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 system organ class
Very              Common                 Uncommon                  Rare common         (≥ 1/100 to < 1/10)        (≥ 1/1,000 to           (≥ 1/10,000 (≥ 1/10)                                    < 1/100)             to < 1/1,000) Neoplasms                                                    Myelodysplastic benign,                                                      syndrome1 malignant and                                                Acute myeloid unspecified                                                  leukemia1 (incl cysts and polyps)
Blood and                            Thrombocytopenia1;      Sickle cell anemia lymphatic system                     Leukocytosis1           with crisis2; 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,                                                 Acute Respiratory          Pulmonary thoracic and                                                 Distress Syndrome2;        hemorrhage mediastinal                                                  Pulmonary adverse disorders                                                    reactions (interstitial pneumonia,
pulmonary edema,
pulmonary infiltrates and pulmonary fibrosis);
Hemoptysis
Gastrointestinal    Nausea1 disorders
Skin and                                                     Sweet’s syndrome          Stevens- subcutaneous                                                 (acute febrile            Johnson tissue disorders                                             dermatosis)1,2;           syndrome Cutaneous vasculitis1,2
Musculoskeletal     Bone pain        Musculoskeletal pain and connective                       (myalgia, arthralgia,
tissue disorders                     pain in extremity,
back pain,
musculoskeletal pain,
neck pain)
Renal and                                                    Glomerulonephritis2 urinary disorders
General disorders                    Injection site pain1;   Injection site 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 pegfilgrastim 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 pegfilgrastim following cytotoxic chemotherapy.
Nausea and headaches were very commonly observed in patients receiving chemotherapy.
Uncommon elevations in liver function tests (LFTs) for ALT (alanine aminotransferase) or AST (aspartate aminotransferase), 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 Pegfilgrastim 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 authorization 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