CASGEVY Dispersion for infusion Ref.[108594] Active ingredients: Exagamglogene autotemcel

Casgevy must be administered in an authorised treatment centre by a physician with experience in HSC transplantation and in the treatment of patients with β-haemoglobinopathies and trained for administration and management of patients treated with the medicinal product.

Before mobilisation, apheresis and myeloablative conditioning are initiated, confirm that haematopoietic stem cell transplantation is appropriate for the patient.

Posology

Casgevy is intended for autologous use (see section 4.4).

Treatment consists of a single dose containing a dispersion for infusion of viable CD34+ cells in one or more vials.

The minimum recommended dose of Casgevy is 3 × 10⁶ CD34+ cells/kg of body weight.

See the accompanying Lot information sheet (LIS) for additional information pertaining to dose.

Mobilisation and apheresis

Patients are required to undergo CD34+ HSPC mobilisation followed by apheresis to isolate the CD34+ cells for medicinal product manufacturing.

Maximise CD34+ cell collection for product manufacturing during each mobilisation and apheresis cycle. Perform two consecutive days of cell collection for product manufacturing per cycle, if clinically tolerated. A total collection target of at least 20 × 10⁶ CD34+ cells/kg is recommended for product manufacture. Collected cells should be sent for product manufacturing even if the total collection target is not achieved. In addition, at least 2 × 10⁶ CD34+ cells/kg are required to be collected for back-up unmodified rescue cells. A third day of cell collection can be used to obtain back-up rescue cells, if needed.

If the minimum dose of Casgevy is not met after initial medicinal product manufacturing, the patient will need to undergo additional cycles of mobilisation and apheresis to obtain more cells for additional product manufacture. Each mobilisation and apheresis cycle must be separated by a minimum of 14 days.

The back-up collection of ≥2 × 10⁶ CD34+ cells/kg of unmodified rescue cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with Casgevy.

The unmodified cells may be needed for rescue treatment under any one of the following conditions: compromise of Casgevy after initiation of myeloablative conditioning and before Casgevy infusion; neutrophil engraftment failure; or loss of engraftment after infusion with Casgevy.

See section 5.1 for a description of the mobilisation regimen used in the clinical study. Refer to the Summary of Product Characteristics for the mobilisation medicinal product(s) prior to treatment with Casgevy.

β-thalassemia: Prior to apheresis procedure it is recommended that patients receive red blood cell (RBC) transfusion(s) with a goal to maintain total haemoglobin (Hb) concentration ≥11 g/dL.

Sickle cell disease: Prior to apheresis it is recommended that patients receive RBC exchange or simple transfusion(s) with a goal of maintaining haemoglobin S (HbS) levels <30% of total Hb while keeping total Hb concentration ≤11 g/dL.

Disease modifying therapies (e.g., hydroxyurea/hydroxycarbamide, crizanlizumab, voxelotor) must be discontinued 8 weeks before the planned start of mobilisation and conditioning.

Granulocyte colony stimulating factor (G-CSF) must not be administered for mobilisation in patients with sickle cell disease.

Pre-treatment conditioning

Full myeloablative conditioning must be administered before infusion of Casgevy. Conditioning must not be initiated until the complete set of vials constituting the full dose of Casgevy has been received at the authorised treatment centre, and the availability of the back-up collection of unmodified CD34+ cells is confirmed. See section 5.1 for a description of the conditioning regimen used in the clinical study. Refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product(s) prior to treatment.

β-thalassemia: It is recommended that patients maintain total Hb concentration ≥11 g/dL for 60 days prior to myeloablative conditioning.

Sickle cell disease: It is recommended that patients receive RBC exchange or simple transfusion(s) for at least the 8 weeks prior to the initiation of myeloablative conditioning with a goal of maintaining HbS levels <30% of total Hb while keeping total Hb concentration ≤11 g/dL. At initiation of red blood cell exchanges or simple transfusions, discontinue disease modifying therapies (e.g., hydroxyurea/hydroxycarbamide, crizanlizumab, voxelotor).

Iron chelation therapy must be stopped at least 7 days prior to myeloablative conditioning.

Prophylaxis for seizures should also be considered. Refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product used for information on drug interactions.

Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome should be considered, per institutional guidelines.

Prior to starting the myeloablative conditioning regimen, confirm availability of the complete set of vials constituting the dose of Casgevy, and unmodified rescue cells. See the Lot information sheet (LIS) provided with the product shipment for confirmation of the number of vials and total dose of Casgevy.

Pre-medication

It is recommended that pre-medication with paracetamol and diphenhydramine, or equivalent medicinal products, be administered per institutional guidelines, before the infusion of Casgevy, to reduce the possibility of an infusion reaction.

Special populations

Patients aged 35 years and older

Casgevy has not been studied in patients >35 years of age. The safety and efficacy of Casgevy in this population has not been established. The benefit of treatment in individual patients should be considered against the risks of HSC transplantation.

Renal impairment

Casgevy has not been studied in patients with renal impairment, defined as estimated glomerular filtration rate <60 mL/min/1.73 m². No dose adjustment is required.

Hepatic impairment

Casgevy has not been studied in patients with hepatic impairment. No dose adjustment is required.

Paediatric population

The safety and efficacy of Casgevy in patients <12 years of age have not been established. No data are available.

Patients seropositive for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)

Casgevy has not been studied in patients with HIV-1, HIV-2, HBV, or HCV. Perform screening for HIV-1, HIV-2, HBV, and HCV and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. Casgevy must not be used in patients with active HIV-1, HIV-2, HBV or HCV.

Patients with prior HSC transplant

Casgevy has not been studied in patients who have received a prior allogeneic or autologous HSC transplant. Treatment with Casgevy is not recommended in these patients.

Method of administration

Casgevy is for intravenous use only.

After completion of the myeloablative conditioning regimen, a minimum of 48 hours must elapse before Casgevy infusion. Casgevy must be administered between a minimum of 48 hours and a maximum of 7 days after the last dose of myeloablative conditioning.

Before thawing and administration, it must be confirmed that the patient’s identity matches the unique patient information on the Casgevy vial(s) and accompanying documentation. The total number of vials must also be confirmed with patient specific information on the Lot information sheet (LIS) (see section 4.4).

Casgevy is administered as an intravenous bolus via a central venous catheter. Casgevy infusion must be completed as soon as possible and no more than 20 minutes after thawing. In the event that more than one vial is provided, all vials must be administered. The entire volume of each vial must be infused.

For detailed instructions on preparation, administration, measures to take in case of accidental exposure and disposal of Casgevy, see section 6.6.

After Casgevy administration

Standard procedures for patient monitoring and management after HSC transplantation must be followed after Casgevy infusion, including monitoring of complete blood counts and transfusion needs.

Blood products required within the first 3 months after Casgevy infusion must be irradiated.

Restarting iron chelation after Casgevy infusion may be necessary. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after Casgevy infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate (see section 4.5).

Not applicable.

2 years at ≤ -135°C.

Once thawed: 20 minutes at room temperature (20°C – 25°C).

Casgevy must be stored and transported in the vapour phase of liquid nitrogen at ≤ -135°C and must remain frozen until the patient is ready for treatment to ensure viable cells are available for patient administration.

Thawed medicinal product must not be refrozen.

For storage conditions after thawing of the medicinal product, see section 6.3.

Casgevy is supplied in cryopreservation vials made of cyclic olefin copolymer. Each vial contains 1.5 ml to 20 ml of Casgevy.

Vials are packed in a paperboard carton box. Each carton may contain up to 9 vials. The final outer carton contains a variable number of vials according to the patient specific dose required.

Casgevy is shipped from the manufacturing facility to the treatment centre storage facility in a cryoshipper. One cryoshipper may contain multiple cartons, which may contain multiple vials, all intended for a single patient.

Precautions to be taken before handling or administering the medicinal product

Do not sample, alter, or irradiate the medicinal product. Irradiation could lead to inactivation of the product.

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

Receipt and storage of Casgevy

• Casgevy is shipped to the treatment centre frozen in the vapor phase of liquid nitrogen.
• Confirm patient identifiers on the product label(s) and Lot information sheet (LIS).
• Store in the vapor phase of liquid nitrogen at ≤ -135°C until ready for thaw and administration.

Preparation prior to administration

Preparation for the infusion:

• Coordinate the timing of Casgevy thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that Casgevy is available for infusion when the patient is ready, as Casgevy must be administered within 20 minutes of thawing the vial. Thaw and infuse the content of one vial at a time.
• Before thaw, confirm the patient’s identity matches the patient information on the Casgevy vial(s). Do not remove the Casgevy vials from cryo-storage if the information on the patient-specific label does not match the intended patient.
• A dose of Casgevy may be contained in one or more cryopreserved patient-specific vial(s). Account for all vials and confirm each vial is within the expiry date using the accompanying Lot information sheet (LIS).
• Inspect the vial(s) for any breaks or cracks prior to thawing. If a vial is compromised, do not infuse the contents.
• Assemble supplies needed to thaw and withdraw the product from the vial(s). With the exception of the water bath, these supplies are single use. Assemble sufficient supplies for each vial to be administered:
  • Water bath
  • Alcohol swabs
  • Vial adapter (to allow for needle-less extraction)
  • 18 micron stainless steel filter
  • 30 mL luer-lock syringe
  • Sodium chloride 9 mg/mL (0.9%) solution for injection (5 to 10 mL needed for each vial)
  • 10 mL luer-lock syringe for sodium chloride 9 mg/mL (0.9%) solution for injection rinse

Thawing the Casgevy vials:

• When the dose consists of multiple vials, thaw and administer one vial at a time. While thawing a vial, remaining vials must remain in cryo-storage at ≤ -135°C.
• Thaw each vial at 37°C using a water bath. Ensure water bath temperature does not exceed 40°C.
• Thaw each vial holding the vial neck, gently agitating clockwise and counterclockwise. This can take between 10 to 15 minutes.
• Do not leave vial unattended during thawing.
• Thawing is complete when ice crystals are no longer visible in the vial.
• Remove vial from water bath immediately once thawed.
• The thawed product should appear as a translucent cell dispersion free from foreign particles.
• Infuse within 20 minutes of thaw.
• Thawed medicinal product must not be refrozen.

Administration of Casgevy

Casgevy is for autologous use only. The patient’s identity must match the patient identifiers on the Casgevy vial(s). Do not infuse Casgevy if the information on the patient-specific label does not match the intended patient.

A patient’s dose may consist of multiple vials. All vials must be administered. The entire volume of each vial provided must be infused. If more than one vial is provided, administer each vial completely before proceeding to thaw and infuse the next vial.

Attaching the vial adapter and filter:

• Remove the flip-away tab of the vial cap; clean the septum with an alcohol swab.
• Remove the cap on the adapter spike.
• With the thumb and forefinger of both hands, push the adapter into the vial septum, applying equal pressure until you hear a single pop.
• Pull up on the adapter until you feel it lock.
• Attach the filter to the vial adapter.

Withdrawing Casgevy from the vial:

• Attach an empty 30 mL syringe to the filter.
• Withdraw the entire vial product volume.
• Remove the product-filled syringe from the filter and set aside.
• Draw 5-10 mL of sodium chloride 9 mg/mL (0.9%) solution for injection into the empty 10 mL syringe.
• Attach the sodium chloride solution-filled syringe to the filter.
• Inject the sodium chloride solution into the Casgevy vial and remove the empty syringe from the filter. Discard the empty syringe.
• Attach the product-filled syringe to the filter.
• Withdraw the contents of the vial into the product syringe, then remove the syringe from the filter.
• The optional product/patient identifier label can be peeled from the Lot information sheet (LIS) and affixed to the syringe.

Administration of Casgevy through a central venous catheter:

• Casgevy must be administered within 20 minutes of product thaw.
• Perform a two-person confirmation and verification of patient’s identification at the bedside prior to the infusion of each vial(s).
• Casgevy is administered as an intravenous bolus (intravenous push).
• The total volume of Casgevy administered within one hour must not exceed 2.6 mL/kg.
• Do not use an inline filter when infusing Casgevy.
• After administration of each vial of Casgevy, flush the primary line with sodium chloride 9 mg/mL (0.9%) solution for injection.

Repeat the steps listed above for each remaining vial.

After administration of Casgevy:

• Monitor vital signs every 30 minutes from when the first vial of Casgevy is infused until 2 hours after the last vial of Casgevy is infused.
• Standard procedures for patient management after HSC transplantation should be followed after Casgevy infusion.
• Irradiate any blood products required within the first 3 months after Casgevy infusion.
• Patients must not donate blood, organs, tissues, or cells at any time in the future.

Measures to take in case of accidental exposure

In case of accidental exposure local guidelines on handling of human-derived material must be followed. Work surfaces and materials which have potentially been in contact with Casgevy must be decontaminated with appropriate disinfectant.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all material that has been in contact with Casgevy (solid and liquid waste) must be handled and disposed of as potentially infectious waste in accordance with local guidelines on handling human-derived material.