6 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 System Organ Class (MedDRA) Very common Common Uncommon Rare Very rare Nervous system disorders Anxiety Eye disorders Eye haemorrhage Vascular disorders Vasodilation Respiratory, thoracic and mediastinal disorders Pharyngitis Gastrointestinal disorders Abdominal pain Diarrhoea Gastrointestinal haemorrhage Haematemesis Vomiting Skin and subcutaneous tissue disorders Pruritis Rash Skin reactions Bone pain 7 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.
System Organ Class (MedDRA) Very common Common Uncommon Rare Very rare Musculoskeletal and connective tissue disorders Arthralgia General disorders and administration site conditions Asthenia Chest pain Chills Fever (no infection) Malaise Weight loss Investigations High glucose Low albumin Hypomagnesaemia Metabolic function test abnormalities NOS 8