Bexxar

Bexxar Manufacturers

• Glaxosmithkline Llc
  

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  Bexxar | Glaxosmithkline Llc

  

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  The BEXXAR therapeutic regimen consists of 2 separate components (tositumomab and iodine I 131 tositumomab) administered in 2 separate steps (dosimetric dose and therapeutic dose) separated by 7 to 14 days.

  Parenteral drug products should be inspected for particulate matter prior to administration, whenever solution and container permit [see Description (11)].

  2.1 Overview of Dosing Schedule

  ]

  2.2 Recommended Dose

  Dosimetric dose

  1. Tositumomab 450 mg by intravenous infusion 2. I-131 tositumomab (5 mCi I-131 and 35 mg protein) by intravenous infusion

  Therapeutic dose (administered 7-14 days after dosimetric dose)

  1. Tositumomab 450 mg by intravenous infusion 2. I-131 tositumomab (35 mg) by intravenous infusion. The iodine-131 dose is calculated based on 1) assessment of dosimetry and biodistribution obtained following the dosimetric dose, and 2) platelet counts obtained within 28 days prior to dosing.   If platelet counts are 150,000 platelets/mm3 or greater:   The recommended dose (mCi) is the activity of Iodine-131 calculated to deliver 75 cGy total body irradiation   If platelet counts are 100,000 to 149,000 platelets/mm3:   The recommended dose is the activity of Iodine-131 calculated to deliver 65 cGy total body irradiation 2.3 Preparation of Dosimetric Dose

  Tositumomab Dosimetric Dose

  1. Withdraw and discard 32 mL from a 50-mL bag 0.9% Sodium Chloride for Injection, USP. 2. Withdraw and transfer entire contents from each of the two 225-mg tositumomab vials (a total of 450 mg tositumomab in 32 mL) to remaining 18 mL in bag of 0.9% Sodium Chloride for Injection, USP to yield a final volume of 50 mL. 3. DO NOT SHAKE. Gently mix the solution by inverting/rotating the bag. The tositumomab solution is clear to opalescent, colorless to slightly yellow, and may contain white particulates. 4. Diluted tositumomab may be stored at 36°F to 46°F (2°C to 8°C) for 24 hours or at room temperature for 8 hours. Discard unused solution.

  I-131 Tositumomab Dosimetric Dose

  Required materials (not supplied):

  • Lead shielding for preparation vial and syringe pump • One sterile 30-mL preparation vial • Two lead pots at room temperature

  Method

  1. Thaw contents (approximately 60 minutes) of I-131 tositumomab dosimetric vial at room temperature with appropriate lead shielding. Thawed undiluted I-131 tositumomab may be stored up to 8 hours at 36°F to 46°F (2°C to 8°C) or at room temperature. 2. Calculate the volume required for I-131 tositumomab activity of 5.0 mCi, based on the activity concentration of dosimetric vial (refer to product specification sheet provided in dosimetric carton). 3. Withdraw and transfer the calculated volume from I-131 tositumomab vial to the shielded preparation vial. 4. Assay preparation vial to confirm activity is 5.0 mCi (±10%) using a suitable radioactivity calibration system operated in accordance with the manufacturer’s specifications and quality control for the measurement of Iodine-131. • If the preparation vial contains the calculated activity (±10%), proceed to step 5. • If the preparation vial does not contain the calculated activity (5 mCi ±10%), determine the activity concentration of the I-131 tositumomab based on the volume and the activity in the preparation vial. Add or subtract the appropriate volume of I-131 tositumomab to the preparation vial to achieve the desired activity of 5.0 mCi (±10%). Re-assay to confirm. 5. Calculate the amount of tositumomab in the shielded preparation vial, based on the volume and labeled protein concentration of the I-131 tositumomab dosimetric vial (see product specification sheet provided in dosimetric carton). If less than 35 mg, add additional tositumomab from the non-radioactive vial to the shielded vial to yield a total of 35 mg tositumomab in the shielded vial. 6. Add a sufficient quantity of 0.9% Sodium Chloride for Injection, USP to the shielded preparation vial to yield a final volume of 30 mL. Gently mix contents. 7. Withdraw the entire contents from the preparation vial into a 60-mL syringe using a large bore needle (18-gauge) and shield contents of syringe and syringe pump.   8. Assay and record the activity. 2.4 Administration of Dosimetric Dose

  Thyroid Protective Pre-medication: Initiate thyroid protective drugs 24 hours prior to the dosimetric dose and continue daily dosing for a minimum of 14 days following the therapeutic dose. The following regimens are recommended:

  • Saturated solution of potassium iodide (SSKI) 4 drops orally 3 times daily or • Lugol’s solution 20 drops orally 3 times daily or • Potassium iodide tablets 130 mg orally once daily

  Do not administer the dosimetric dose unless the patient has received at least 3 doses of SSKI, 3 doses of Lugol’s solution, or 1 dose of 130-mg potassium iodide tablet.

  Tositumomab

  1. Premedicate with oral diphenhydramine 50 mg and oral acetaminophen 650 mg, 30 minutes prior to initiation of the dosimetric dose. 2. Administer 450 mg tositumomab in 50 mL 0.9% sodium chloride by intravenous infusion through a 0.22 micron in-line filter over 60 minutes (refer to Site Training Manual for diagram showing assembly of the infusion set components). Decrease the rate of infusion by 50% for mild to moderate infusion reactions. Discontinue for serious allergic reactions; interrupt for severe infusion reactions. If severe infusion reaction completely resolves, the infusion may be continued at 50% of the previous infusion rate.

  I-131 Tositumomab

  3. Attach the shielded syringe containing the I-131 tositumomab dose in a syringe pump to the intravenous line containing the in-line filter used in step 2 above . A change in filter can result in loss of up to 7% of the I-131 tositumomab dose. 4. Set syringe pump to deliver the entire dose of I-131 tositumomab over 20 minutes, immediately following completion of the tositumomab infusion. Decrease the rate of infusion by 50% for mild to moderate infusion reactions. Discontinue for serious allergic reactions; interrupt for severe infusion reactions. If severe infusion reaction completely resolves, the infusion may be continued at 50% of the previous infusion rate. 5. Upon completion of the I-131 tositumomab infusion, flush the IV line with 0.9% Sodium Chloride for Injection, USP. 6. Determine the combined residual activity of the syringe and infusion set components (stopcock, extension set, primary infusion set, and in-line filter set) by assaying these items in a suitable radioactivity calibration system immediately following completion of administration of all components of the dosimetric dose. 7. Calculate and record the dose delivered to the patient by subtracting the residual activity in the syringe and the infusion set components from the activity of I-131 tositumomab in the syringe prior to infusion.   8. Discard unused portion of Iodine I-131 tositumomab and infusion set components according to federal and state laws regarding radioactive and biohazardous waste. 2.5 Assessment of Dosimetry and Biodistribution

  Additional copies of templates for recording dosimetry and calculation of the I-131 tositumomab therapeutic dose and the Site Training Manual may be obtained from the GlaxoSmithKline Wholesale Service Center (1-877-423-9927).

  Obtain total body gamma camera counts and whole body images at the following timepoints:

  1. Count 1 (Day 0) : Within 1 hour following the end of the I-131 tositumomab infusion and prior to urination, obtain total body gamma camera count and whole body images. 2. Count 2 (Day 2, 3, or 4): Obtain total body gamma camera counts and whole body images, immediately following urination. 3. Count 3 (Day 6 or 7): Obtain total body gamma camera counts and whole body images, immediately following urination.   Verify that the expected biodistribution is present.

  Assess Biodistribution: Determine total body residence time and examine whole body camera images done at Count 1 and Count 2. Examine image performed at Count 3 as needed to resolve ambiguities.

  Expected biodistribution characteristics:

  Count 1 (day of dosimetric dose)

  • Most of the activity is in the blood pool (heart and major blood vessels). Uptake in normal liver and spleen is less than in the heart.

  Count 2 (Day 2, 3, or 4) and Count 3 (Day 6 or 7)

  • Activity in the blood pool decreases significantly. Decreased accumulation of activity in normal liver and spleen. Possible uptake present in thyroid, kidney, and urinary bladder with minimal uptake in the lungs. Possible increased intensity at known lymphoma sites.

  Biodistribution is altered if any of the following is present:

  Count 1:

  • Blood pool is not visualized • Diffuse, intense tracer uptake in the liver and/or spleen or uptake suggestive of urinary obstruction • Diffuse uptake in normal lung greater than that of blood pool.

  Count 2 and Count 3:

  • Uptake is suggestive of urinary obstruction • Diffuse uptake in normal lung which is greater than that of the blood pool • Total body residence time is less than 50 hours • Total body residence time is more than 150 hours.
  2.6 Calculation of I-131 Therapeutic Dose

  The therapeutic dose may be calculated manually using the total body residence time and activity hours (refer to the Site Training Manual). The therapeutic dose may also be derived by using the GlaxoSmithKline BEXXAR therapeutic regimen Patient Management Templates (refer to the Site Training Manual). For assistance with either manual or automated calculations call the GlaxoSmithKline Wholesale 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:

  2.7 Preparation of Therapeutic Dose

  Tositumomab

  A 450-mg dose of tositumomab should be prepared as previously described [see Dosage and Administration (2.3)].

  I-131 tositumomab

  Required materials (not supplied):

  • Lead shielding for preparation vial and syringe pump • One sterile 50-mL preparation vial • Two lead pots at room temperature.

  Method

  Thaw contents (approximately 60 minutes) of I-131 tositumomab therapeutic vial at room temperature with appropriate lead shielding. Thawed, undiluted I-131 tositumomab may be stored up to 8 hours at 36°F to 46°F (2°C to 8°C) or at room temperature. Do not freeze solutions of diluted I-131 tositumomab; store refrigerated until time of use.

  1. Calculate the volume (see activity concentration on the product specification sheet provided with the therapeutic vial) of I-131 tositumomab activity required to deliver either 75cGy or 65cGy total body irradiation [see Dosage and Administration (2.6)]. 2. Withdraw and transfer the calculated volume from I-131 tositumomab vial to the shielded preparation vial. 3. Assay preparation vial to confirm calculated activity using a suitable radioactivity calibration system operated in accordance with the manufacturer’s specifications and quality control for the measurement of Iodine-131. • If the assayed dose in the preparation vial contains the calculated activity (±10%), proceed to step 5. • If the assayed dose in the preparation vial does not contain the calculated activity (±10%), determine the activity concentration of I-131 tositumomab based on the volume and the activity in the preparation vial. Add or subtract the appropriate volume of I-131 tositumomab to the preparation vial to achieve the required I-131 tositumomab activity. Re-assay the preparation vial contents to confirm. 4. Calculate the amount of tositumomab in the shielded preparation vial, based on the volume and protein concentration of I-131 tositumomab (refer to product specification sheet for the vial in the therapeutic carton). If the amount of tositumomab in the preparation vial is less than 35 mg, add additional tositumomab from the non-radioactive 35-mg vial to the shielded preparation vial to yield a total of 35 mg tositumomab in the shielded vial. 5. Add a sufficient quantity of 0.9% Sodium Chloride for Injection, USP to the shielded preparation vial to yield a final volume of 30 mL. Gently mix contents. 6. Withdraw the entire contents from the shielded preparation vial into a 60-mL syringe using a large bore needle (18-gauge) and shield contents of syringe and syringe pump.   7. Assay and record activity. 2.8 Administration of Therapeutic Dose

  Do not administer the therapeutic dose if biodistribution is altered [see Dosage and Administration (2.5)].

  Tositumomab

  Premedicate with oral diphenhydramine 50 mg and oral acetaminophen 650 mg 30 minutes prior to initiation of the therapeutic dose.

  Administer 450 mg tositumomab in 50 mL 0.9% sodium chloride by intravenous infusion through a 0.22 micron in-line filter over 60 minutes (refer to Site Training Manual for diagram showing assembly of the infusion set components). Decrease the rate of infusion by 50% for mild to moderate infusion reactions. Discontinue for serious allergic reactions; interrupt for severe infusion reactions. If severe infusion reaction completely resolves, the infusion may be continued at 50% of the previous infusion rate.

  I-131 Tositumomab

  Attach the shielded syringe containing the I-131 tositumomab therapeutic dose to the intravenous line containing the in-line filter used in step 2 above. A change in filter can result in loss of up to 7% of the I-131 tositumomab dose. Set syringe pump to deliver the entire dose of I-131 tositumomab over 20 minutes, immediately following completion of the tositumomab infusion. Decrease the rate of infusion by 50% for mild to moderate infusion reactions. Discontinue for serious allergic reactions; interrupt for severe infusion reactions. If severe infusion reaction completely resolves, the infusion may be continued at 50% of the previous infusion rate.

  1. Upon completion of I-131 tositumomab infusion, flush the IV line with 0.9% Sodium Chloride for Injection, USP. 2. Determine the combined residual activity of the syringe and infusion set components (stopcock, extension set, primary infusion set and in-line filter set) by assaying these items in a suitable radioactivity calibration system immediately following completion of administration of all components of the therapeutic dose. 3. Calculate and record the dose delivered to the patient by subtracting the residual activity in the syringe and the infusion set components from the activity of I-131 tositumomab in the syringe prior to infusion.   4. Discard unused portion of Iodine I-131 tositumomab and infusion set components according to federal and state laws regarding radioactive and biohazardous waste. 2.9 Radiation Dosimetry

  Estimations of radiation-absorbed doses for 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 1.

  Table 1. Estimated Radiation-Absorbed Organ Doses

  The BEXXAR therapeutic regimen

  mGy/MBq

  Median

  The BEXXAR therapeutic regimen

  mGy/MBq

  Range

  Organ Regions of Interest (ROIs)

     Thyroid

  2.71

  1.4 - 6.2

     Kidneys

  1.96

  1.5 - 2.5

     Upper large intestine wall

  1.34

  0.8 - 1.7

     Lower large intestine wall

  1.30

  0.8 - 1.6

     Heart wall

  1.25

  0.5 - 1.8

     Spleen

  1.14

  0.7 - 5.4

     Testes

  0.83

  0.3 - 1.3

     Liver

  0.82

  0.6 - 1.3

     Lungs

  0.79

  0.5 - 1.1

     Marrow space

  0.65

  0.5 - 1.1

     Stomach wall

  0.40

  0.2 - 0.8

  Whole Body ROIs

     Urine bladder wall

  0.64

  0.6 - 0.9

     Bone surfaces

  0.41

  0.4 - 0.6

     Pancreas

  0.31

  0.2 - 0.4

     Gall bladder wall

  0.29

  0.2 - 0.3

     Adrenals

  0.28

  0.2 - 0.3

     Ovaries

  0.25

  0.2 - 0.3

     Small intestine

  0.23

  0.2 - 0.3

     Thymus

  0.22

  0.1 - 0.3

     Uterus

  0.20

  0.2 - 0.2

     Muscle

  0.18

  0.1 - 0.2

     Breasts

  0.16

  0.1 - 0.2

     Skin

  0.13

  0.1 - 0.2

     Brain

  0.13

  0.1 - 0.2

     Total body

  0.24

  0.2 - 0.3

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