ZEVALIN Kit for radiopharmaceutical preparations for infusion Ref.[11002] Active ingredients:

[⁹⁰Y]-radiolabelled Zevalin must only be received, handled and administered by qualified personnel and must be prepared in accordance with both radiation safety and pharmaceutical quality requirements (for more details see also sections 4.4, 6.6 and 12).

Posology

Zevalin must be used following pretreatment with rituximab. Please refer to the Summary of Product Characteristics of rituximab for detailed guidance on its use. The treatment regimen consists of two intravenous administrations of rituximab and one administration of [⁹⁰Y]-radiolabelled Zevalin solution in the following order:

Day 1: intravenous infusion of 250 mg/m² rituximab.

Day 7 or 8 or 9:

• intravenous infusion of 250 mg/m² rituximab shortly (within 4 hours) before administration of [⁹⁰Y]-radiolabelled Zevalin solution.
• 10-minute intravenous infusion of [⁹⁰Y]-radiolabelled Zevalin solution.

Repeated use: Data on the re-treatment of patients with Zevalin are not available. The recommended radioactivity dose of [⁹⁰Y]-radiolabelled Zevalin solution is:

Treatment of rituximab relapsed or refractory CD20+ follicular B-cell non-Hodgkin’s lymphoma (NHL)

• patients with ≥150,000 platelets/mm³: 15 MBq/kg body weight.
• patients with 100,000-150,000 platelets/mm³: 11 MBq/kg

The maximum dose must not exceed 1200 MBq.

Repeated use: Data on the re-treatment of patients with [⁹⁰Y]-radiolabeled Zevalin are not available.

Consolidation therapy after remission induction in previously untreated patients with follicular lymphoma

• patients with ≥150,000 platelets/mm³: 15 MBq/kg up to a maximum of 1200 MBq
• for patients with less than 150,000 platelets per mm³ see section '4.4'

Repeated use: Data on the re-treatment of patients with [⁹⁰Y]-radiolabelled Zevalin are not available.

Special populations

Paediatric population

Zevalin is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

Older people

Limited data in elderly patients (aged ≥ 65 years) are available. No overall differences in safety or efficacy were observed between these patients and younger patients.

Patients with hepatic impairment

The safety and efficacy have not been studied in patients with hepatic impairment.

Patients with renal impairment

The safety and efficacy have not been studied in patients with renal impairment.

Method of administration

The [⁹⁰Y]-radiolabelled Zevalin solution must be prepared according to section 12. Before administration to the patient, the percent radioincorporation of the prepared [⁹⁰Y]-radiolabelled Zevalin must be checked according to the procedure outlined in section 12. If the average radiochemical purity is less than 95%, the preparation must not be administered.

The prepared solution must be given as a slow intravenous infusion over 10 minutes. The infusion must not be administered as an intravenous bolus.

Zevalin may be infused directly by stopping the flow from an infusion bag and administering it directly into the line. A 0.2 or 0.22 micron low protein-binding filter must be on line between the patient and the infusion port. The line must be flushed with at least 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection after the infusion of Zevalin.

Dosimetry

Yttrium-90 decays by the emission of high-energy beta particles, with a physical half-life of 64.1 hours (2.67 days). The product of radioactive decay is stable zirconium-90. The path length of beta emission (χ90) by yttrium-90 in tissue is 5 mm.

Analyses of estimated radiation absorbed dose were carried out using quantitative imaging with the gamma-emitter [¹¹¹In]-radiolabelled Zevalin, blood sampling, and the MIRDOSE3 software program. The imaging dose of [¹¹¹In]-radiolabelled Zevalin was always given immediately following an infusion with rituximab at 250 mg/m² to deplete peripheral CD20+ cells and to optimise biodistribution. Following administration of [¹¹¹In]-radiolabelled Zevalin, whole body scans were performed at up to eight time-points, acquiring both anterior and posterior images. Blood samples, used to calculate residence times for red marrow, were drawn up to eight time-points.

Based upon dosimetry studies with [¹¹¹In]-radiolabelled Zevalin, the estimated radiation dosimetry for individual organs following administration of [90Y]-radiolabelled Zevalin at activities of 15 MBq/kg and 11 MBq/kg was calculated according to Medical Internal Radiation Dosimetry (MIRD) (Table 3). The estimated radiation-absorbed doses to normal organs were substantially below recognised upper safety limits. Individual patient dosim

Table 3. Estimated Radiation Absorbed Doses From [90Y]-Zevalin:

¹ Organ region of interest
² Sacrum region of interest
³ Whole body region of interestetry

Doses up to 19.2 MBq/kg of Zevalin have been administered in clinical trials. Expected haematological toxicity was observed, including grade 3 or 4. Patients recovered from these toxicity signs, and overdoses were not associated with serious or fatal outcome.

There is no known specific antidote for [⁹⁰Y]-radiolabelled Zevalin overdosage. Treatment consists of discontinuation of Zevalin and supportive therapy, which may include growth factors. If available, autologous stem cell support must be administered to manage haematological toxicity.

66 months.

After radiolabelling, an immediate use is recommended. Chemical and physical in-use stability has been demonstrated for 8 hours at 2°C – 8°C and protected from light.

Store in a refrigerator (2°C – 8°C). Do not freeze.

Store the vials in the original package in order to protect from light.

Storage of radiopharmaceuticals should be in accordance with national regulation on radioactive materials.

For storage conditions of the radiolabelled product, see section 6.3.

Zevalin is supplied as a kit for the preparation of yttrium-90 (90Y) radiolabelled ibritumomab tiuxetan.

Zevalin contains 1 of each of the following:

Ibritumomab tiuxetan vial: type I glass vial with a rubber stopper (teflon-lined bromobutyl) containing 2 ml solution.

Sodium acetate vial: type I glass vial with a rubber stopper (teflon-lined bromobutyl) containing 2 ml solution.

Formulation buffer vial: type I glass vial with a rubber stopper (teflon-lined bromobutyl) containing 10 ml solution.

Reaction vial: type I glass vial with a rubber stopper (teflon-lined bromobutyl)

Pack size of 1 kit.

General warning

Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or approporiate licences of the competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

Contents of the kit are intended only for use in the preparation of yttrium-90 radiolabelled ibritumomab tiuxetan and are not to be administered directly to the patient without first undergoing the preparative procedure.

For instructions on extemporary preparation of the medicinal product before administration,see section 12.

If at any time in the preparation of this product the integrity of the containers is compromised it should not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

The content of the kit before extemporary preparation is not radioactive. However, after Yttrium-90 is added, adequate shielding of the final preparation must be maintained.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements. Contaminated materials must be disposed of as radioactive waste by the authorised route.