IMREPLYS Powder for solution for injection Ref.[116016] Active ingredients: Sargramostim

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

General recommendations

Imreplys may be used in conjunction with other supportive care to treat H-ARS.

Given that the mechanism of radiation toxicity begins at the time of exposure, treatment with Imreplys should start as soon as possible after radiation exposure. However, efficacy studies for sargramostim when administered earlier than 24 hours after exposure to myelosuppressive doses of radiation, have not been conducted in a large animal model of total body irradiation-induced H-ARS.

Hypersensitivity and anaphylaxis

Hypersensitivity reactions, including anaphylactic reactions, have been reported with sargramostim. Sargramostim treatment should be discontinued in those who have experienced anaphylaxis after a prior dose of sargramostim.

Haemodynamic oedema, effusions and fluid overload

Oedema, capillary leak syndrome, and pleural and/or pericardial effusion have been reported in patients after sargramostim administration in haematological conditions.

In patients with pre-existing pleural and pericardial effusions, administration of sargramostim may aggravate fluid retention. Fluid retention associated with or worsened by sargramostim has been reversible after interruption or dose reduction of sargramostim with or without diuretic therapy.

Imreplys should be used with caution in patients with pre-existing fluid retention, pulmonary infiltrates, or congestive heart failure. Body weight and hydration status should be carefully monitored during sargramostim administration.

Supraventricular arrhythmias

Supraventricular arrhythmia has been reported in uncontrolled studies during sargramostim administration in haematological conditions, particularly in patients with a previous history of cardiac arrhythmia. These arrhythmias have been reversible after discontinuation of treatment. Imreplys should be used with caution in patients with pre-existing cardiac disease. A physician or other health care professional should be consulted if any new or worsening arrhythmia is observed.

Potential effect on malignant cells

Sargramostim is a growth factor that stimulates normal myeloid precursors. However, the possibility that sargramostim can act as a growth factor for any tumour type, particularly myeloid malignancies, cannot be excluded. Patients with pre-existing, or a history of, cancer should be treated with Imreplys as soon as possible following radiation exposure due to the life-threatening nature of the exposure and consult an oncologist as soon as practical.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.

Treatment with sargramostim in persons who have not been exposed to myelosuppressive doses of radiation may induce neutralising anti-drug antibodies which may be related to duration of exposure to sargramostim.

Risk of leucocytosis

White blood cell (WBC) counts of ≥50 000/mm³ were observed in patients receiving sargramostim for haematological conditions. Following discontinuation of sargramostim treatment, leucocytosis has resolved within 3 to 7 days. If WBC counts exceed ≥50 000/mm³ in any patient, Imreplys should be discontinued immediately.

Limitations of effectiveness

The effectiveness of sargramostim may be limited in immunocompromised patients and those with underlying conditions affecting bone marrow function. Patients with pre-existing bone marrow suppression, such as those with haematologic malignancies, autoimmune disorders, or those undergoing chemotherapy/radiation therapy, may exhibit a suboptimal response to sargramostim due to reduced progenitor cell reserves or impaired haematopoiesis. Additionally, there is uncertainty regarding the efficacy of sargramostim in individuals acutely exposed to high-dose radiation exceeding 7.3 Gy (see section 5.1, nonclinical efficacy). High-dose radiation exposure can cause irreversible bone marrow failure, limiting the potential benefit of Imreplys in promoting haematopoietic recovery.

Limited data are available on drug-drug interactions. Patients receiving both sargramostim and medicinal products that induce leucocytosis (e.g., corticosteroids, other colony-stimulating factors, lithium) may have an increased risk of leucocytosis (see section 4.4).

Acute exposure to myelosuppressive doses of radiation has per se a toxic effect on fertility and embryo/foetal development. This should be considered for clinical judgement on the use of Imreplys in pregnant and/or lactating women.

Pregnancy

There are no or limited data on the use of sargramostim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Imreplys can be used in pregnant women with H-ARS if clinically needed.

Breast-feeding

It is unknown whether sargramostim/metabolites are excreted in human milk. A risk to the suckling child cannot be excluded.

Breast-feeding may be considered during treatment with Imreplys, keeping in mind that the newborns may also need treatment.

Fertility

There is no data available on sargramostim and human fertility. Studies in rabbits have shown adverse effects on female fertility (see section 5.3).

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

The safety of sargramostim was evaluated using all available sources, including clinical studies in adults and children across various indications, healthy human volunteer studies, solicited and unsolicited reports, and literature-reported events.

Summary of the safety profile

The most serious adverse drug reactions (ADR) that occurred during sargramostim treatment were:

• Serious hypersensitivity reactions including anaphylaxis
• Haemodynamic oedema, effusions and fluid overload
• Supraventricular arrhythmias

The most common ADRs observed in haematological cancer patients treated with intravenously administered sargramostim are: fever (without infection; up to 95%), diarrhoea (up to 88%), vomiting (up to 84%), skin reactions (up to 77%), rash (up to 70%), asthenia (up to 69%), metabolic laboratory abnormalities (up to 58%), malaise (up to 58%), high glucose (up to 49%), abdominal pain (up to 38%), weight loss (up to 37%), low albumin (up to 36%), pruritis (up to 23%), GI haemorrhage (up to 27%), chills (up to 25%), pharyngitis (up to 23%), bone pain (up to 21%), chest pain (up to 15%), hypomagnesaemia (up to 15%), haematemesis (up to 13%), arthralgia (joint pain; up to 11%), anxiety (up to 11%), eye haemorrhage (up to 11%). In some subjects, the underlying diseases may have contributed to the occurrence of those ADRs.

Tabulated list of adverse reactions

The tabulated ADRs table is based on 5 clinical studies in 182 patients with haematological cancers where WBC are affected similarly to what occurs during acute exposure to myelosuppressive doses of radiation. In these studies, sargramostim was administered intravenously.

The adverse reactions are listed by MedDRA system organ class and categories of frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data).

Table 1. Adverse reactions reported in adults and children with haematological cancers treated with intravenous sargramostim in controlled clinical studies:

Paediatric population

A total of 332 paediatric subjects were treated with intravenous sargramostim in 15 clinical studies in haematological conditions, premature neonates and Crohn's disease of which 5 were controlled, 190 patients were 0-1 month of age, 6 patients were >1 month to <2 years of age, 1 patient was <1 year of age (not otherwise specified), 86 patients were 2 to <12 years of age, and 49 patients were 12 to <18 years of age. The overall safety profile was similar to that seen in adults.

Adverse drug reactions reported with subcutaneous administration of sargramostim

Additional ADRs have been observed in clinical studies in healthy adult volunteers and children with Crohn's disease, where the majority of patients were administered sargramostim via the subcutaneous route. From these studies, in addition to Table 1, ADRs include injection site reactions (up to 91%), headache (up to 50%) back pain, (up to 47%), nausea (up to 23%), abdominal cramps (up to 17%), dyspnoea (up to 12%), and general body pain (up to 13%).

Solicited, unsolicited, and literature-reported events in patients treated with sargramostim (across various routes of administration)

The most common ADRs were pyrexia, injection site reaction, dyspnoea, nausea, chest pain, vomiting, diarrhoea, chills, rash, hypotension, abdominal pain, febrile neutropenia, sepsis, pneumonia, dizziness, and syncope.

Serious hypersensitivity reactions including anaphylaxis, haemodynamic oedema, effusions and fluid overload and supraventricular arrhythmias have been reported with the use of sargramostim in various health conditions.

No overall differences in safety profile are observed between reports from adult and paediatric populations.

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 via the national reporting system listed in Appendix V.

Not applicable.