Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and musculoskeletal pain (common [≥ 1/100 to < 1/10]). Bone pain was generally of mild to moderate severity, transient and could be controlled in most patients with standard analgesics.

Hypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnea, erythema, flushing, and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon [≥ 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patients receiving pegfilgrastim (uncommon) (see section 4.4).

Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported as uncommon (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following administration of G-CSFs; see section 4.4 and section “Description of selected adverse reactions” below.

Splenomegaly, generally asymptomatic, is uncommon.

Splenic rupture including some fatal cases is uncommonly reported following administration of pegfilgrastim (see section 4.4).

Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary edema, pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly, cases have resulted in respiratory failure or ARDS, which may be fatal (see section 4.4).

Isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell disease (uncommon in sickle cell patients) (see section 4.4).

Tabulated list of adverse reactions

The data in the table below describe adverse reactions reported from clinical trials and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

MedDRA               Very common         Common                  Uncommon                 Rare system organ         (≥ 1/10)            (≥ 1/100 to <1/10)      (≥ 1/1,000 to <          (≥ 1/10,000 to < class                                                            1/100)                   1/1,000) Neoplasms                                                        Myelodysplastic benign,                                                          syndrome1 Acute malignant and                                                    myeloid leukemia1 unspecified (incl cysts and polyps)
Blood and                                Thrombocytopenia1 Sickle cell anemia lymphatic                                ; Leukocytosis1   with crisis2 ; system disorders                                           Splenomegaly2 ; Splenic rupture2
Immune system                                              Hypersensitivity disorders                                                  reactions; Anaphylaxis
Metabolism and                                             Elevations in uric nutrition                                                  acid disorders
Nervous system       Headache1 disorders
Vascular                                                         Capillary leak           Aortitis disorders                                                        syndrome1 Respiratory,                                                     Adult Respiratory thoracic and                                                     Distress Syndrome2       Pulmonary mediastinal                                                      ; Pulmonary              haemorrha ge disorders                                                        adverse reactions (interstitial pneumonia,
pulmonary oedema,
pulmonary infiltrates and pulmonary fibrosis)
Haemoptysis
Gastrointestin al    Nausea1 disorders
Skin and                                                         Sweet’s syndrome         Stevens-Johnson subcutaneous                                                     (acute febrile           syndrome tissue disorders                                                 neutrophilic dermatosis)1,2;
Cutaneous vasculitis1, 2

Musculoskeletal    Bone pain        Musculoskeletal and connective                      pain (myalgia,
tissue disorders                    arthralgia, pain in extremity, back pain,
musculoskeletal pain, neck pain)
Renal and                                                  Glomerulonephritis2 urinary disorders
General                             Injection site pain1   Injection site disorders and                       ; Non-cardiac chest    reactions2 administrative                      pain site conditions
Investigations                                             Elevations in lactate dehydrogenase and alkaline phosphatase1 ;
Transient elevations in LFT's for ALT or
AST1


1
See section “Description of selected adverse reactions” below.
2
This adverse reaction was identified through post-marketing surveillance but not observed in randomized, controlled clinical trials in adults. The frequency category was estimated from a statistical calculation based upon 1,576 patients receiving StimoPeg in nine randomized clinical trials 
Description of selected adverse reactions
Uncommon cases of Sweet’s syndrome have been reported, although in some cases underlying hematological malignancies may play a role.

Uncommon events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim.
The mechanism of vasculitis in patients receiving pegfilgrastim is unknown.

Injection site reactions, including injection site erythema (uncommon) as well as injection site pain (common) have occurred on initial or subsequent treatment with pegfilgrastim.

Common cases of leukocytosis (White Blood Count [WBC] > 100 × 109 /l) have been reported (see section 4.4).

Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical effects, were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase, with no associated clinical effects, were uncommon in patients receiving StimoPeg following cytotoxic chemotherapy.

Nausea and headaches were very commonly observed in patients receiving chemotherapy.

Uncommon elevations in liver function tests (LFTs) for alanine aminotransferase (ALT) or aspartate aminotransferase (AST), have been observed in patients after receiving pegfilgrastim following cytotoxic chemotherapy. These elevations are transient and return to baseline.

An increased risk of MDS/AML following treatment with StimoPeg in conjunction with chemotherapy and/or radiotherapy has been observed in an epidemiological study in breast and lung cancer patients (see section 4.4).


Common cases of thrombocytopenia have been reported
Cases of capillary leak syndrome have been reported in the post-marketing setting with G-CSF use.
These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy medications or undergoing apheresis (see section 4.4).

Pediatric population

The experience in children is limited. A higher frequency of serious adverse reactions in younger children aged 0-5 years (92%) has been observed compared to older children aged 6-11 and 12-21 years respectively (80% and 67%) and adults. The most common adverse reaction reported was bone pain (see sections 5.1 and 5.2).

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