Zalmoxis

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zalmoxis 5-20 x 106 cells/mL dispersion for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

2.1 General description 

 

Allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the 

human low affinity nerve growth factor receptor (ΔLNGFR) and the herpes simplex I virus thymidine 

kinase (HSV-TK Mut2). 

 

2.2 Qualitative and quantitative composition 

 

Each bag of Zalmoxis contains a volume of 10-100 mL of frozen dispersion at the concentration of 

5-20 x 106 cells/mL. The cells are of human origin and genetically modified with a replication-

defective γ-retroviral vector coding for the HSV-TK and ΔLNGFR genes so that these sequences are 

integrated in the genome of the host cells. 

 

The cellular composition and the final cell number will vary according to the weight of the patient. In 

addition to T cells, NK cells and residual levels of monocytes and of B cells may be present. 

 

Excipient with known effect 

 

Each bag contains approximately 13.3 mmol (305.63 mg) of sodium per dose. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Dispersion for infusion. 

Opaque, off-white frozen dispersion. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Zalmoxis is indicated as adjunctive treatment in haploidentical haematopoietic stem cell 

transplantation (HSCT) of adult patients with high-risk haematological malignancies (see section 5.1). 

 

4.2 Posology and method of administration 

 

Zalmoxis must be administered under the supervision of a physician experienced in HSCT for 

haematological malignancies.  

 

Posology 

The recommended dose and schedule is 1 ± 0.2 x 107 cells/kg given as an intravenous infusion at a 

time interval of 21-49 days from transplantation, in the absence of spontaneous immune reconstitution 

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and/or development of graft-versus-host disease (GvHD). Additional infusions are administered at 

approximately one month intervals for a maximum of four times, until a circulating T lymphocyte 

count is equal to or more than 100 per µL. 

 

Zalmoxis should not be administered if the circulating T lymphocytes are ≥100 per μL at the day of 

planned infusion after haploidentical HSCT. 

 

Paediatric population 

The safety and efficacy in children and adolescents (less than 18 years) have not been established. No 

data are available. Zalmoxis is therefore not recommended for use in children and adolescent below 18 

years. 

 

Method of administration 

Zalmoxis is solely for use as patient specific medicinal product to be administered after HSCT and it is 

administered by intravenous infusion. 

 

Zalmoxis should be infused intravenously over a period of 20-60 minutes. The entire volume of the 

bag should be infused. 

 

If the infusion must be interrupted, it should not be resumed if the infusion bag has been held at room 

temperature (15 °C-30 °C) for more than 2 hours. 

 

Precautions to be taken before handling or administering the medicinal product 

Before infusion it must be confirmed that the patient identity matches the essential unique information 

reported on the Zalmoxis bag label and on the related Certificate of Analysis (CoA). 

 

The bag should be removed from the liquid nitrogen, put in a double bag container and thawed in a 

pre-warmed water bath at 37 °C. Upon full cell dispersion thawing, the bag is dried, disinfected and 

ready to be infused at a rate prescribed by the physician. Once the bag is infused, it is flushed 2 to 3 

times with sodium chloride solution in order to completely administer Zalmoxis. The entire volume of 

the bag has to be infused. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

Immune reconstitution defined as circulating T lymphocytes ≥100 per μL at the day of planned 

infusion after haploidentical HSCT. 

 

GvHD requiring systemic immunosupressive therapy. 

 

4.4 Special warnings and precautions for use 

 

General 

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

patients. It must not be administered if the following conditions occur: 

a) infections requiring administration of ganciclovir (GCV) or valganciclovir (VCV) at the time 

of infusion; 

b) GvHD requiring systemic immunosupressive therapy; 

c) ongoing systemic immunosupressive therapy or administration of granulocyte colony 

stimulating factor (G-CSF) after haploidentical HSCT. 

 

Patients characterized by condition a) could be administered Zalmoxis 24 hours following the antiviral 

therapy discontinuation; patients characterized by conditions b) and c) could be administered Zalmoxis 

after an adequate wash out period.  

 

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Zalmoxis 5-20 x 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. 

 

It is strongly recommended that, at the end of Zalmoxis infusion, the product label is removed from 

the bag and placed in the patient record sheet. 

 

Treatment should be discontinued in case of occurrence of any 3-4 grade event related to Zalmoxis 

administration or grade 2 adverse event not resolving in a grade 1 or less in the next 30 days. 

 

Zalmoxis is obtained by donor blood cells. Even if donors are preliminary tested and found negative 

for transmissible infectious disease, precautions should be employed when handling Zalmoxis. 

Healthcare professionals handling Zalmoxis should therefore take appropriate precautions (wearing 

gloves and glasses) to avoid potential transmission of infectious diseases. 

 

Cases in which Zalmoxis cannot be supplied / infused 

In some cases, the patient may be unable to receive Zalmoxis because of manufacturing issues.  

 

There may be cases in which the treating physician may still consider preferable to give the treatment 

or select an alternative treatment.  

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

No interaction studies have been performed. 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential / Contraception in males and females 

The risk on virus shedding vertical viral transmission is theoretically negligible however not excluded.  

Women of childbearing potential have to provide a negative pregnancy test (serum or urine) within 14 

days prior to start the treatment. Both male and female patients (to be) treated with Zalmoxis and their 

partners need to use effective contraception during and up to 6 months after treatment with Zalmoxis. 

 

Pregnancy 

There are no data from the use of Zalmoxis in pregnant women. 

Studies in animals have not been performed. Given the intended clinical use in the context of a 

haploidentical bone marrow transplantation, a need for treatment during pregnancy is not expected. 

As a precautionary measure, Zalmoxis must not be administered during pregnancy and in women of 

childbearing potential not using contraception. 

 

It has been shown that Zalmoxis cells may circulate for years after the last administration. In the event 

of pregnancy following Zalmoxis treatment adverse effect on pregnancy and the developing foetus are 

not expected as lymphocytes do not pass the placenta. 

 

Breast-feeding 

There are no data on the use of Zalmoxis during breast-feeding. Immune cells are excreted in human 

milk in low amounts. 

It is recommended not to breast-feed during or after treatment with Zalmoxis therapy. 

 

Fertility 

There are no data on the effect of Zalmoxis treatment on fertility. However myeloablative 

conditioning regimens performed in the context of a haploidentical bone marrow transplantation is 

associated with sterility. 

 

4.7 Effects on ability to drive and use machines 

 

Zalmoxis has no or negligible influence on the ability to drive and use machines. 

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No detrimental effects on such activities are predicted from the pharmacology of the medicinal 

product. The clinical status of the patient and the ADR profile of Zalmoxis should be born in mind 

when considering the patient’s ability to perform tasks that require judgement, motor or cognitive 

skills. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

In the clinical study TK007, 30 patients with high-risk haematological malignancies undergoing 

HSCT received Zalmoxis monthly up to a maximum of four infusions. 

The most common adverse reaction reported by patients treated with Zalmoxis in clinical trial TK007 

was acute GvHD.  

 

Tabulated list of adverse reactions 

Undesirable effects recorded in the clinical study TK007 are listed in Table 1 by system organ class 

and by frequency of occurrence. 

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 

 

Table 1. Zalmoxis adverse reactions recorded in TK007 study 

System Organ Class 

Frequency and Adverse reactions 

Very common 

(≥ 1/10) 

Common 

(≥ 1/100 to < 1/10) 

Neoplasm benign, malignant and 

unspecified (including cysts and 

polyps) 

 

Post transplant 

lymphoproliferative 

disorder 

Immune system disorders 
Acute GvHD (33% of 

patients) 
Chronic GvHD 

Gastrointestinal disorders  Intestinal haemorrhage 

Hepatobiliary disorders  Hepatic failure 

Blood and lymphatic system disorders  

Febrile neutropenia 

Haemoglobin decreased 

Platelet count decreased 

Infections and infestations  Bronchitis 

General disorders and administration 

site conditions 
 Pyrexia 

 

Description of selected adverse reactions 

Globally, acute episodes of GvHD occurred in 10 patients (33%) with a median time to onset of 90 

days after HSCT and 42 days after last infusion of Zalmoxis cells. Severity of acute GvHD was grade 

1 in one case (3%), grade 2 in seven (23%), grade 3 in one (3%) and grade 4 in one (3%). All acute 

GvHD events fully resolved after a median duration of 12 days. Only one patient (3%) developed an 

extensive chronic GvHD that occurred 159 days and 129 days from HSCT and last infusion, 

respectively, and fully resolved after 107 days. There were no GvHD-related deaths or long-term 

complications. Both acute and chronic GvHD events developed only in patients who had achieved 

immune reconstitution. 
For treating Zalmoxis-related GvHD through activation of the suicide gene, patients received GCV 

intravenously or VCV orally, for better patient convenience. All signs and symptoms of grade 2 to 4 

acute and extensive chronic GvHD fully resolved after a median treatment duration of GCV or VCV 

of 15 days. One patient with grade 1 acute GvHD did not receive any treatment. Seven patients needed 

to add an immunosuppressive treatment consisting of steroids, mycophenolate and/or cyclosporine. 

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Paediatric population 

No specific paediatric group has been studied at present. Only one 17-year-old male, affected by T 

lymphoblastic lymphoma, was treated in the TK007 trial with two infusions of Zalmoxis. No adverse 

reactions were reported for this patient. 

 

Other special populations 

In the TK007 clinical study only one 66-year-old female was treated with one infusion of Zalmoxis. 

The patient did not experience any adverse reactions. No implications on the use of Zalmoxis in 

patients of 65 and older have been established. 

 

Reporting of suspected adverse reactions  

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions the national reporting system 

listed in Appendix V. 
 

4.9 Overdose 

 

Symptoms of overdose are not known. In case of overdose, patients should be closely monitored for 

signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted immediately.  

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: not yet assigned 

 

Mechanism of action 

The primary mechanism of action of Zalmoxis relies on its ability to engraft and stimulate immune-

reconstitution.  

Zalmoxis is constituted of donor’s T lymphocytes genetically modified to express the HSV-TK Mut2, 

as suicide gene. This allows the selective killing of dividing cells upon administration of the pro-drug 

GCV, which is enzymatically phosphorylated to an active triphosphate analogue by HSV-TK. 

Triphosphate GCV competitively, inhibits incorporation of deoxyguanosine triphosphate (dGTP) into 

elongating DNA, thus killing the proliferating cells. 

If GvHD occurs, GCV/VCV will be administered. The activated, transduced T lymphocytes that are 

causing the GvHD should convert the GCV to its toxic form and thereby undergo apoptosis. This 

strategy allows the direct targeting of those T lymphocytes that are initiating the GvHD response. 

 

Pharmacodynamic effects 

Overall, in the clinical study TK007, the 30 treated patients received their first infusion of Zalmoxis 

cells at a median time of 43 days from the date of HSCT. The median interval time between the first and 

the subsequent infusions of Zalmoxis cells was 30 days. 

Immune-reconstituted patients reached a CD3+ cell count ≥ 100/μL at a median of 77 days after HSCT.  

In particular, at immune reconstitution Zalmoxis represents a high proportion of the circulating 

lymphocytes, while at later time points the proportion of Zalmoxis progressively decreases and 

untransduced lymphocytes expand from donor-derived precursors. One year post-Zalmoxis 

administration the newly reconstituted T cell repertoire is dominated by untransduced cells of donor 

origin which displayed a polyclonal pattern comparable to healthy individuals.  

 

Clinical efficacy and safety 

Zalmoxis was evaluated in a phase I/II clinical study (TK007) in adult patients with haematological 

malignancies at high risk of relapse who have received a stem-cell transplantation from a human 

leukocyte antigen (HLA) mismatched (haploidentical) donor. High-risk haematological malignancies 

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treated with Zalmoxis included acute myeloid leukaemia (AML), secondary AML, acute 

lymphoblastic leukaemia, myelodysplastic syndrome and non-Hodgkin lymphoma. 

Treatment plan consisted of the administration of genetically modified donor’s T lymphocytes 

(ranging from 1 x 106 to 1 x 107 cells/kg body weight). Primary aims of the TK007 study were to 

evaluate incidence and time to immune reconstitution, defined by the number of circulating CD3+ ≥ 

100/μL for two consecutive observations, and incidence of GvHD and response to GCV. Criteria for 

receiving Zalmoxis infusions included the lack of both immune reconstitution and GvHD. 

 

Of 30 patients receiving Zalmoxis, 23 patients (77%) obtained immune reconstitution, with a median 

time of 31 days after the first infusion. For the patients who achieved immune reconstitution, a non-

relapse mortality (NRM) of 17% was reported, with 35% of these patients being disease free at 5 years 

and 34% alive at 10 years. 

 

Results from a matched-pair analyses that included 36 Zalmoxis patients (22 from TK007 trial and 14 

from the ongoing phase III TK008 trial) and 127 control patients, showed that the Zalmoxis treated 

patients that had survived the first 3 weeks post-transplant without relapse benefited in terms of 1 year 

overall survival (OS) (40% vs 51% (p=0.03)) and 1-year NRM (42% vs 23% (p=0.04)). There was no 

significant difference regarding leukaemia free survival and the chance for relapse. 

 

Paediatric population 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

Zalmoxis in one or more subsets of the paediatric population in the following condition: adjunctive 

treatment in haematopoietic cell transplantation (see section 4.2 for information on paediatric use). 

 

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This 

means that further evidence on this medicinal product is awaited. 

 

The European Medicines Agency will review new information on this medicinal product at least every 

year and this SmPC will be updated as necessary. 

 

5.2 Pharmacokinetic properties 

 

The nature and the intended use of the product are such that conventional studies on pharmacokinetics 

including absorption, distribution, metabolism and excretion are not applicable. 

 

5.3 Preclinical safety data 

 

Conventional toxicology, carcinogenicity, mutagenicity and reproductive toxicology studies have not 

been performed. 

Non clinical safety data obtained in two different immunedeficient animal models for GvHD did not 

indicate special hazards for humans, but allowed only a very limited safety assessment. In vitro 

evaluation of oncological potential indicate that the risk of malignant transformation is low.  

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Sodium chloride 

Human serum albumin 

Dimethyl sulfoxide 

 

6.2 Incompatibilities 

 

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In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 

products. 

 

6.3 Shelf life 

 

18 months when stored in liquid nitrogen vapour. 

 

The product should be administered immediately after thawing. In-use storage times and conditions 

should not exceed 2 hours at room temperature (15 °C – 30 °C). 

 

6.4 Special precautions for storage 

 

Store in liquid nitrogen vapour.  

 

6.5 Nature and contents of container and special equipment for use, administration or 

implantation 

 

One individual treatment dose in 50-500 mL ethylene-vinyl-acetate cryo bag, inside a plastic bag and 

then a metal box. 

 

6.6 Special precautions for disposal and other handling 

 

Zalmoxis is a patient specific medicinal product. The identity of the patient must be matched with the 

essential unique donor information prior to infusion. 

 

Zalmoxis is obtained by donor blood cells. Even if donors are preliminary tested and found negative 

for transmissible infectious disease, precautions should be employed when handling Zalmoxis (see 

section 4.4).  

 

This medicinal product contains genetically-modified cells. Local biosafety guidelines applicable for 

such products should be followed for unused medicinal product or waste material. 

 

Work surfaces and material which have potentially been in contact with Zalmoxis must be 

decontaminated with appropriate disinfectant. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

MolMed S.p.A. 

Via Olgettina 58 

20132 Milano 

Italy 

+39-02-212771 

+39-02-21277220 

e-mail: info@molmed.com 

 

 

8. MARKETING AUTHORISATION NUMBER 

 

EU/1/16/1121/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

 

10. DATE OF REVISION OF THE TEXT 

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Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

  

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ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE CONDITIONAL MARKETING AUTHORISATION 
 

 

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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. 

 

B. CONDITIONS OR RESTRICTIONS 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 

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• 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: 

1. Relevant information about the safety concerns of Graft versus Host Disease (GvHD) 

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. 

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. 

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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)

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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/µL, 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 TK011 using 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 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 

 

  

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ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  

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A. LABELLING 

  

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER BOX 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zalmoxis 5-20 x 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 (ΔLNGFR) and herpes simplex I virus thymidine 

kinase (HSV-TK Mut2) 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

The bag contains a volume of 10-100 mL of frozen dispersion at a concentration of 5-20 x 106 

cells/mL 

 

 

3. LIST OF EXCIPIENTS 

 

Human serum albumine, dimethyl sulphoxide, sodium chloride.  

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Dispersion for infusion 

Bag volume:___________mL  

Dose: 1x107 cells /kg  

Concentration: _____x10x cells/mL 

Total cell number: _____x10X  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Intravenous use 

Read the package leaflet before use. 

 

 

6. 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. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

Patient specific product not to be administered to other patients 

 

 

8. EXPIRY DATE 

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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. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

MolMed S.p.A. 

Via Olgettina 58 

20132 Milano 

Italy 

 

 

12. MARKETING AUTHORISATION NUMBER 

 

EU/1/16/1121/001 

 

13. BATCH NUMBER, DONATION AND PRODUCT CODES 

 

Batch: 

Patient code:  

Donor code:  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

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 

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Not applicable 

 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

PLASTIC BAG 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zalmoxis 5-20 x 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 (ΔLNGFR) and herpes simplex I virus thymidine 

kinase (HSV-TK Mut2) 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

The bag contains a volume of 10-100 mL of frozen dispersion at a concentration of 5-20 x 106 

cells/mL 

 

 

3. LIST OF EXCIPIENTS 

 

Human serum albumine, dimethyl sulphoxide, sodium chloride.  

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Dispersion for infusion 

Bag volume:___________mL  

Dose: 1x107 cells /kg  

Concentration: _____x10x cells/mL 

Total cell number: _____x10X   

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Intravenous use 

Read the package leaflet before use. 

 

 

6. 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. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

Patient specific product not to be administered to other patients 

 

 

8. EXPIRY DATE 

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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. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

MolMed S.p.A. 

Via Olgettina 58 

20132 Milano 

Italy 

 

 

12. MARKETING AUTHORISATION NUMBER 

 

EU/1/16/1121/001 

 

13. BATCH NUMBER, DONATION AND PRODUCT CODES 

 

Batch:  

Patient code:  

Donor code:  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

Not applicable 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

Not applicable 

 

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18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

Not applicable 

 

  

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

BAG 

 

 

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

 

Zalmoxis 5-20x106 cells/mL dispersion for infusion  

Intravenous use 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

Expiry date:  

Shelf life after thawing: 2 hours 

 

 

4. BATCH NUMBER, DONATION AND PRODUCT CODES 

 

Batch:  

Patient code: 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

Total cell number: ____x10X  

 

 

6. OTHER 

 

MolMed SpA 

 

 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the patient 

 

Zalmoxis 5-20 x 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 (ΔLNGFR) 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 

 

 

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.  

 

 

2. 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 

μL. 

 

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- 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 infusion of Zalmoxis. This may be because 

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 Zalmoxis 

 

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 

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Zalmoxis 5-20 x 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 

x 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. 

 

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 EFFECTS 

 

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) 

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- 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. 

 

 

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 (ΔLNGFR) 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 x 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  

 

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MolMed SpA 

Via Olgettina 58 

20132 Milano 

Italy 

Tel +39-02-212771 

Fax +39-02-21277220 

info@molmed.com 

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 means that there is more evidence to come 

about this medicine. 

The European Medicines Agency will review new information on this medicine at least every year and 

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: 

http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

--------------------------------------------------------------------------------------------------------------------------- 

The following information 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 ΔLNGFR at the 

concentration of 5-20 x 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 µL.  

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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-specific-

label 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 envelopment) 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 the Zalmoxis bag out from the double envelopment, dry it off 

and disinfect the outside. 

• Proceed with the infusion as quickly as possible, avoiding keeping the bag in the water bath after 

thawing. 

• The entire volume of the bag must be infused. The recommended infusion time is around 20-60 

minutes 

 

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. 

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• 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. 
  

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Annex IV 

Conclusions on the granting of the conditional marketing authorisation and similarity 

presented by the European Medicines Agency 

 

 

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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. 

 

 

 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET
	Conclusions on the granting of the conditional marketing authorisation and similarity presented by the European Medicines Agency