ZYNTEGLO Dispersion for infusion Ref.[50056] Active ingredients: Betibeglogene autotemcel

Zynteglo must be administered in a qualified treatment centre by a physician(s) with experience in HSC transplantation and in the treatment of patients with TDT.

Patients are expected to enrol in a registry and will be followed in the registry in order to better understand the long-term safety and efficacy of Zynteglo.

Posology

The minimum recommended dose of Zynteglo is 5.0 × 10⁶ CD34+ cells/kg. In clinical studies doses up to 20 × 10⁶ CD34+ cells/kg have been administered. The minimum recommended dose is the same for adults and adolescents 12 years of age and older.

Zynteglo is intended for autologous use (see section 4.4) and should only be administered once.

Mobilisation and apheresis

Patients are required to undergo HSC mobilisation followed by apheresis to obtain CD34+ stem cells which will be used for medicinal product manufacturing (see section 5.1 for a description of the mobilisation regimen used in clinical studies).

The minimum target number of CD34+ cells to be collected is 12 × 10⁶ CD34+ cells/kg. If the minimum dose of Zynteglo of 5.0 × 10⁶ CD34+ cells/kg is not met after initial medicinal product manufacturing, the patient may undergo one or more additional cycles of mobilisation and apheresis, separated by at least 14 days, in order to obtain more cells for additional manufacture.

A back-up collection of CD34+ stem cells of ≥1.5 × 10⁶ CD34+ cells/kg (if collected by apheresis) or >1.0 × 10⁸ TNC/kg (if collected by bone marrow harvest) is required. These cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with Zynteglo. The back-up collection may be needed for rescue treatment if there is: 1) compromise of Zynteglo after initiation of myeloablative conditioning and before Zynteglo infusion, 2) primary engraftment failure, or 3) loss of engraftment after infusion with Zynteglo (see section 4.4).

Pre-treatment conditioning

The treating physician should confirm that HSC transplantation is appropriate for the patient before myeloablative conditioning is initiated (see section 4.4).

Full myeloablative conditioning must be administered before infusion of Zynteglo (see section 5.1 for a description of the myeloablative regimen used in clinical studies). It is recommended that patients maintain haemoglobin (Hb) ≥11 g/dL for at least 30 days prior to mobilisation and during myeloablative conditioning. Iron chelation should be stopped at least 7 days prior to myeloablative conditioning. Prophylaxis for hepatic veno-occlusive disease (VOD) is recommended. Prophylaxis for seizures should be considered (see section 5.1 for a description of the prophylaxis regimen used in clinical studies).

Myeloablative conditioning should not begin until the complete set of infusion bag(s) constituting the dose of Zynteglo has been received and stored at the administration site, and the availability of the back-up collection is confirmed.

Zynteglo administration

See Method of Administration below and section 6.6 for details on Zynteglo administration and handling.

After Zynteglo administration

Any blood products required within the first 3 months after Zynteglo infusion should be irradiated.

Restarting iron chelation after Zynteglo infusion may be necessary and should be based on clinical practice (see sections 4.5 and 5.1). Phlebotomy can be used in lieu of iron chelation, when appropriate.

Special populations

Elderly

Zynteglo has not been studied in patients >65 years of age. HSC transplantation must be appropriate for a patient with TDT to be treated with Zynteglo (see section 4.4). No dose adjustment is required.

Renal impairment

Zynteglo has not been studied in patients with renal impairment. Patients should be assessed for renal impairment defined as creatinine clearance ≤70 mL/min/1.73 m² to ensure HSC transplantation is appropriate. No dose adjustment is required.

Hepatic impairment

Zynteglo has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate (see section 4.4.). No dose adjustment is required.

Paediatric population

The safety and efficacy of Zynteglo in children <12 years of age have not yet been established.

Patients seropositive for human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV)

Zynteglo has not been studied in patients with HIV-1, HIV-2, HTLV-1, or HTLV-2. A negative serology test for HIV is necessary to ensure acceptance of apheresis material for Zynteglo manufacturing. Apheresis material from patients with a positive test for HIV will not be accepted for Zynteglo manufacturing.

Method of administration

Zynteglo is for intravenous use only (see section 6.6 for full details on the administration process).

After completion of the 4-day course of myeloablative conditioning, there must be a minimum of 48 hours of washout before Zynteglo infusion.

Before infusion, it must be confirmed that the patient’s identity matches the unique patient information on the Zynteglo infusion bag(s). The total number of infusion bags to be administered should also be confirmed with the Lot Information Sheet (see section 4.4).

Zynteglo infusion should be completed as soon as possible and no more than 4 hours after thawing. Each infusion bag should be administered in less than 30 minutes. In the event that more than one infusion bag is provided, all infusion bags must be administered. The entire volume of each infusion bag should be infused.

Standard procedures for patient management after HSC transplantation should be followed after Zynteglo infusion.

No data from clinical studies are available regarding overdose of Zynteglo.

Frozen: 1 year at ≤-140°C.

Once thawed: maximum 4 hours at room temperature (20°C-25°C).

Store in the vapour phase of liquid nitrogen at ≤-140°C until ready for thaw and administration.

Keep the infusion bag(s) in the metal cassette(s).

Do not re-freeze after thawing.

20 mL fluorinated ethylene propylene infusion bag(s), each packed in a transparent pouch inside a metal cassette.

Zynteglo is shipped from the manufacturing facility to the infusion centre storage facility in a cryoshipper, which may contain multiple metal cassettes intended for a single patient. Each metal cassette contains one infusion bag with Zynteglo. A patient may have multiple infusion bags.

Irradiation could lead to inactivation of the product.

Precautions to be taken before handling or administering the medicinal product:

• This medicinal product contains genetically modified human blood cells. Healthcare professionals handling Zynteglo should take appropriate precautions (wearing gloves, protective clothing and eye protection) to avoid potential transmission of infectious diseases.

Preparation for the infusion:

• Remove each metal cassette from liquid nitrogen storage and remove each infusion bag from the metal cassette.
• Confirm that Zynteglo is printed on the infusion bag(s).
• Confirm that patient identity matches the unique patient identification information located on the Zynteglo infusion bag(s). Do not infuse Zynteglo if the information on the patient specific-label on the infusion bag does not match the intended patient.
• Account for all infusion bags and confirm each infusion bag is within the expiry date using the accompanying Lot Information Sheet.
• Each infusion bag should be inspected for any breaches of integrity before thawing and infusion. If an infusion bag is compromised, follow the local guidelines and contact bluebird bio immediately.

Thaw and administration:

• Thaw Zynteglo at 37°C in a water bath or dry bath. Thawing of each infusion bag takes approximately 2 to 4 minutes. Do not overthaw the medicinal product. Do not leave the medicinal product unattended and do not submerge the infusion ports if thawed in a water bath.
• After thaw, mix the medicinal product gently by massaging the infusion bag until all of the contents are uniform. Expose the sterile port on the infusion bag by tearing off a protective wrap covering the port.
• Access the medicinal product infusion bag and infuse per the administration site’s standard procedures for administration of cell therapy products. Do not use an in-line blood filter or an infusion pump.
• Do not sample, alter, or irradiate the medicinal product.
• Administer each infusion bag of Zynteglo via intravenous infusion over a period of less than 30 minutes. If more than one infusion bag is provided, administer each infusion bag completely before proceeding to thaw and infuse the next bag.
• Infuse Zynteglo as soon as possible and no more than 4 hours after thawing. Flush all Zynteglo remaining in the infusion bag and any associated tubing with at least 50 mL of 0.9% sodium chloride solution to ensure as many cells as possible are infused into the patient.

Precautions to be taken for the disposal of the medicinal product

The medicinal product contains genetically-modified cells. Local guidelines on handling humanderived material should be followed for unused medicinal products or waste material. All material that has been in contact with Zynteglo (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local guidelines on handling human-derived material.