ZEMCELPRO Dispersion for infusion Ref.[116219] Active ingredients:

Traceability

The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability, the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the medicinal product.

Transmission of an infectious agent

A risk of transmission of infectious agents exists. Virus testing performed on cord blood units are human immunodeficiency virus (HIV) 1 and HIV 2, hepatitis B and hepatitis C, human T-cell lymphotropic virus (HTLV) I and HTLV II, syphilis and cytomegalovirus (CMV). Specific viruses from the mother may be documented as part of the medical history, such as transmissible spongiform encephalopathy (TSE), Epstein-Barr virus (EBV), toxoplasma, hepatitis E (HEV) and malaria. Cord banks also document if the infant is free of any finding suggestive of disease potentially transmissible through administration of a cord blood unit.

Test results may be found on the accompanying product documentation.

Healthcare professionals administering Zemcelpro must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.

Blood, organ, tissue and cell donation

Patients treated with Zemcelpro must not donate blood, organs, tissues or cells.

Hypersensitivity reactions Serious hypersensitivity reactions, including anaphylaxis, may be due to ingredients contained in Zemcelpro, e.g., DMSO. Reactions should be treated appropriately in accordance with institutional guidelines.

Infections

Serious infections, including life-threatening or fatal infections occurred in patients after Zemcelpro infusion (see section 4.8). Median onset was 109 days post-transplant, with some late events (ranging 0-945). Patients should be informed of the importance of a prompt notification of signs of infection to their treating physician. Patients should be monitored for signs and symptoms of infection, using appropriate diagnostic tests, and treated appropriately in accordance with institutional guidelines. As appropriate, prophylactic antibiotics should be administered, and surveillance testing should be employed prior to and after treatment with Zemcelpro (see section 4.2).

Graft-vs-Host disease

Fatal and life-threatening events of acute and chronic Graft-vs-Host Disease (GvHD) have occurred following treatment with Zemcelpro (see section 4.8). GvHD following treatment with Zemcelpro do not differ from standard allogeneic stem cell transplant, with a median onset at 40 days post-transplant, and 93% of them resolving in a median of 18 days. It is recommended that patients be monitored for evidence of GvHD and appropriately treated in accordance with institutional guidelines. Prophylactic and supportive care should be considered following treatment with Zemcelpro. Tacrolimus and mycophenolate mofetil combination is the preferred GvHD prophylaxis (see section 4.2).

Engraftment syndrome

Life threatening cases of engraftment syndrome have been reported during clinical trials with Zemcelpro (see section 4.8), occurring at a median time of 13 days post-transplant. Occurrence of unexplained fever, rash, hypoxemia, weight gain, and pulmonary infiltrates in the peri-engraftment period should be monitored. Patients should be treated in accordance with institutional guidelines with corticosteroids as soon as engraftment syndrome is recognized to ameliorate symptoms. If untreated, engraftment syndrome may progress to multiorgan failure and death.

Graft failure

Life threatening cases of graft failure, defined as failure to achieve an absolute neutrophil count greater than 500 per microliter blood by Day 42 after transplantation, have been reported during clinical trials with Zemcelpro (see section 4.8). Patients should be monitored for laboratory evidence of hematopoietic recovery.

Because it could interfere with engraftment of cord blood cells, the use of ATG is not recommended as part of the conditioning regimen and prior to engraftment. Granulocyte colony-stimulating factor (G-CSF) should be administered to minimize the risk of neutropenia and infection, 5 μg/kg/day starting 1-3 days post-transplant until neutrophil count reaches 1 000 per microliter blood (see section 4.2).

Pulmonary alveolar haemorrhage (PAH)

PAH is a well-documented adverse reaction in patients undergoing treatment with Zemcelpro. Cases of PAH were reported, occurring at a median time of 22 days post-transplant, including fatal events (see section 4.8). It is characterized by the development of dyspnea, fever, sometimes haemoptysis, multifocal infiltrates on chest X-ray, and rapid progression to respiratory failure. It is recommended that patients be monitored for evidence of PAH and appropriately treated in accordance with institutional guidelines.

Pneumonitis

Pneumonitis, such as idiopathic pneumonia syndrome (IPS) or cryptogenic organizing pneumonia (COP), is a well-documented event after treatment with Zemcelpro. Cases of pneumonitis were reported in the clinical trials of Zemcelpro including fatal events (see section 4.8). Both IPS and COP usually manifest with shortness of breath, cough, and sometimes fever. While IPS usually occur on average on day +22 after transplant, partly related to pre-transplant conditioning regimen, COP usually occur 3-6 months after transplant. It is recommended that patients be monitored for evidence of pneumonitis and appropriately treated in accordance with institutional guidelines.

Post-transplant lymphoproliferative disorder (PTLD)

Post-transplant lymphoproliferative disorder (PTLD) is an adverse reaction observed in patients after treatment with Zemcelpro. Cases of PTLD have been reported among patients who were transplanted with Zemcelpro in the clinical trials (see section 4.8). PTLD is one of the most common post-transplant malignancies, in most cases associated with Epstein-Barr virus (EBV) infection of B cells, either as a consequence of reactivation of the virus post-transplant or from primary EBV infection. Serial monitoring of blood for EBV DNA may be warranted in patients with persistent cytopenias. PTLD must be appropriately treated in accordance with institutional guidelines.

Infusion-related reactions (IRR)

Infusion-related reactions may occur following infusion with Zemcelpro. These reactions predominantly occur during the initial infusion(s) and can be characterised by flushing, rash, fever, rigors, chills, dyspnoea, mild, and/or severe hypotension with(out) bronchospasms, cardiac dysfunction, and/or anaphylaxis.

Premedication with antipyretics, histamine antagonists, anti-emetics, and corticosteroids may reduce the incidence and intensity of infusion reactions. Monitor patients for signs and symptoms of infusion reactions during and after Zemcelpro administration. When an IRR occurs, pause the infusion and institute supportive care as needed (see section 4.2). Resuming the infusion must follow institutional guideline recommendations.

Hypogammaglobulinaemia

Hypogammaglobulineamia is a well-documented event that has been reported following treatment with Zemcelpro and that could be associated with decreased survival. It has been reported in 19% of the patients transplanted with Zemcelpro (see section 4.8). It is recommended that patients be monitored for laboratory evidence of hypogammaglobulinaemia and treated appropriately in accordance with institutional guidelines.

Veno-occlusive disease

Veno-occlusive disease (VOD) is a well-documented event sometimes reported following HSCT. Rare cases of VOD were reported in the clinical trials of Zemcelpro (see section 4.8, Table 1), including one fatal event. Whereas not different from a usual HSCT, it is recommended that patients be monitored for evidence of VOD and treated appropriately in accordance with institutional guidelines.

Haemolytic uremic syndrome

Haemolytic uremic syndrome (HUS) is a well-documented event sometimes reported following HSCT. Rare cases of HUS were reported in the clinical trials of Zemcelpro (see section 4.8, Table 1). Whereas not different from a usual HSCT, it is recommended that patients be monitored for evidence of HUS and treated appropriately in accordance with institutional guidelines.

Excipients

Sodium

This medicinal product contains 477 mg sodium per dose, equivalent to 24% of the WHO recommended maximum daily intake of sodium for an adult.

Potassium

This medicinal product contains potassium, less than 1.3 mmol (50 mg) per dose.

Dimethyl sulfoxide (DMSO)

This medicinal product contains 17.6 g DMSO per dose. For an adult of 70 kg, the DMSO infused represents 25% of daily maximal recommended dose of 1 g of DMSO/kg.

This excipient is known to possibly cause anaphylactic reaction following parenteral administration.

All patients should be observed closely during the infusion period.

Theoretical risks associated with the donor

Whereas not supported by the clinical experience, clonal haematopoiesis and risks associated with the donor (e.g. malignancies or hereditary genetic disorders) could occur after treatment with Zemcelpro. Patients should be appropriately monitored in accordance with institutional guidelines.

No interaction studies have been performed.

Live vaccines

The safety of immunisation with live vaccines during or following treatment with Zemcelpro has not been studied. Vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of conditioning regimen, and until immune recovery following treatment with Zemcelpro.

Anti-thymocyte globulin (ATG)

Use of ATG is not recommended as part of the conditioning regimen and prior to engraftment.

For risks related to myeloablative conditioning therapy needed before the use of Zemcelpro and the concurrent advice, the product information of the myeloablative conditioning therapy should be consulted.

Women of childbearing potential

Female patients of childbearing potential must have a negative serum pregnancy test within 30 days before treatment with Zemcelpro and must be willing to use an effective contraceptive method.

Contraception in males and females

There is insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Zemcelpro. Effective methods of contraception should be used in males and females of reproductive potential who have received Zemcelpro.

Pregnancy

There are no data from the use of dorocubicel in pregnant women. No animal studies have been conducted with dorocubicel to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3). Zemcelpro should not be used during pregnancy or by women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether dorocubicel is excreted in human milk. Use of Zemcelpro is not recommended during breast-feeding.

Fertility

There is no human or animal data on the effect of dorocubicel on fertility.

It is unknown whether Zemcelpro has an influence on the ability to drive and use machines. As conditioning, prophylactic, and supportive therapy administered in conjunction with Zemcelpro may result in fatigue and alter mental ability, patients are advised to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery during this initial period.

Summary of the safety profile

The most frequently occurring adverse reactions of Grade 3 of higher were lymphopenia (46.6%), infections (44.8%), anaemia (44.0%), neutropenia (35.3%), thrombocytopenie (31.9%), leukopenia (29.3%), hypogammaglobulinaemia (18.1%), febrile neutropenia (15.5%), hypertension (12.9%), engraftment syndrome (11.2%), and pneumonia (11.2%). According to NIH criteria, acute GvHD was reported in 60.0% of patients, and chronic GvHD was reported in 16.0% of patients.

Fatal adverse reactions occurred in 7.8% of patients treated with Zemcelpro, including infections (2.6% including sepsis (0.9%), enterococcal infection (0.9%), pneumonia (0.9%), acute GvHD (1.7%), PAH (1.7%), IPS (0.9%), COP (0.9%), and pulmonary hypertension (0.9%).

Tabulated list of adverse reactions

The frequencies of adverse reactions with Zemcelpro included in Table 1 are based on pooled data from 5 studies (001, 002, 003, 004, and 007) in 116 patients, who received a dose of Zemcelpro and followed for a median duration of 24 months. The adverse reaction frequencies from clinical studies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes.

Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher and unusual grade 1-2 adverse reactions are presented below. These adverse reactions are presented by MedDRA system organ class and by frequency. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first, using the following convention: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1 000 to <1/100). Within each frequency grouping, adverse drug reactions are presented in the order of decreasing seriousness.

Table 1. CTCAE adverse reactions observed in clinical studies with Zemcelpro presented by System Organ Class:

^* as per NIH criteria (45.7% grade II, 10.3% grade III and 0.9% grade IV aGvHD at 100 days post-transplant)
^** as per NIH criteria (7.8% moderate and 5.2% moderate-severe cGvHD at 1-year post-transplant).
^*** infections and infestations presented reflect high-level group terms.

Description of selected adverse reactions

Infections

Severe infections including life-threatening and fatal infections occurred after Zemcelpro infusion. The overall incidence of CTCAE Grade ≥3 post-transplant infections was 75.0% (62.1% severe, 6.0% life-threatening and 6.9% fatal). They were from bacterial (52.6% with sepsis and pneumonia being the most frequent), viral (45.7% with Epstein-Barr virus, cytomegalovirus, coronavirus and adenovirus being the most frequent), fungal (9.5%) or unspecified (8.6%) origins. Their onset is widely spread out with a median of 109 days post-transplant. Most of them resolved with a median duration of 13 days. Fatal infections include sepsis, septic shock and pneumonia. See section 4.4 for management recommendations.

Engraftment syndrome

Engraftment syndrome was reported in 11.2% (13/116) of patients transplanted with Zemcelpro, with an incidence of 8.6% without severe cases among those treated with tacrolimus/MMF as GvHD prophylaxis. The median onset was 13 days post-transplant (range: 8-25). All cases recovered with corticosteroid therapy with a median duration of 5 days (range: 1-18. See section 4.4 for management recommendations,

Pulmonary alveolar haemorrhage

Pulmonary alveolar haemorrhage was reported in 3 (2.6%) patients transplanted with Zemcelpro with a median onset of 22 days post-transplant (range: 20-355). Whereas one patient recovered at 9 days, 2 patients died despite appropriate therapy. See section 4.4 for management recommendations.

Pneumonitis

Pneumonitis was reported in 8 (6.9%) patients transplanted with Zemcelpro with a median onset of 157 days post-transplant (range: 7-283). Cases included 3 idiopathic pneumonia syndromes (IPS) (2.6%), 4 cryptogenic organizing pneumonia (3.4%) (COP) and 1 unspecified pneumonitis (0.9%). Recovery was achieved in 66.7% of cases, with a median duration of 29 days (range: 9-201). Two patients (1.7%) (one with IPS and one with COP) succumbed to the condition. See section 4.4 for management recommendations.

Post-transplant lymphoproliferative disease

Post-transplant lymphoproliferative disease was reported in 3 (2.6%) patients transplanted with Zemcelpro with a median onset of 90 days post-transplant (range: 70-112). All recovered with rituximab therapy with a median duration of 39 days (range: 33-157). See section 4.4 for management recommendations.

Graft versus host disease

Overall, the incidence of acute and chronic GvHD were 66.4% and 14.7%, respectively. At 100 days post-transplant, grade II, III and IV acute GvHD was reported in 52.0%, 11.8% and 1.0%, respectively. Similarly, mild and moderate-severe cases of chronic GvHD was reported at 1-year post-transplant in 12.9% and 8.6%, respectively. Most of the case could be controlled with a corticosteroid-based therapy with a median duration of 18 (0-321) days, but 2 (1.7%) patients died of GvHD-associated infections. GvHD management should follow local institution guidelines (See section 4.4 for management recommendations).

Graft failure

Graft failure was reported in 5.2% of patients transplanted with Zemcelpro with a median onset of 26.5 days post-transplant (range: 7-28). Rescue therapy could be implemented with a median duration of 23 days (range: 7-32) in all but one patient who died from a non-related non-relapse mortality event prior to been rescued.

Prolonged cytopenias

Prolonged cytopenias, including neutropenia (64.7%), thrombocytopenia (63.8%), leukopenia (62.9%), lymphopenia (61.2%), and anaemia (56.9%) are very common following a myeloablative conditioning regimen. See section 4.4 for management recommendations.

Paediatric population

Although data is limited, safety profile is similar to that in adults (Adverse Drug Reactions with a frequency ≥20%: anaemia, decreased appetite, febrile neutropenia, nausea, stomatitis, and epistaxis). Median follow-up time of 7 months does not allow further interpretations of the clinical outcomes.

Reporting of suspected adverse drug 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 via the national reporting system listed in Appendix V.

In the absence of compatibility studies, Zemcelpro should not be mixed with other medicinal products.