Zalmoxis - patient leaflet, side effects, dosage

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

MolMed SpA

Via Olgettina 58

20132

Milan

Italy

MolMed SpA

Via Meucci 3

20091

Bresso (MI)

Italy

Name and address of the manufacturer responsible for batch release

MolMed SpA

Via Olgettina 58

20132

Milan

Italy

MolMed SpA Via Meucci 3 20091 Bresso (MI) Italy

The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.

CTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

• Periodic safety update reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.

The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
• Additional risk minimisation measures

Prior to launch of Zalmoxis in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational materials for the Health Care Professionals (HCPs), with the National Competent Authority.

The MAH shall ensure that in each Member State where Zalmoxis is marketed, all HCPs who are expected to prescribe, dispense, and administer Zalmoxis are provided with a guidance document containing the following key elements:

During and after treatment with Zalmoxis the physician must be aware of acute and chronic sign and symptoms of GvHD at any time and ensure that either ganciclovir or valganciclovir is available at ward for early treatment of GvHD.

If at any time during or after treatment with Zalmoxis an acute GvHD of grade equal to or greater than 2 or a chronic GvHD develop, the patient has to be treated with ganciclovir at a dose of 10 mg/kg/day divided into 2 administrations intravenously, or valganciclovir 900 mg two times per day orally for 14 days.

In case of GvHD progression after 3 days of treatment with ganciclovir or valganciclovir alone, a standard immunosuppressive therapy has to be added.

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Zalmoxis should be administered after a 24-hour discontinuation period of ganciclovir or valganciclovir and immunosuppressive therapy.

• 2. Relevant information about the safety concern of Concomitant administration of

Ganciclovir and Valganciclovir

The treating physician must ensure that patients do not receive ganciclovir or valganciclovir within 24 hours prior to the administration of Zalmoxis. A longer interval might apply in case of renal failure.

• 3. Relevant information about the safety concern of Concomitant immunosuppressive therapy

Patients should not be administered Zalmoxis in case of:

o Onset of GVHD requiring systemic immunosuppressive therapy

o Ongoing systemic immunosuppressive therapy or administration of granulocyte colony stimulating factor (G-CSF) after haploidentical hematopoietic stem-cell transplantation

Patients could be treated with Zalmoxis 24 hours after the antiviral or immunosuppressive therapy discontinuation.

Zalmoxis shall not be administered to patients with concurrent systemic immunosuppressive therapy as the efficacy of Zalmoxis treatment in early immune reconstitution may be reduced.

Immunosuppressive therapy also affects immunocompetent cells as such infused with Zalmoxis. An adequate wash-out period shall be applied prior to infusion of this medicinal product.

• 4. Remarks on the importance of reporting ADRs and encourage patients to be enrolled into study TK011 (linked with the EBMT registry)

• 5. A Detailed step-by step description of Zalmoxis administration procedure, also focusing on:

o The room requirements for Zalmoxis administration

o Storage, transport and thawing of Zalmoxis bag

o Surveillance of Zalmoxis efficacy (Immune reconstitution – IR)

To monitor IR, the quantification analyses of CD3+ cells should be performed weekly during the first month after Zalmoxis administration. In absence of IR, an additional Zalmoxis dose has to be administered with an interval of 30 days up to a maximum number of four doses. In case of IR achievement, documented by two consecutive CD3+ cell counts > 100/pL, Zalmoxis treatment has to be stopped.

Obligation to complete post-authorisation measures

Description

Due date

Non Interventional PASS: In order to investigate the safety and effectiveness in real clinical practice as well as long-term safety and effectiveness in all patients treated with Zalmoxis, the MAH should conduct and submit the results of study TKOLlUsing the EBMT registry including all patients treated with Zalmoxis. Progress updates should be submitted yearly with the annual renewal. The clinical study report should be submitted by Q4 2022.

Q4 2022

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION

This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures:

Description Kp

Due date

The MAH shall complete, within the stated timeframe, the below measures: In order to confirm the efficacy and safety of Zalmoxis as an adjunctive treatment in haploidentical haematopoietic stem-cell transplantation of adult patients with high-risk haematological malignancies, the MAH should submit the results of study TK008, a randomized phase III trial of haploidentical HCT with an add back strategy of HSV-Tk donor lymphocytes in patients with high risk acute leukaemia. In addition updates on recruitment should be submitted within the PSURs. The clinical study report should be submitted by March 2021.

March 2021

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX

1. NAME OF THE MEDICINAL PRODUCT

Zalmoxis 5–20 × 10 cells/mL dispersion for infusion

Allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor (ALNGFR) and herpes simplex I virus thymidine kinase (HSV-TK Mut2)

Intravenous use

Read the package leaflet before use.

EXP:

Shelf life after thawing: 2 hours at room temperature (15 °C – 30 °C)

• 9. SPECIAL STORAGE CONDITIONS

Store in liquid nitrogen vapour.

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

This medicinal product contains genetically-modified cells. Local biosafety guidelines applicable for such products should be followed for unused medicinal product or waste material.

• 15. INSTRUCTIONS ON USE

• 16. INFORMATION IN BRAILLE

Justification for not including Braille accepted

• 17. UNIQUE IDENTIFIER – 2D BARCODE

Not applicable

• 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

  Not applicable

  
  
  
  

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

PLASTIC BAG

1. NAME OF THE MEDICINAL PRODUCT

Zalmoxis 5–20 × 10 cells/mL dispersion for infusion

Allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor (ALNGFR) and herpes simplex I virus thymidine kinase (HSV-TK Mut2)

Intravenous use

Read the package leaflet before use.

EXP:

Shelf life after thawing: 2 hours at room temperature (15 °C – 30 °C)

• 9. SPECIAL STORAGE CONDITIONS

Store in liquid nitrogen vapour.

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

This medicinal product contains genetically-modified cells. Local biosafety guidelines applicable for such products should be followed for unused medicinal product or waste material.

• 15. INSTRUCTIONS ON USE

Not applicable

• 16. INFORMATION IN BRAILLE

Justification for not including Braille accepted

• 17. UNIQUE IDENTIFIER – 2D BARCODE

Not applicable

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

BAG

• 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Zalmoxis 5–20×106 cells/mL dispersion for infusion Intravenous use

• 2. METHOD OF ADMINISTRATION

Package leaflet: Information for the patient

Zalmoxis 5–20 × 106 cells/mL dispersion for infusion

Allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor (ALNGFR) and the herpes simplex I virus thymidine kinase (HSV-TK Mut2)

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, or a physician experienced in the medical

treatment of blood cancer.

• – If you get any side effects, talk to your doctor, or a physician experienced in the medical

treatment of blood cancer. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Zalmoxis is and what it is used for

• 2. What you need to know before you are given Zalmoxis

• 3. How Zalmoxis is given to you

• 4. Possible side effects

• 5. How to store Zalmoxis

• 6. Contents of the pack and other information

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1. WHAT ZALMOXIS IS AND WHAT IT IS USED FOR

Zalmoxis consists of white blood cells called T cells that are obtained from the donor. These cells will be genetically modified by introducing a “suicide” gene (HSV-TK Mut2) in their genetic code which can be activated later on in case of graft-versus-host disease. This will ensure that the cells can be eliminated before they can cause damage to the patient’s cells.

Zalmoxis is intended for use in adults with certain tumours of the blood known as high-risk haemotological malignancies. It is given after haploidentical bone marrow transplantation (haematopoietic cell transplantation). Haploidentical means that the cells have been obtained from a donor whose tissues partially match the patient's tissue. Zalmoxis is given to prevent a complication of transplantations that are not fully matched known as ‘graft-versus-host disease’ whereby the cells of the donor attack the patient’s own ce­lls.

• – If you suffer from graft-versus-host disease which requires the use of medicines to suppress

your immune system.

Warnings and precautions

Zalmoxis is a patient specific product and should under no circumstances be administered to other patients.

Your doctor will closely supervise the treatment therapy. You should tell your doctor before using Zalmoxis if:

You suffer from infections requiring administration of ganciclovir (GCV) or valganciclovir (VCV) (antiviral) at the time of infusion. In this case treatment with Zalmoxis should be delayed until 24 hours after the end of the antiviral therapy.

You suffer from graft-versus-host disease which requires the use of medicines to suppress your immune system.

If you are taking medicines to suppress your immune system or you are taking G-CSF (that stimulates the bone marrow to produce blood cells) after receiving stem-cell transplantation. In this case, Zalmoxis may be administered after an adequate wash out period (the time necessary to remove a medicine from your body).

If you have previously experienced any adverse reaction following Zalmoxis administration and this has not been resolved within 30 days after its occurrence.

When Zalmoxis cannot be given

In some cases you may not be able to receive a scheduled i of manufacturing issues.

In such cases your physician will be informed and may still consider preferable to give the treatment or may select an alternative treatment for you.

Children and adolescents

Currently, no data are available for these patients. The use of Zalmoxis is not recommended for children and adolescents under the age of 18.

Other medicines and Za

No interaction studies have been performed.

Please inform your doctor if you are taking, have recently taken or might take any other medicines.

Pregnancy and breast-feeding

The safe use of Zalmoxis has not been demonstrated during pregnancy and breast-feeding.

Zalmoxis must not be used in pregnant and breast-feeding women.

Women of childbearing potential have to use effective contraception during and up to 6 months after treatment with Zalmoxis.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Driving and using machines

Zalmoxis should not have any effects on your ability to drive and use machines. However, you should pay attention to your overall status when considering performing tasks that require judgment, motor or cognitive skills.

Zalmoxis contains sodium

Zalmoxis 5–20 × 106 cells/mL cell dispersion for infusion contains 13.3 mmol (305.63 mg) of sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

• 3. HOW ZALMOXIS IS GIVEN TO YOU

Zalmoxis can only be prescribed and administered in a hospital by a doctor or a nurse who is trained in administering this medicine. Practical information for handling and administration of Zalmoxis for the doctor or nurse can be found at the end of this leaflet.

Zalmoxis has been manufactured specifically for you and cannot be administered to any other patient. The amount of cells to be administered depends on your body weight. The dose corresponds to 1 ± 0.2 × 107 cells/kg.

Zalmoxis is given intravenously (into a vein) as a drip infusion over approximately 20–60 minutes at a time interval of 21–49 days from transplantation. Additional infusions are given once a month, for up to 4 months. The decision to proceed with the next treament is determined by your physician/doctor and is related to your immune status.

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If you receive more Zalmoxis than you should

As this medicine is prescribed by a doctor, each dose is prepared for you only and each preparation consists of a single dose. It is unlikely that you will be given too much.

If you forget to use Zalmoxis

This medicine is prescribed by a doctor and given in a hospital under strict survelliance and predetermined schedule so that you cannot forget your dose.

If you have any further questions on the use of this medicine, ask your doctor.

• 4. POSSIBLE SIDE EFFE

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these side effects may be serious and may lead to hospitalization.

If you have any questions about symptoms or side effects, or if any symptoms concern you

^ Talk immediately to your doctor.

Very common side effects (may affect more than 1 in 10 people)

Acute graft-versus-host disease (a complication that can occur after a stem-cell or bone marrow transplantation in which the newly transplanted donor cells attack the patient’s body).

Common side effects (may affect up to 1 in 10 people)

• – Post-transplantation lymphoproliferative disorder (increase in the number of white blood cells in

the blood after a transplantation)

• – Chronic graft-versus-host disease (a complication that can occur after a stem-cell or bone

marrow transplantation in which the newly transplanted donor cells attack the patient’s body)

• – Intestinal haemorrage (bleeding in the gut)

• – Hepatic failure (liver malfunction)

• – Febrile neutropenia (fever associated with reduction of the number of white blood cells)

• – Decreased haemoglobin (reduction of the number of red blood cells)

• – Decreased platelet count (reduction of the number of platelets in the blood)

• – Bronchitis (lung infection)

• – Pyrexia (fever)

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. HOW TO STORE ZALMOXIS

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the container. The expiry date refers to the last day of that month.

Store in liquid nitrogen vapour.

The infusion solution should be used immediately after thawing. Maximum time elapsed from thawing and infusion is 2 hours at room temperature (15 °C – 30 °C).

The package is checked for the presence of any abnormality in the outer box and the label is checked for patient/donor correspondance.

Any unused medicine or waste should be disposed of as biological hazard material containing genetically modified organisms and in accordance with local requirements.

The hospital staff are responsible for the correct storage of the product both before and during its use, as well as for correct disposal.

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6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Zalmoxis contains

The active substance consists of allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor (ALNGFR) and the herpes simplex I virus thymidine kinase (HSV-TK Mut2).

Each bag contains a volume of 10–100 mL of frozen dispersion at a concentration of 5–20 × 106 cells/mL.

The other ingredients are sodium chloride, human serum albumin and dimethyl sulfoxide (see section 2).

What Zalmoxis looks like and contents of the pack

Zalmoxis is a cell dispersion for infusion appearing as opaque, off-white frozen dispersion of cells.

Zalmoxis is supplied as one individual treatment dose in a 50–500 mL ethylene-vinyl-acetate cryo bags.

Marketing Authorisation Holder

MolMed SpA

Via Olgettina 58 20132 Milano

Italy

Tel +39–02–212771

Fax +39–02–21277220

Manufacturers

MolMed SpA Via Olgettina 58 20132 Milano

Italy

MolMed SpA

Via Meucci 3 20091 Bresso (MI) Italy

This leaflet was last revised in

This medicine has been given ‘conditional approval’. This me about this medicine.

The European Medicines Agency will review new info this leaflet will be updated as necessary.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:. There are also links to other websites about rare diseases and treatments.

The following infor ation is intended for healthcare professionals only:

Practical information for medical or healthcare professionals on the handling and administration of Zalmoxis.

Zalmoxis must be administered under the supervision of a physician experienced in haematopoietic stem cell transplantation for haematological malignacies.

It is important that you read the entire content of this procedure prior to administering Zalmoxis.

Dose and course of treatment

One bag contains donor T cells genetically modified to express HSV-TK and ALNGFR at the concentration of 5–20 × 106 cells/mL.

The course of treatment is a maximum of four infusions at approximately one month intervals. The decision to proceed with a new treatment depends on the immune reconstitution status of the patient achieved when a circulating T lymphocyte count is equal to or more than 100 per ^L.

Handling instructions

Before handling or administering Zalmoxis

• Zalmoxis is shipped directly to the medical facility where the infusion will be administered. The shipping is performed in liquid nitrogen vapour. The bag is put in a second bag (intermediate container) and this one is placed in an aluminium box (outer container). The whole package is secured in a liquid nitrogen container designed to maintain the appropriate transportation and storage temperature until the time of infusion. If the medicinal product is not immediately prepared for infusion, transfer the bag in liquid nitrogen vapour. Do not irradiate.
• Zalmoxis is prepared from human blood of a specific donor and it consists of genetically modified cells. Donors are tested for transmissible infectious agents in line with applicable local requirements. However, the risk of transmitting infectious viruses to healthcare professionals cannot be totally excluded. Accordingly, healthcare professionals should take appropriate precautions (e.g. wearing gloves and glasses) when handling Zalmoxis.
• The outer and intermediate package should be checked to verify the product and patient-specificlabel located on the top of the box and on the intermediate bag.

What to check before infusion

• Check that the Certificate of Analysis containing the patient identifiers, expiry date and approval for infusion has been received from the Marketing Authorization Holder.
• Check that the patient identity matches the essential and unique patient information reported on the Zalmoxis bag and on the Certificate of Analysis.
• Once the patient is prepared for infusion, inspect the Zalmoxis bag for integrity. The bag should appear as an opaque, off-white frozen cell dispersion. If the bag appears to have clear breaks or to be non-intact, do not use the product.
• Put the bag into two plastic envelopes (double envel t) to avoid direct contact with water.
• While holding the top of the envelope bag out of the water, put it in a 37±1°C water bath being careful not to allow water to penetrate the seal. If leakage occurs during thawing, do not use the product.

Administration

• When completely thawed, remove and disinfect the outside.
• Proceed with the infusion as quick

g must be infused. The recommended infusion time is around 20–60

After the infusion

• At the end of infusion, wash the bag 2 or 3 times with a physiological solution using a sterile technique, in order to completely administer Zalmoxis.
• Upon completion of washing, the patient specific label on the bag should be removed and adhered to the patient specific file.
• The cryobag and any unused product or waste material contains genetically modified organisms and should be disposed of in accordance with local requirements.

Do not infuse Zalmoxis if

• You have not received the Certificate of Analysis.
• The Certificate of Analysis is marked as rejected.
• The expiry date has passed.
• The unique patient information on the infusion bag does not match that of the scheduled patient.
• The product integrity has been breached in anyway.

Shelf life and special precautions for storage

• Zalmoxis has a shelf life of 18 months when stored in liquid nitrogen vapour.

Zalmoxis must be used be immediately after removal from the shipping container. If not used immediately, transfer the Zalmoxis bag from the shipping container to liquid nitrogen vapour. Shelf life after thawing is of 2 hours.

Annex IV

Conclusions on the granting of the conditional marketing authorisation and similarity presented by the European Medicines Agency

Conclusions presented by the European Medicines Agency on:

• Conditional marketing authorisation

The CHMP having considered the application is of the opinion that the risk-benefit balance is favourable to recommend the granting of the conditional marketing authorisation as further explained in the European Public Assessment Report.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

OTHER SPECIAL WARNING(S), IF NECESSARY

Patient specific product not to be administered to other patients

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

OTHER SPECIAL WARNING(S), IF NECESSARY

Patient specific product not to be administered to other patients

WHAT YOU NEED TO KNOW BEFORE YOU ARE GIVEN ZALMOXIS

Do not use Zalmoxis:

– If you are allergic to the active substance or any of the ingredients of this medicine (listed in

section 6).

– If, before infusion, the value of CD3+ lymphocytes in your tests is equal to or more than 100 per

^L.