Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequent undesirable effects are musculoskeletal pain and nausea.

Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported mostly in cancer patients undergoing chemotherapy after administration of G-CSF or derivatives (see section 4.4 and section 4.8).

Tabulated list of adverse reactions
The safety of lipegfilgrastim has been evaluated based on results from clinical studies including 506 patients and 76 healthy volunteers treated at least once with lipegfilgrastim.

The adverse reactions listed below in table 1 are classified according to system organ class.
Frequency groupings are defined according to the following convention: 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), not known (cannot be estimated from the available data).

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



Table 1: Adverse reactions
System organ class                 Frequency                   Adverse reaction Blood and lymphatic system         Common                      Thrombocytopenia* disorders                          Uncommon                    Leukocytosis*, Splenomegaly*
Immune system disorders            Uncommon                    Hypersensitivity reactions* Metabolism and nutrition           Common                      Hypokalaemia* disorders
Nervous system disorders           Common                      Headache Vascular disorders                 Not known                   Capillary leak syndrome* Aortitis*
Respiratory, thoracic and          Common                      Haemoptysis mediastinal disorders              Uncommon                    Pulmonary adverse reactions*, Pulmonary Haemorrhage
Gastrointestinal disorders         Very common                 Nausea* Skin and subcutaneous              Common                      Skin reactions* tissue disorders                   Uncommon                    Injection site reactions* Musculoskeletal and                Very common                 Musculoskeletal pains* connective tissue disorders
General disorders and              Common                      Chest pain administration site conditions
Investigations                     Uncommon                 Blood alkaline phosphatase increased*, Blood lactate dehydrogenase increased*
*See subsection “Description of selected adverse reactions” below 
Description of selected adverse reactions

Thrombocytopenia and leukocytosis have been reported (see section 4.4).
Splenomegaly, generally asymptomatic, has been reported (see section 4.4).

Hypersensitivity reactions such as allergic skin reactions, urticaria, angioedema and serious allergic reactions may occur.

Hypokalaemia has been reported (see section 4.4).

Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported (see section 4.4). These pulmonary adverse reactions may also include pulmonary oedema, pulmonary infiltrates, pulmonary fibrosis, respiratory failure or ARDS (see section 4.4).

Nausea was very commonly observed in patients receiving chemotherapy.

Skin reactions such as erythema and rash may occur.
Injection site reactions such as injection site induration and injection site pain may occur.
The most frequent adverse reactions include musculoskeletal pains such as bone pain and myalgia. Musculoskeletal pain is generally of mild to moderate severity, transient and can be controlled in most patients with standard analgesics. However cases of severe musculoskeletal pain (mainly bone pain and back pain) have been reported, including cases that led to hospitalisation.
Reversible, mild to moderate elevations in alkaline phosphatase and lactate dehydrogenase may occur, with no associated clinical effects. Elevations in alkaline phosphatase and lactate dehydrogenase most likely originate from the increase in neutrophils.

Certain adverse reactions have not yet been observed with lipegfilgrastim, but are generally accepted as being attributable to G-CSF and derivatives:
Blood and lymphatic system disorders
-      Splenic rupture including some fatal cases (see section 4.4)
-      Sickle cell crisis in patients with sickle cell anaemia (see section 4.4) 
Vascular disorders
-     Capillary leak syndrome
Cases of capillary leak syndrome have been reported in postmarketing experience after administration of G-CSF or derivatives. These have generally occurred in patients suffering from advanced malignant diseases, having sepsis, taking multiple chemotherapy medicinal products or undergoing apheresis (see section 4.4).
-     Aortitis (see section 4.4)

Skin and subcutaneous tissue disorders
-       Acute febrile neutrophilic dermatosis (Sweet’s syndrome)
-       Cutaneous vasculitis

Renal and urinary disorders
-      Glomerulonephritis (see section 4.4)
Paediatric population

The safety assessment in paediatric patients is limited to the clinical study data from the following studies:
-     a phase I study with 21 paediatric patients aged 2 to 16 years with Ewing family of tumours or rhabdomyosarcoma receiving lipegfilgrastim after a single cycle of chemotherapy (see also section 5.1)
-     a phase II study with 21 paediatric patients aged 2 to 18 years with Ewing family of tumours or rhabdomyosarcoma receiving one dose of lipegfilgrastim per chemotherapy cycle, for 4 consecutive cycles (see also section 5.1).

Overall, the safety profile in paediatric patients appeared similar to that observed in adult clinical studies. Some blood and lymphatic system disorders (anaemia, lymphopenia, thrombocytopenia) and gastrointestinal disorders (vomiting) were observed with a higher frequency in paediatric patients than those in adult clinical studies (see also section 5.1).

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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/