counts from Calibrated
Source for Quality Control Camera
sensitivity for Iodine-131 must be determined each day. Determination
of the gamma camera's sensitivity is obtained by scanning a
calibrated activity of Iodine-131 (e.g., 200���250��Ci
in at least 20 mL of saline within a sealed pharmaceutical vial).
The radioactivity of the Iodine-131 source is first determined using
a NIST-traceable-calibrated clinical dose calibrator at the Iodine-131
setting. Background
Counts The background count is
obtained from a scan with no radioactive source. This should be obtained
following the count of the calibrated source and just prior to obtaining
the patient count. If abnormally high background
counts are measured, the source should be identified and, if possible,
removed. If abnormally low background counts are measured, the camera
energy window setting and collimator should be verified before repeating
the background counts. The counts per��Ci
are obtained by dividing the background-corrected source count by
the calibrated activity for that day. For a specific camera and collimator,
the counts per��Ci should be relatively constant. When values
vary more than 10% from the established ratio, the reason for the
discrepancy should be ascertained and corrected and the source countrepeated. Patient
Total Body Counts The source
and background counts are obtained first and the camera sensitivity
(i.e., constant counting efficiency) is established prior to obtaining
the patient count. The same rectangular region of interest (ROI) must
be used for the whole body counts, the quality control counts of the
radioactive source, and the background counts. Acquire anterior and posterior whole body images for gamma camera
counts. For any particular patient, the same gamma camera must be
used for all scans. To obtain proper counts, extremities must be included
in the images, and arms should not cross over the body. The scans
should be centered on the midline of the patient. Record the time
of the start of the radiolabeled dosimetric infusion and the time
of the start of each count acquisition. Gamma
camera counts will be obtained at the three imaging timepoints: Assessment of Biodistribution
of Iodine I 131 Tositumomab The
biodistribution of Iodine I 131 Tositumomab should be assessed by
determination of total body residence time and by visual examination
of whole body camera images from the first image taken at the time
of Count 1 (within an hour of the end of the infusion) and from the
second image taken at the time of Count 2 (at 2 to 4 days after administration).
To resolve ambiguities, an evaluation of the third image at the time
of Count 3 (6 to 7 days after administration) may be necessary. If
either of these methods indicates that the biodistribution is altered,
the Iodine I 131 Tositumomab therapeutic dose should not be administered. Expected Biodistribution Results Indicating Altered Biodistribution CALCULATION OF IODINE-131
ACTIVITY FOR THE THERAPEUTIC DOSE There are two options for calculation of the Iodine-131 activity
for the therapeutic dose. The derived values and calculation of the
therapeutic dose may be determined manually [see���Workbook for Dosimetry Methodology and Administration
Set-Up���] or calculated automatically using the GlaxoSmithKline
proprietary software program [BEXXAR Patient Management Templates].
The following describes in greater detail the stepwise method for
manual determination of the Iodine-131 activity for the therapeutic
dose. Residence Time
(hr) For each timepoint, calculate
the background corrected total body count at each timepoint (defined
as the geometric mean). The following equation is used: In this equation, C= the anterior counts, C= the anterior background
counts, C= the posterior counts, and C=
the posterior background counts. Once the
geometric mean of the counts has been calculated for each of the 3
timepoints, the % injected activity remaining for each timepoint is
calculated by dividing the geometric mean of the counts from that
timepoint by the geometric mean of the counts from Day 0 and multiplying
by 100. The residence time (h) is then determined
by plotting the time from the start of infusion
and the % injected activity values for the 3 imaging timepoints on Graph 1 (see Worksheet���Determination
of Residence Time���in the���Workbook for Dosimetry Methodology and Administration Set-Up���supplied with Dosimetric Dose Packaging). A best-fit line is then
drawn from 100% (the pre-plotted Day 0 value) through the other 2
plotted points (if the line does not intersect the two points, one
point must lie above the best-fit line and one point must lie below
the best-fit line). The residence time (h) is read from the x-axis
of the graph at the point where the fitted line intersects with the
horizontal 37% injected activity line. Activity Hours (mCi hr) In order to determine the activity hours (mCi hr), look up the
patient's maximum effective mass derived from the patient's
sex and height (see Worksheet���Determination
of Maximum Effective Mass���in the���Workbook for Dosimetry Methodology and Administration
Set-Up���supplied with Dosimetric Dose Packaging).
If the patient's actual weight is less than the maximum effective
mass, the actual weight should be used in the activity hours table
(see Worksheet���Determination of
Activity Hours���in the���Workbook for Dosimetry Methodology and Administration Set-Up���supplied with Dosimetric Dose Packaging). If the patient's
actual weight is greater than the maximum effective mass, the mass
from the worksheet for���Determination
of Maximum Effective Mass���should be used. Calculation of Iodine-131 Activity
for the Therapeutic Dose The following
equation is used to calculate the activity of Iodine-131 required
for delivery of the desired total body dose of radiation.
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The BEXXAR therapeutic regimen (Tositumomab and
Iodine I 131 Tositumomab) is an anti-neoplastic radioimmunotherapeutic
monoclonal antibody-based regimen composed of the monoclonal antibody,
Tositumomab, and the radiolabeled monoclonal antibody, Iodine I 131
Tositumomab.<br/>Tositumomab: Tositumomab is a murine
IgGlambda monoclonal antibody directed against the CD20
antigen, which is found on the surface of normal and malignant B lymphocytes.
Tositumomab is produced in an antibiotic-free culture of mammaliancells and is composed of two murine gamma 2a heavy chains of 451 amino
acids each and two lambda light chains of 220 amino acids each. The
approximate molecular weight of Tositumomab is 150 kD. Tositumomab is supplied as a sterile, pyrogen-free,
clear to opalescent, colorless to slightly yellow, preservative-free
liquid concentrate. It is supplied at a nominal concentration of 14 mg/mL
Tositumomab in 35 mg and 225 mg single-use vials. The formulation
contains 10% (w/v) maltose, 145 mM sodium chloride, 10 mM phosphate,
and Water for Injection, USP. The pH is approximately 7.2.<br/>Iodine I 131 Tositumomab: Iodine I 131 Tositumomab
is a radio-iodinated derivative of Tositumomab that has been covalently
linked to Iodine-131. Unbound radio-iodine and other reactants have
been removed by chromatographic purification steps. Iodine I 131 Tositumomab
is supplied as a sterile, clear, preservative-free liquid for IV administration.
The dosimetric dosage form is supplied at nominal protein and activity
concentrations of 0.1 mg/mL and 0.61 mCi/mL (at date of calibration),
respectively. The therapeutic dosage form is supplied at nominal protein
and activity concentrations of 1.1 mg/mL and 5.6 mCi/mL (at date of
calibration), respectively. The formulation for the dosimetric and
the therapeutic dosage forms contains 4.4%���6.6% (w/v) povidone,
1���2 mg/mL maltose (dosimetric dose) or 9���15 mg/mL maltose
(therapeutic dose), 8.5���9.5 mg/mL sodium chloride, and
0.9���1.3 mg/mL ascorbic acid. The pH is approximately 7.0.<br/>BEXXAR Therapeutic Regimen: The BEXXAR therapeutic
regimen is administered in two discrete steps: the dosimetric and
therapeutic steps. Each step consists of a sequential infusion of
Tositumomab followed by Iodine I 131 Tositumomab. The therapeutic
step is administered 7-14 days after the dosimetric step. The BEXXAR
therapeutic regimen is supplied in two distinct package configurations
as follows: BEXXAR Dosimetric Packaging BEXXAR Therapeutic Packaging<br/>Physical/Radiochemical Characteristics
of Iodine-131: Iodine-131 decays with
beta and gamma emissions with a physical half-life of 8.04 days. The
principal beta emission has a mean energy of 191.6 keV and the
principal gamma emission has an energy of 364.5 keV (Ref 1).<br/>External Radiation: The specific gamma ray constant for Iodine-131 is
2.2 R/millicurie hour at 1 cm. The first half-value layer is
0.24 cm lead (Pb) shielding. A range of values is shown in Table 1
for the relative attenuation of the radiation emitted by this radionuclide
that results from interposition of various thicknesses of Pb. To facilitate
control of the radiation exposure from this radionuclide, the use
of a 2.55 cm thickness of Pb will attenuate the radiation emitted
by a factor of about 1,000. The fraction of Iodine-131 radioactivity that
remains in the vial after the date of calibration is calculated as
follows: Fraction of remaining radioactivity
of Iodine-131 after x days
= 2. Physical decay
is presented in Table 2. *(Calibration day)
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General Pharmacology: Tositumomab binds specifically
to the CD20 (human B-lymphocyte���restricted differentiation
antigen, Bp 35 or B1) antigen. This antigen is a transmembrane phosphoprotein
expressed on pre-B lymphocytes and at higher density on mature B lymphocytes
(Ref. 2). The antigen is also expressed on>90% of B-cell non-Hodgkin's
lymphomas (NHL) (Ref. 3). The recognition epitope for Tositumomab
is found within the extracellular domain of the CD20 antigen. CD20
does not shed from the cell surface and does not internalize following
antibody binding (Ref. 4).<br/>Mechanism of Action: Possible mechanisms of action of the BEXXAR therapeutic
regimen include induction of apoptosis (Ref. 5), complement-dependent
cytotoxicity (CDC) (Ref. 6), and antibody-dependent cellular cytotoxicity
(ADCC) (Ref. 5) mediated by the antibody. Additionally, cell death
is associated with ionizing radiation from the radioisotope.<br/>Pharmacokinetics/Pharmacodynamics: The phase 1 study of Iodine
I 131 Tositumomab determined that a 475 mg predose of unlabeled antibody
decreased splenic targeting and increased the terminal half-life of
the radiolabeled antibody. The median blood clearance following administration
of 485 mg of Tositumomab in 110 patients with NHL was 68.2 mg/hr
(range: 30.2���260.8 mg/hr). Patients with high tumor burden,
splenomegaly, or bone marrow involvement were noted to have a faster
clearance, shorter terminal half-life, and larger volume of distribution.
The total body clearance, as measured by total body gamma camera counts,
was dependent on the same factors noted for blood clearance. Patient-specific
dosing, based on total body clearance, provided a consistent radiation
dose, despite variable pharmacokinetics, by allowing each patient's
administered activity to be adjusted forindividual patient variables.
The median total body effective half-life, as measured by total body
gamma camera counts, in 980 patients with NHL was 67 hours (range:
28-115 hours). Elimination of Iodine-131
occurs by decay (see Table 2) and excretion in the urine. Urine was
collected for 49 dosimetric doses. After 5 days, the whole body clearance
was 67% of the injected dose. Ninety-eight percent of the clearance
was accounted for in the urine. Administration
of the BEXXAR therapeutic regimen results in sustained depletion of
circulating CD20 positive cells. The impact of administration of the
BEXXAR therapeutic regimen on circulating CD20 positive cells was
assessed in two clinical studies, one conducted in chemotherapy na��ve
patients and one in heavily pretreated patients. The assessment of
circulating lymphocytes did not distinguish normal from malignant
cells. Consequently, assessment of recovery of normal B cell function
was not directly assessed. At seven weeks, the median number of circulating
CD20 positive cells was zero (range: 0-490 cells/mm).
Lymphocyte recovery began at approximately 12 weeks following treatment.
Among patients who had CD20 positive cell counts recorded at baseline
and at 6 months, 8 of 58 (14%) chemotherapy na��ve patients had
CD20 positive cell counts below normal limits at six months and 6
of 19 (32%) heavily pretreated patients had CD20 positive cell counts
below normal limits at six months. There was no consistent effect
of the BEXXAR therapeutic regimen on post-treatment serum IgG, IgA,
or IgM levels.<br/>Radiation Dosimetry: Estimations of radiation-absorbed
doses for Iodine I 131 Tositumomab were performed using sequential
whole body images and the MIRDOSE 3 software program. Patients with
apparent thyroid, stomach, or intestinal imaging were selected for
organ dosimetry analyses. The estimated radiation-absorbed doses to
organs and marrow from a course of the BEXXAR therapeutic regimen
are presented in Table 3.
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The BEXXAR therapeutic regimen is contraindicated
in patients with known hypersensitivity to murine proteins or any
other component of the BEXXAR therapeutic regimen.
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TOSITUMOMAB DOSIMETRIC
PACKAGING The components of the
dosimetric step will be shipped ONLY to individuals who are participating in the certification program
or have been certified in the preparation and administration of the
BEXXAR therapeutic regimen. The components are shipped from separate
sites; when ordering, ensure that the components are scheduled to
arrive on the same day. The components of the Tositumomab Dosimetric
Step include: TOSITUMOMAB THERAPEUTIC
PACKAGING The components of the
therapeutic step will be shipped ONLY to individuals who are participating in the certification program
or have been certified in the preparation and administration of the
BEXXAR therapeutic regimen for an individual patient who has completed
the Dosimetric Step. The components of the therapeutic step are shipped
from separate sites; whenordering, ensure that the components are
scheduled to arrive on the same day. The components of the Tositumomab
Therapeutic Step include:
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WARNINGS:<br/>Hypersensitivity Reactions,
including Anaphylaxis: Serious hypersensitivity reactions, including some
with fatal outcome, have been reported with the BEXXAR therapeutic
regimen. Medications for the treatment of severe hypersensitivity
reactions should be available for immediate use. Patients who develop
severe hypersensitivity reactions should have infusions of the BEXXAR
therapeutic regimen discontinued and receive medical attention (see WARNINGS).<br/>Prolonged and Severe Cytopenias: The majority of patients who received the BEXXAR
therapeutic regimen experienced severe thrombocytopenia and neutropenia.
The BEXXAR therapeutic regimen should not be administered to patients
with>25% lymphoma marrow involvement and/or impaired bone marrow
reserve (see WARNINGS and ADVERSE REACTIONS).<br/>Pregnancy Category X: The BEXXAR therapeutic regimen can cause fetal harm
when administered to a pregnant woman.<br/>Special requirements: The BEXXAR therapeutic regimen (Tositumomab and
Iodine I 131 Tositumomab) contains a radioactive component and should
be administered only by physicians and other health care professionals
qualified by training in the safe use and handling of therapeutic
radionuclides. The BEXXAR therapeutic regimen should be administered
only by physicians who are in the process of being or have been certified
by GlaxoSmithKline in dose calculation and administration of the BEXXAR
therapeutic regimen.
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diseasome-diseases:1173,
diseasome-diseases:1693,
diseasome-diseases:1694,
diseasome-diseases:181,
diseasome-diseases:2789,
diseasome-diseases:3004,
diseasome-diseases:3020,
diseasome-diseases:3365,
diseasome-diseases:4136,
diseasome-diseases:602,
diseasome-diseases:698,
diseasome-diseases:701,
diseasome-diseases:833
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Radionuclide Precautions: Iodine I 131 Tositumomab is radioactive. Care should
be taken, consistent with the institutional radiation safety practices
and applicable federal guidelines, to minimize exposure of medical
personnel and other patients.<br/>Renal Function: Iodine I 131 Tositumomab and Iodine-131 are excreted
primarily by the kidneys. Impaired renal function may decrease the
rate of excretion of the radiolabeled iodine and increase patient
exposure to the radioactive component of the BEXXAR therapeutic regimen.
There are no data regarding the safety of administration of the BEXXAR
therapeutic regimen in patients with impaired renal function.<br/>Immunization: The safety of immunization with live viral vaccines
following administration of the BEXXAR therapeutic regimen has not
been studied. The ability of patients who have received the BEXXAR
therapeutic regimen to generate a primary or anamnestic humoral response
to any vaccine has not been studied.<br/>Information for Patients: Prior to administration of the BEXXAR therapeutic
regimen, patients should be advised that they will have a radioactive
material in their body for several days upon their release from the
hospital or clinic. After discharge, patients should be provided with
both oral and written instructions for minimizing exposure of family
members, friends and the general public. Patients should be given
a copy of the written instructions for use as a reference for the
recommended precautionary actions. The pregnancy
status of women of childbearing potential should be assessed and these
women should be advised of the potential risks to the fetus (see CONTRAINDICATIONS). Women who are breastfeeding
should be instructed to discontinue breastfeeding and should be apprised
of the resultant potential harmful effects to the infant if these
instructions are not followed. Patients
should be advised of the potential risk of toxic effects on the male
and female gonads following the BEXXAR therapeutic regimen, and be
instructed to use effective contraceptive methods during treatment
and for 12 months following the administration of the BEXXAR therapeutic
regimen. Patients should be informed of
the risks of hypothyroidism and be advised of the importance of compliance
with thyroid blocking agents and need for life-long monitoring. Patients should be informed of the possibility of
developing a HAMA immune response and that HAMA may affect the results
of in vitro and in vivo diagnostic tests as well as
results of therapies that rely on murine antibody technology. Patients should be informed of the risks of cytopenias
and symptoms associated with cytopenia, the need for frequent monitoring
for up to 12 weeks after treatment, and the potential for persistent
cytopenias beyond 12 weeks. Patients should
be informed that MDS, secondary leukemia, and solid tumors have also
been observed in patients receiving the BEXXAR therapeutic regimen. Due to lack of controlled clinical studies, and high
background incidence in the heavily pretreated patient population,
the relative risk of development of myelodysplastic syndrome/acute
leukemia and solid tumors due to the BEXXAR therapeutic regimen cannot
be determined.<br/>Laboratory Monitoring: A complete blood count (CBC) with differential and
platelet count should be obtained prior to, and at least weekly following
administration of the BEXXAR therapeutic regimen. Weekly monitoring
of blood counts should continue for a minimum of 10 weeks or,
if persistent, until severe cytopenias have completely resolved. More
frequent monitoring is indicated in patients with evidence of moderate
or more severe cytopenias (see BOXED WARNINGS and WARNINGS). Thyroid stimulating
hormone (TSH) level should be monitored before treatment and annually
thereafter. Serum creatinine levels should be measured immediately
prior to administration of the BEXXAR therapeutic regimen.<br/>Drug Interactions: No formal drug interaction studies have been performed.
Due to the frequent occurrence of severe and prolonged thrombocytopenia,
the potential benefits of medications that interfere with platelet
function and/or anticoagulation should be weighed against the potential
increased risk of bleeding and hemorrhage.<br/>Drug/Laboratory Test Interactions: Administration of the BEXXAR therapeutic regimen
may result in the development of HAMA. The presence of HAMA may affect
the accuracy of the results of in vitro and in vivo diagnostic tests
and may affect the toxicity profile and efficacy of therapeutic agents
that rely on murine antibody technology. Patients who are HAMA positive
may be at increased risk for serious allergic reactions and other
side effects if they undergo in vivo diagnostic testing or treatment with murine monoclonal antibodies.<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility: No long-term animal studies have been performed
to establish the carcinogenic or mutagenic potential of the BEXXAR
therapeutic regimen or to determine its effects on fertility in males
or females. However, radiation is a potential carcinogen and mutagen.
Administration of the BEXXAR therapeutic regimen results in delivery
of a significant radiation dose to the testes. The radiation dose
to the ovaries has not been established. There have been no studies
to evaluate whether administration of the BEXXAR therapeutic regimen
causes hypogonadism, premature menopause, azoospermia and/or mutagenic
alterations to germ cells. There is a potential risk that the BEXXAR
therapeutic regimen may cause toxic effects on the male and female
gonads. Effective contraceptive methods should be used during treatment
and for 12 months following administration of the BEXXAR therapeutic
regimen.<br/>Pregnancy Category X: (See CONTRAINDICATIONS; WARNINGS.)<br/>Nursing Mothers: Radioiodine is excreted in breast milk and may reach
concentrations equal to or greater than maternal plasma concentrations.
Immunoglobulins are also known to be excreted in breast milk. The
absorption potential and potential for adverse effects of the monoclonal
antibody component (Tositumomab) in the infant are not known. Therefore,
formula feedings should be substituted for breast feedings before
starting treatment. Women should be advised to discontinue nursing.<br/>Pediatric Use: The safety and effectiveness of the BEXXAR therapeutic
regimen in children have not been established.<br/>Geriatric Use: Clinical studies of the BEXXAR therapeutic regimen
did not include sufficient numbers of patients aged 65 and over to
determine whether they respond differently from younger patients.
In clinical studies, 230 patients received the BEXXAR therapeutic
regimen at the recommended dose. Of these, 27% (61 patients) were
age 65 or older and 4% (10 patients) were age 75 or older. Across
all studies, the overall response rate was lower in patients age 65
and over (41% vs. 61%) and the duration of responses was shorter (10
months vs. 16 months); however, these findings are primarily derived
from 2 of the 5 studies. While the incidence of severe hematologic
toxicity was lower, the duration of severe hematologic toxicity was
longer in those age 65 or older as compared to patients less than
65 years ofage. Due to the limited experience greater sensitivity
of some older individuals cannot be ruled out.
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| dailymed-instance:overdosag... |
The maximum dose of the BEXXAR therapeutic regimen
that was administered in clinical trials was 88 cGy. Three patients
were treated with a total body dose of 85 cGy of Iodine I 131 Tositumomab
in a dose escalation study. Two of the 3 patients developed Grade
4 toxicity of 5 weeks duration with subsequent recovery. In addition,
accidental overdose of the BEXXAR therapeutic regimen occurred in
one patient at a total body dose of 88 cGy. The patient developed
Grade 3 hematologic toxicity of 18 days duration. Patients who receive
an accidental overdose of Iodine I 131 Tositumomab should be monitored
closely for cytopenias and radiation-related toxicity. The effectiveness
of hematopoietic stem cell transplantation as a supportive care measure
for marrow injury has not been studied; however, the timing of such
support should take into account the pharmacokinetics of the BEXXAR
therapeutic regimen and decay rate of the Iodine-131 in order to minimize
the possibility of irradiation of infused hematopoietic stem cells.
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| dailymed-instance:genericMe... |
tositumomab
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BEXXAR (Kit)
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| dailymed-instance:adverseRe... |
The most serious adverse reactions observed in
the clinical trials were severe and prolonged cytopenias and the sequelae
of cytopenias which included infections (sepsis) and hemorrhage in
thrombocytopenic patients, allergic reactions (bronchospasm and angioedema),
secondary leukemia and myelodysplasia (see BOXED WARNINGS and WARNINGS). The most common adverse reactions occurring
in the clinical trials included neutropenia, thromobocytopenia, and
anemia that are both prolonged and severe. Less common but severe
adverse reactions included pneumonia, pleural effusion and dehydration. Data regarding adverse events were primarily obtained
in 230 patients with non-Hodgkin's lymphoma enrolled in five
clinical trials using the recommended dose and schedule. Patients
had a median follow-up of 39 months and 79% of the patients were followed
at least 12 months for survival and selected adverse events. Patients
had a median of 3 prior chemotherapy regimens, a median age of 55
years, 60% male, 27% had transformation to a highergrade histology,
29% were intermediate grade and 2% high grade histology (IWF) and
68% had Ann Arbor stage IV disease. Patients enrolled in these studies
were not permitted to have prior hematopoietic stem cell transplantation
or irradiation to more than 25% of the red marrow. In the expanded
access program, which included 765 patients, data regarding clinical
serious adverse events and HAMA and TSH levels were used to supplement
the characterization of delayed adverse events (see ADVERSE REACTIONS, Hypothyroidism, Secondary Leukemia
and Myelodysplastic Syndrome, Immunogenicity). 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 todrug use and for approximating rates.<br/>Hematologic Events: Hematologic toxicity was the most frequently observed
adverse event in clinical trials with the BEXXAR therapeutic regimen
(Table 6). Sixty-three (27%) of 230 patients received one or more
hematologic supportive care measures following the therapeutic dose:
12% received G-CSF; 7% received Epoetin alfa; 15% received platelet
transfusions; and 16% received packed red blood cell transfusions.
Twenty-eight (12%) patients experienced hemorrhagic events; the majority
were mild to moderate.<br/>Infectious Events: One hundred and four of the 230 (45%) patients experienced
one or more adverse events possibly related to infection. The majority
were viral (e.g., rhinitis, pharyngitis, flu symptoms, or herpes)
or other minor infections. Twenty of 230 (9%) patients experienced
infections that were considered serious because the patient was hospitalized
to manage the infection. Documented infections included pneumonia,
bacteremia, septicemia, bronchitis, and skin infections.<br/>Hypersensitivity Reactions: Fourteen patients
(6%) experienced one or more of the following adverse events: allergic
reaction, face edema, injection site hypersensitivity, anaphylactic
reaction, laryngismus, and serum sickness. In the post-marketing setting,
severe hypersensitivity reactions, including fatal anaphylaxis have
been reported.<br/>Gastrointestinal Toxicity: Eighty-seven patients (38%) experienced one or more
gastrointestinal adverse events, including nausea, emesis, abdominal
pain, and diarrhea. These events were temporally related to the infusion
of the antibody. Nausea, vomiting, and abdominal pain were often reported
within days of infusion, whereas diarrhea was generally reported days
to weeks after infusion.<br/>Infusional Toxicity: A constellation of symptoms, including fever, rigors
or chills, sweating, hypotension, dyspnea, bronchospasm, and nausea,
have been reported during or within 48 hours of infusion. Sixty-seven
patients (29%) reported fever, rigors/chills, or sweating within 14
days following the dosimetric dose. Although all patients in the clinical
studies received pretreatment with acetaminophen and an antihistamine,
the value of premedication in preventing infusion-related toxicity
was not evaluated in any of the clinical studies. Infusional toxicities
were managed by slowing and/or temporarily interrupting the infusion.
Symptomatic management was required in more severe cases. Adjustment
of the rate of infusion to control adverse reactions occurred in 16
patients (7%); seven patients required adjustments for only the dosimetric
infusion, two required adjustments for only the therapeutic infusion,
and seven required adjustments for both the dosimetric and the therapeutic
infusions. Adjustments included reduction in the rate of infusion
by 50%, temporary interruption of the infusion, and in 2 patients,
infusion was permanently discontinued. Table
5 lists clinical adverse events that occurred in���5% of patients.
Table 6 provides a detailed description of the hematologic toxicity. Excludes laboratory
derived hematologic adverse events (see Table 6). The COSTART term for infection
includes a subset of infections (e.g., upper respiratory infection).
Other terms are mapped to preferred terms (e.g., pneumonia and sepsis).
For a more inclusive summary see ADVERSE REACTIONS, Infectious Events. Grade 3/4
toxicity was assumed if patient was missing 2 or more weeks of hematology
data between Week 5 and Week 9. Duration of Grade 3/4 of 1,000+
days (censored) was assumed for those patients with undocumented Grade
3/4 and no hematologic data on or after Week 9. Grade 4 toxicity was assumed
if patient had documented Grade 3 toxicity and was missing 2 or more
weeks of hematology data between Week 5 and Week 9.<br/>Delayed Adverse Reactions: Delayed adverse reactions,
including hypothyroidism, HAMA, and myelodysplasia/leukemia, were
assessed in 230 patients included in clinical studies and 765 patients
included in expanded access programs. The entry characteristics of
patients included from the expanded access programs were similar to
the characteristics of patients enrolled in the clinical studies,
except that the median number of prior chemotherapy regimens was fewer
(2 vs. 3) and the proportion with low-grade histology was higher (77%
vs. 70%) in patients from the expanded access programs.<br/>Secondary Leukemia and Myelodysplastic
Syndrome (MDS): There were 44 cases of MDS/secondary leukemia reported
among 995 (4.0%) patients included in clinical studies and expanded
access programs, with a median follow-up of 29 months. The overall
incidence of MDS/secondary leukemia among the 230 patients included
in the clinical studies was 10% (24/230), with a median follow-up
of 39 months and a median time to development of MDS of 34 months.
The cumulative incidence of MDS/secondary leukemiain this patient
population was 4.7% at 2 years and 15% at 5 years. The incidence of
MDS/secondary leukemia among the 765 patients in the expanded access
programs was 3% (20/765), with a median follow-up of 27 months
and a median time to development of MDS of 31 months. The cumulative
incidence of MDS/secondary leukemia in this patient population was
1.6% at 2 years and 6% at 5 years.<br/>Secondary Malignancies: Of the 995 patients in clinical studies and the
expanded access programs, there were 65 reports of second malignancies
in 54 patients, excluding secondary leukemias. The most common included
non-melanomatous skin cancers (26), colorectal cancer (7), head and
neck cancer (6), breast cancer (5), lung cancer (4), bladder cancer
(4), melanoma (3), and gastric cancer (2). Someof these events included
recurrence of an earlier diagnosis of cancer.<br/>Hypothyroidism: Of the 230 patients in the clinical studies, 203
patients did not have elevated TSH upon study entry. Of these, 137
patients had at least one post-treatment TSH value available and were
not taking thyroid hormonal treatment upon study entry. With a median
follow up period of 46 months, the incidence of hypothyroidism based
on elevated TSH or initiation of thyroid replacement therapy in these
patients was 18% with a median time to development of hypothyroidism
of 16 months. The cumulative incidences of hypothyroidism at 2 and
5 years in these 137 patients were 11% and 19% respectively. New events
have been observed up to 90 months post-treatment. Of the 765 patients in the expanded access programs, 670 patients
did not have elevated TSH upon study entry. Of these, 455 patients
had at least one post-treatment TSH value available and were not taking
thyroid hormonal treatment upon study entry. With a median follow
up period of 33 months, the incidence of hypothyroidism based on elevated
TSH or initiation of thyroid replacement therapy in these 455 patients
was 13% with a median time to development of hypothyroidism of 15
months. The cumulative incidences of hypothyroidismat 2 and 5 years
in these patients were 9% and 17%, respectively.<br/>Immunogenicity: One percent (11/989) of the chemotherapy-relapsed
or refractory patients included in the clinical studies or the expanded
access program had a positive serology for HAMA prior to treatment
and six patients had no baseline assessment for HAMA. Of the 230 patients
in the clinical studies, 220 patients were seronegative for HAMA prior
to treatment, and 219 had at least one post-treatment HAMA value obtained.
With a median observation period of 6 months, a total of 23 patients
(11%) became seropositive for HAMA post-treatment. The median time
of HAMA development was 6 months. The cumulative incidences of HAMA
seropositivity at 6 months, 12 months, and 18 months were 6%, 17%
and 21% respectively. Of the 765 patients
in the expanded access programs, 758 patients were seronegative for
HAMA prior to treatment, and 569 patients had at least one post-treatment
HAMA value obtained. With a median observation period of 7 months,
a total of 57 patients (10%) became seropositive for HAMA post-treatment.
The median time of HAMA development was 5 months. The cumulative incidences
of HAMA seropositivity at 6 months, 12 months, and 18 months were
7%, 12% and 13%, respectively. In a study
of 76 previously untreated patients with low-grade non-Hodgkin's
lymphoma who received the BEXXAR therapeutic regimen, the incidence
of conversion to HAMA seropositivity was 70%, with a median time to
development of HAMA of 27 days. The data
reflect the percentage of patients whose test results were consideredpositive for HAMA in an ELISA assay that detects antibodies to the
Fc portion of IgGmurine immunoglobulin 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 HAMA in patients treated with the BEXXAR therapeutic regimen with
the incidence of HAMA in patients treated with other products may
be misleading.
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| dailymed-instance:warning |
Hypersensitivity Reactions,
including Anaphylaxis: Serious hypersensitivity reactions, including some
with fatal outcome, have been reported with the BEXXAR therapeutic
regimen. Medications for the treatment of severe hypersensitivity
reactions should be available for immediate use. Patients who develop
severe hypersensitivity reactions should have infusions of the BEXXAR
therapeutic regimen discontinued and receive medical attention (see WARNINGS).<br/>Prolonged and Severe Cytopenias: The majority of patients who received the BEXXAR
therapeutic regimen experienced severe thrombocytopenia and neutropenia.
The BEXXAR therapeutic regimen should not be administered to patients
with>25% lymphoma marrow involvement and/or impaired bone marrow
reserve (see WARNINGS and ADVERSE REACTIONS).<br/>Pregnancy Category X: The BEXXAR therapeutic regimen can cause fetal harm
when administered to a pregnant woman.<br/>Special requirements: The BEXXAR therapeutic regimen (Tositumomab and
Iodine I 131 Tositumomab) contains a radioactive component and should
be administered only by physicians and other health care professionals
qualified by training in the safe use and handling of therapeutic
radionuclides. The BEXXAR therapeutic regimen should be administered
only by physicians who are in the process of being or have been certified
by GlaxoSmithKline in dose calculation and administration of the BEXXAR
therapeutic regimen.
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| dailymed-instance:indicatio... |
The BEXXAR therapeutic regimen (Tositumomab and
Iodine I 131 Tositumomab) is indicated for the treatment of patients
with CD20 antigen-expressing relapsed or refractory, low grade, follicular,
or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory
non-Hodgkin's lymphoma. Determination of the effectiveness
of the BEXXAR therapeutic regimen is based on overall response rates
in patients whose disease is refractory to chemotherapy alone or to
chemotherapy and Rituximab. The effects of the BEXXAR therapeutic
regimen on survival are not known. The BEXXAR
therapeutic regimen is not indicated for the initial treatment of
patients with CD20 positive non-Hodgkin's lymphoma. (See ADVERSE REACTIONS, Immunogenicity.) The BEXXAR therapeutic regimen is intended as a single
course of treatment. The safety of multiple courses of the BEXXAR
therapeutic regimen, or combination of this regimen with other forms
of irradiation or chemotherapy, has not been evaluated.
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| dailymed-instance:name |
BEXXAR
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