Zevalin (Ibritumomab Tiuxetan) - Indications and Dosage

INDICATIONS AND USAGE

ZEVALIN, as part of the ZEVALIN therapeutic regimen (see DOSAGE AND ADMINISTRATION), is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma, including patients with Rituximab refractory follicular non-Hodgkin's lymphoma. Determination of the effectiveness of the ZEVALIN therapeutic regimen in a relapsed or refractory patient population is based on overall response rates (see CLINICAL STUDIES). The effects of the ZEVALIN therapeutic regimen on survival are not known.

DOSAGE AND ADMINISTRATION

The ZEVALIN therapeutic regimen is administered in two steps: Step 1 includes a single infusion of 250 mg/m² Rituximab (not included in the ZEVALIN kits) preceding a fixed dose of 5.0 mCi (1.6 mg total antibody dose) of In-111 ZEVALIN administered as a 10 minute IV push. Step 2 follows step 1 by seven to nine days and consists of a second infusion of 250 mg/m² of Rituximab prior to 0.4 mCi/kg of Y-90 ZEVALIN administered as a 10 minute IV push.

Rituximab Administration: NOTE THAT THE DOSE OF RITUXIMAB IS LOWER WHEN USED AS PART OF THE ZEVALIN THERAPEUTIC REGIMEN, AS COMPARED TO THE DOSE OF RITUXIMAB WHEN USED AS A SINGLE AGENT. DO NOT ADMINISTER RITUXIMAB AS AN INTRAVENOUS PUSH OR BOLUS. Hypersensitivity reactions may occur (see WARNINGS). Premedication, consisting of acetaminophen and diphenhydramine, should be considered before each infusion of Rituximab.

ZEVALIN Therapeutic Regimen Dose Modification in Patients with Mild Thrombocytopenia: The Y-90 ZEVALIN dose should be reduced to 0.3 mCi/kg (11.1 MBq/kg) for patients with a baseline platelet count between 100,000 and 149,000 cells/mm³.

Two separate and distinctly-labeled kits are ordered for the preparation of a single dose each of In-111 ZEVALIN and Y-90 ZEVALIN. In-111 ZEVALIN and Y-90 ZEVALIN are radiopharmaceuticals and should be used only by physicians and other professionals qualified by training and experienced in the safe use and handling of radionuclides. Changing the ratio of any of the reactants in the radiolabeling process may adversely impact therapeutic results. In-111 ZEVALIN and Y-90 ZEVALIN should not be used in the absence of the Rituximab pre-dose.

ZEVALIN THERAPEUTIC REGIMEN ADMINISTRATION

Step 1:

First Rituximab Infusion: Rituximab at a dose of 250 mg/m² should be administered intravenously at an initial rate of 50 mg/hr. Rituximab should not be mixed or diluted with other drugs. If hypersensitivity or infusion-related events do not occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. If hypersensitivity or an infusion-related event develops, the infusion should be temporarily slowed or interrupted (see WARNINGS). The infusion can continue at one-half the previous rate upon improvement of patient symptoms.

In-111 ZEVALIN Injection: Within 4 hours following completion of the Rituximab dose, 5.0 mCi (1.6 mg total antibody dose) of In-111 ZEVALIN is injected intravenously (I.V.) over a period of 10 minutes. A 0.22 micrometer low-protein-binding filter should be in-line between the syringe and the infusion port prior to injection of In-111 ZEVALIN. After injection, the line should be flushed with at least 10 mL of normal saline.

Step 2:

Step 2 of the ZEVALIN therapeutic regimen is initiated seven to nine days following Step 1 administrations.

Second Rituximab Infusion: Rituximab at a dose of 250 mg/m² is administered I.V. at an initial rate of 100 mg/hr (50 mg/hr if infusion related events were documented during the first Rituximab administration) and increased by 100 mg/hr increments at 30 minute intervals, to a maximum of 400 mg/hr, as tolerated.

Y-90 ZEVALIN Injection:

Within 4 hours following completion of the Rituximab dose, Y-90 ZEVALIN at a dose of 0.4 mCi/kg (14.8 MBq/kg) actual body weight for patients with a platelet count >/=150,000 cells/mm³, and 0.3 mCi/kg (11.1 MBq/kg) actual body weight for patients with a platelet count of 100,000-149,000 cells/mm³ is injected intravenously (I.V.) over a period of 10 minutes. A 0.22 micrometer low-protein-binding filter should be in-line between the syringe and the infusion port prior to injection of Y-90 ZEVALIN. After injection, the line should be flushed with at least 10 mL of normal saline. Precautions should be taken to avoid extravasation. A free flowing I.V. line should be established prior to Y-90 ZEVALIN injection. Close monitoring for evidence of extravasation during the injection of Y-90 ZEVALIN is required. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. The prescribed, measured, and administered dose of Y-90 ZEVALIN must not exceed the absolute maximum allowable dose of 32.0 mCi (1184 MBq), regardless of the patient's body weight. Do not give Y-90 ZEVALIN to patients with a platelet count <100,000/mm³(see WARNINGS).

DIRECTIONS FOR PREPARATION OF RADIOLABELED ZEVALIN

1. PREPARATION OF THE IN-111 ZEVALIN DOSE
   GENERAL:
   Read all directions thoroughly and assemble all materials before starting the radiolabeling procedure. Important, significant differences exist in the preparation of the In-111 ZEVALIN dose and the Y-90 ZEVALIN dose.
   The patient dose 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 In-111.
   Proper aseptic technique and precautions for handling radioactive materials should be employed. Waterproof gloves should be utilized in the preparation and during the determination of radiochemical purity of In-111 ZEVALIN. Appropriate shielding should be used during radiolabeling, and use of a syringe shield is recommended during administration to the patient. The radiolabeling of ZEVALIN shall be done according to the following directions.
   Required materials not supplied in the kit:
   
   1. Indium-111 Chloride Sterile Solution (In-111 Chloride) from Amersham Health, Inc. or Mallinckrodt, Inc.
   2. Three sterile 1 mL syringes
   3. One sterile 3 mL syringe
   4. Two sterile 10 mL syringes with 18-20 G needles
   5. Instant thin-layer chromatographic silica gel strips
   6. 0.9% sodium chloride aqueous solution for the chromatography solvent
   7. Developing chamber for chromatography
   8. Suitable radioactivity counting apparatus
   9. Filter, 0.22 micrometer, low-protein-binding (see DOSAGE AND ADMINISTRATION, Zevalin Therapeutic Regimen Administration)
   10. Vial and syringe shield
   
   Method:
   
   1. Sterile, pyrogen-free In-111 chloride must be used for the preparation of In-111 ZEVALIN. The use of high purity In-111 chloride manufactured by Amersham Health, Inc. or Mallinckrodt, Inc. is required.
   2. Before radiolabeling, allow contents of the refrigerated carton to reach room temperature. Note: The ZEVALIN vial contains a protein solution that may develop translucent particulates. These particulates will be removed by filtration prior to administration.
   3. Clean the rubber stoppers of all of the vials in the kit and the In-111 chloride vial with a suitable alcohol swab and allow to air dry.
   4. Place the empty Reaction Vial in a suitable dispensing shield (pre-warmed to room temperature). To avoid the buildup of excessive pressure during the procedure, use a 10 mL syringe to withdraw 10 mL of air from the Reaction Vial.
   5. Prior to initiating the radiolabeling reaction, determine the amount of each component needed according to the directions below:
      
      1. Calculate the volume of In-111 chloride that is equivalent to 5.5 mCi based on the activity concentration of the In-111 chloride stock.
      2. The volume of 50 mM sodium acetate solution needed is 1.2 times the volume of In-111 chloride solution determined in step 5.a., above. (The 50 mM sodium acetate is used to adjust the pH for the radiolabeling reaction.)
      3. Calculate the volume of Formulation Buffer needed to bring the Reaction Vial contents to a final volume of 10 mL. This is the volume of Formulation Buffer needed to protect the labeled product from radiolysis and to terminate the labeling reaction. For example, if volumes of 0.5 mL of In-111 chloride, 0.6 mL of sodium acetate and 1.0 mL of ZEVALIN were used, then the amount of formulation buffer would be 10-(0.5 + 0.6 + 1.0) = 7.9 mL.
   6. With a sterile 1 mL syringe, transfer the calculated volume of 50 mM of sodium acetate to the empty Reaction Vial. Coat the entire inner surface of the Reaction Vial by gentle inversion or rolling.
   7. Transfer 5.5 mCi of In-111 chloride to the Reaction Vial with a sterile 1 mL syringe. Mix the two solutions and coat the entire inner surface of the Reaction Vial by gentle inversion or rolling.
   8. With a sterile 3 mL syringe, transfer 1.0 mL of ZEVALIN (Ibritumomab Tiuxetan) to the Reaction Vial. Coat the entire surface of the Reaction Vial by gentle inversion or rolling. Do not shake or agitate the vial contents, since this will cause foaming and denaturation of the protein.
   9. Allow the labeling reaction to proceed at room temperature for 30 minutes. Allowing the labeling reaction to proceed for a longer or shorter time may result in inadequate labeling.
   10. Immediately after the 30-minute incubation period, using a sterile 10 mL syringe with a large bore needle (18 G-20 G), transfer the calculated volume of Formulation Buffer from step 5.c. to the Reaction Vial. Gently add the Formulation Buffer down the side of the Reaction Vial. If necessary, to normalize air pressure, withdraw an equal volume of air. Coat the entire inner surface of the Reaction Vial by gentle inversion or rolling. Do not shake or agitate the vial contents. Avoid foaming.
   11. Using the supplied labels, record the patient identification, the date and time of preparation, the total activity and volume, and the date and time of expiration, and affix these labels to the reaction vial and shielded reaction vial container.
   12. Calculate the volume required for an In-111 ZEVALIN dose of 5 mCi. Withdraw the required volume from the Reaction Vial contents into a sterile 10 mL syringe with a large bore needle (18 G-20 G). Assay the syringe and contents in a dose calibrator. The syringe should contain the dose of In-111 ZEVALIN to be administered to the patient. Using the supplied labels, record the patient identification, the date and time of preparation, the total activity and volume added, and the date and time of expiration, and affix these labels to the syringe and shielded unit dose container.
   13. Determine Radiochemical purity. See Section C: Procedure for Determining Radiochemical Purity Section that follows DIRECTIONS FOR PREPARATION OF THE Y-90 ZEVALIN DOSE.
   14. Indium-111 ZEVALIN should be stored at 2-8°C (36-46°F) until use and administered within 12 hours of radiolabeling.
   15. See DOSAGE AND ADMINISTRATION: ZEVALIN Therapeutic Regimen Administration: Step 1
   16. Discard vials, needles and syringes in accordance with local, state, and federal regulations governing radioactive and biohazardous waste.
2. PREPARATION OF THE Y-90 ZEVALIN DOSE
   GENERAL:
   Read all directions thoroughly and assemble all materials before starting the radiolabeling procedure. Important, significant differences exist in the preparation of the In-111 ZEVALIN dose and the Y-90 ZEVALIN dose.
   The patient dose 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 Y-90.
   Proper aseptic technique and precautions for handling radioactive materials should be employed. Waterproof gloves should be utilized in the preparation and during the determination of radiochemical purity of Y-90 ZEVALIN. Appropriate shielding should be used during radiolabeling, and use of a syringe shield is recommended during administration to the patient. The radiolabeling of ZEVALIN shall be done according to the following directions.
   Required materials not supplied in the kit:
   
   1. Yttrium-90 Chloride Sterile Solution from MDS Nordion (shipped directly from MDS Nordion upon placement of an order for the Y-90 ZEVALIN kit)
   2. Three sterile 1 mL syringes
   3. One sterile 3 mL syringe
   4. Two sterile 10 mL syringes with 18-20 G needles
   5. Instant thin-layer chromatographic silica gel strips (ITLC-SG)
   6. 0.9% sodium chloride aqueous solution for the chromatography solvent
   7. Suitable radioactivity counting apparatus
   8. Developing chamber for chromatography
   9. Filter, 0.22 micrometer, low-protein-binding (see DOSAGE AND ADMINISTRATION, Zevalin Therapeutic Regimen Administration)
   10. Vial and syringe shield
   
   Method:
   
   1. Sterile, pyrogen-free Y-90 chloride must be used for the preparation of Y-90 ZEVALIN. The use of high purity Y-90 chloride manufactured by MDS Nordion is required.
   2. Before radiolabeling, allow the contents of the refrigerated carton to reach room temperature. Note: The ZEVALIN vial contains a protein solution that may develop translucent particulates. These particulates will be removed by filtration prior to administration.
   3. Clean the rubber stoppers of all of the vials in the kit and the Y-90 chloride vial with a suitable alcohol swab and allow to air dry.
   4. Place the empty Reaction Vial in a suitable dispensing shield (pre-warmed to room temperature). To avoid the buildup of excessive pressure during the procedure, use a 10 mL syringe to withdraw 10 mL of air from the Reaction Vial.
   5. Prior to initiating the radiolabeling reaction, determine the amount of each component needed according to the directions below:
      
      1. Calculate the volume of Y-90 chloride that is equivalent to 40 mCi based on the activity concentration of the Y-90 chloride stock.
      2. The volume of 50 mM sodium acetate solution needed is 1.2 times the volume of Y-90 chloride solution determined in step 5.a., above. (The 50 mM sodium acetate is used to adjust the pH for the radiolabeling reaction.)
      3. Calculate the volume of Formulation Buffer needed to bring the Reaction Vial contents to a final volume of 10 mL. This is the volume of Formulation Buffer needed to protect the labeled product from radiolysis and to terminate the labeling reaction. For example if the volumes were 0.5 mL of Y-90 chloride, 0.6 mL of sodium acetate and 1.3 mL of ZEVALIN, then the amount of formulation buffer would be 10-(0.5 + 0.6 + 1.3) = 7.6 mL.
   6. With a sterile 1 mL syringe, transfer the calculated volume of 50 mM sodium acetate to the empty Reaction Vial. Coat the entire inner surface of the Reaction Vial by gentle inversion or rolling.
   7. Transfer 40 mCi of Y-90 chloride to the Reaction Vial with a sterile 1 mL syringe. Mix the two solutions and coat the entire inner surface of the Reaction Vial by gentle inversion or rolling.
   8. With a sterile 3 mL syringe, transfer 1.3 mL of ZEVALIN (Ibritumomab Tiuxetan) to the Reaction Vial. Coat the entire surface of the Reaction Vial by gentle inversion or rolling. Do not shake or agitate the vial contents, since this will cause foaming and denaturation of the protein.
   9. Allow the labeling reaction to proceed at room temperature for 5 minutes. Allowing the labeling reaction to proceed for a longer or shorter time may result in inadequate labeling.
   10. Immediately after the 5-minute incubation period, using a sterile 10 mL syringe with a large bore needle (18 G-20 G), transfer the calculated volume of Formulation Buffer from step 5.c. to the Reaction Vial, terminating incubation. Gently add the Formulation Buffer down the side of the Reaction Vial. If necessary to normalize air pressure, withdraw an equal volume of air. Coat the entire inner surface of the Reaction Vial by gentle inversion or rolling. Do not shake or agitate the vial contents. Avoid foaming.
   11. Using the supplied labels, record the patient identification, the date and time of preparation, the total activity and volume, and the date and time of expiration and affix these labels to the reaction vial and shielded reaction vial container.
   12. Calculate the volume required for a Y-90 ZEVALIN dose of 0.4 mCi/kg (14.8 MBq/kg) actual body weight for patients with normal platelet count, and 0.3 mCi/kg (11.1 MBq/kg) actual body weight for patients with platelet count of 100,000-149,000 cells/mm³. The prescribed, measured, and administered dose of Y-90 ZEVALIN must not exceed the absolute maximum allowable dose of 32.0 mCi (1184 MBq), regardless of the patient's body weight. Withdraw the required volume from the Reaction Vial contents into a sterile 10 mL syringe with a large bore needle (18 G-20 G). Assay the syringe and contents in a dose calibrator. The dose calibrator must be operated in accordance with the manufacturer's specifications and quality control for the measurement of Y-90. The syringe should contain the dose of Y-90 ZEVALIN to be administered to the patient, and should be within 10% of the actual prescribed dose of Y-90 ZEVALIN, not to exceed a maximum dose of 32.0 mCi. Do not exceed ± 10% of the prescribed dose. Using the supplied labels, record the patient identification, the date and time of preparation, the total activity and volume added, and the date and time of expiration and affix these labels to the syringe and shielded unit dose container.
   13. Determine Radiochemical Purity. See Section C: Procedure for Determining Radiochemical Purity Section that follows these DIRECTIONS FOR PREPARATION OF THE Y-90 ZEVALIN DOSE.
   14. Yttrium-90 ZEVALIN should be stored at 2-8°C (36-46°F) until use and administered within 8 hours of radiolabeling.
   15. See DOSAGE AND ADMINISTRATION: ZEVALIN Therapeutic Regimen Administration: Step 2.
   16. Discard vials, needles and syringes in accordance with local, state, and federal regulations governing radioactive and biohazardous waste.
       Yttrium-90 ZEVALIN is suitable for administration on an outpatient basis. Beyond the use of vial and syringe shields for preparation and injection, no special shielding is necessary.
3. PROCEDURE FOR DETERMINING RADIOCHEMICAL PURITY (RCP)
   The following procedure should be used for both In-111 ZEVALIN and Y-90 ZEVALIN:
   
   1. At room temperature, place a small drop of either In-111 ZEVALIN or Y-90 ZEVALIN at the origin of an ITLC-SG strip.
   2. Place the ITLC-SG strip into a chromatography chamber with the origin at the bottom and the solvent front at the top. Allow the solvent (0.9% NaCl) to migrate at least 5 cm from the bottom of the strip. Remove the strip from the chamber and cut the strip in half. Count each half of the ITLC-SG strip for one minute (CPM) with a suitable counting apparatus.
   3. Calculate the percent RCP as follows:
      

      % RCP = CPM bottom half CPM bottom half + CPM top half × 100

      
      
   4. If the radiochemical purity is <95%, the ITLC procedure should be repeated. If repeat testing confirms that radiochemical purity is <95%, the preparation should not be administered.

IMAGE ACQUISITION AND INTERPRETATION

The biodistribution of In-111 ZEVALIN should be assessed by a visual evaluation of whole body planar view anterior and posterior gamma images at 2-24 hours and 48-72 hours after injection. To resolve ambiguities, a third image at 90-120 hours may be necessary. Images should be acquired using a large field of view gamma camera equipped with a medium energy collimator. Whole body anterior/posterior planar images should be acquired using a large field-of-view gamma camera and medium energy collimators. Suggested gamma camera settings: 256 × 1024 matrix; dual energy photopeaks set at 172 and 247 keV; 15% symmetric window; scan speed of 10 cm/min for the 2-24 hour scan, 7-10 cm/min for the 48-72 hour scan and 5 cm/min for the optional 90-120 hour scan.

The radiopharmaceutical is expected to be easily detectable in the blood pool areas at the first time point, with less activity in the blood pool on later images. Moderately high to high uptake is seen in the normal liver and spleen, with low uptake in the lungs, kidneys, and urinary bladder. Localization to lymphoid aggregates in the bowel wall has been reported. Tumor uptake may be visualized in soft tissue as areas of increased intensity, and tumor-bearing areas in normal organs may be seen as areas of increased or decreased intensity.

If a visual inspection of the gamma images reveals an altered biodistribution, the patient should not proceed to the Y-90 ZEVALIN dose. The patient may be considered to have an altered biodistribution if the blood pool is not visualized on the first image indicating rapid clearance of the radiopharmaceutical by the reticuloendothelial system to the liver, spleen, and/or marrow. Other potential examples of altered biodistribution may include diffuse uptake in the normal lungs or kidneys more intense than the liver on the second or third image.

During ZEVALIN clinical development, individual tumor radiation absorbed dose estimates as high as 778 cGy/mCi have been reported. Although solid organ toxicity has not been directly attributed to radiation from adjacent tumors, careful consideration should be applied before proceeding with treatment in patients with very high tumor uptake next to critical organs or structures.

HOW SUPPLIED

The In-111 ZEVALIN kit provides for the radiolabeling of Ibritumomab Tiuxetan with In-111. The Y-90 ZEVALIN kit provides for the radiolabeling of Ibritumomab Tiuxetan with Y-90.

The kit for the preparation of a single dose of In-111 ZEVALIN includes four vials: one ZEVALIN vial containing 3.2 mg of Ibritumomab Tiuxetan in 2 mL of 0.9% sodium chloride solution; one 50 mM Sodium Acetate vial; one Formulation Buffer vial; one empty Reaction vial and four identification labels.

The kit for the preparation of a single dose of Y-90 ZEVALIN includes four vials: one ZEVALIN vial containing 3.2 mg of Ibritumomab Tiuxetan in 2 mL of 0.9% sodium chloride solution; one 50 mM Sodium Acetate vial; one Formulation Buffer vial; one empty Reaction vial and four identification labels.

The contents of all vials are sterile, pyrogen-free and contain no preservatives.

The Indium-111 Chloride Sterile Solution (In-111 Chloride) must be ordered separately from either Amersham Health, Inc. or Mallinckrodt, Inc. at the time the In-111 ZEVALIN kit is ordered. The Yttrium-90 Chloride Sterile Solution will be shipped directly from MDS Nordion upon placement of an order for the Y-90 ZEVALIN kit.

STORAGE

Store at 2-8°C (36-46°F). Do not freeze.