Adverse reactions : תופעות לוואי

4.8    Undesirable effects
 a.     Summary of the safety profile
The most serious adverse reactions that may occur during Neupogen treatment include: anaphylactic reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary leak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or leukemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral blood cell progenitor cell transplant and sickle cell crisis in patients with sickle cell disease.

The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain), anemia, vomiting, and nausea. In clinical trials in cancer patients musculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients.
 b.    Tabulated summary 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                                            Adverse reactions organ class
Very common             Common                Uncommon                    Rare (≥ 1/10)        (≥ 1/100 to < 1/10)        (≥ 1/1,000 to          (≥ 1/10,000 to < 1/100)               < 1/1,000)
Infections and                           Sepsis infestations                             Bronchitis
Upper respiratory tract infection
Urinary tract infection
Blood and           Thrombocytopenia     Splenomegalya          Leukocytosisa          Splenic rupturea lymphatic system    Anemiae              Hemoglobin                                    Sickle cell anemia with disorders                                decreasede                                    crisis Extramedullary haematopoiesis
Immune system                                                   Hypersensitivity       Anaphylactic reaction disorders                                                       Drug hypersensitivitya
Graft versus host diseaseb
Metabolism and                           Decreased appetitee    Hyperuricemia          Blood glucose nutrition                                Blood lactate          Blood uric acid        decreased disorders                                dehydrogenase          increased              Pseudogouta increased                                     (Chondrocalcinosis
Pyrophosphate)
Fluid volume disturbances
Psychiatric                              Insomnia disorders
Nervous system      Headachea            Dizziness disorders                                Hypoesthesia
Paresthesia
Vascular                                 Hypertension           Veno-occlusive         Capillary leak disorders                                Hypotension            diseased               syndromea Aortitis
Respiratory,                             Hemoptysis             Acute respiratory thoracic and                             Dyspnea                distress syndromea mediastinal                              Cougha                 Respiratory failurea disorders                                Oropharyngeal          Pulmonary edemaa paina, e               Pulmonary
Epistaxis              hemorrhage
Interstitial lung diseasea
Lung infiltrationa
Hypoxia
Gastrointestinal    Diarrheaa, e         Oral pain disorders           Vomitinga, e         Constipatione
Nauseaa


MedDRA system                                                       Adverse reactions organ class
Very common                Common                  Uncommon                         Rare (≥ 1/10)           (≥ 1/100 to < 1/10)          (≥ 1/1,000 to               (≥ 1/10,000 to < 1/100)                    < 1/1,000)
Hepatobiliary                                     Hepatomegaly             Aspartate disorders                                         Blood alkaline           aminotransferase phosphatase              increased increased                Gamma-glutamyl transferase increased
Skin and                 Alopeciaa                Rasha                    Rash maculo-papular        Cutaneous vasculitisa subcutaneous                                      Erythema                                            Sweets syndrome tissue disorders                                                                                      (acute febrile neutrophilic dermatosis)
Musculoskeletal          Musculoskeletal          Muscle spasms            Osteoporosis               Bone density and connective           painc                                                                        decreased tissue disorders                                                                                      Exacerbation of rheumatoid arthritis
Renal and urinary                                 Dysuria                  Proteinuria                Glomerulonephritis disorders                                         Hematuria                                           Urine abnormality General disorders        Fatiguea                 Chest paina              Injection site reaction and                      Mucosal                  Paina administration           inflammationa            Astheniaa site conditions          Pyrexia                  Malaisee
Edema peripherale
Injury, poisoning                                 Transfusion and procedural                                    reactione complications a See section c (Description of selected adverse reactions) b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow transplantation (see section c) c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain d Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or PBPC mobilization e Adverse events with higher incidence in Neupogen patients compared to placebo and associated with the sequelae of the underlying  malignancy or cytotoxic chemotherapy
 c.        Description of selected adverse reactions
Hypersensitivity

Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angiedema, dyspnea and hypotension occurring on initial or subsequent treatment have been reported in clinical studies and in post-marketing experience. Overall, reports were more common after IV administration. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Neupogen should be permanently discontinued in patients who experience a serious allergic reaction.

Pulmonary adverse events

In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial lung disease, pulmonary edema, and lung infiltration have been reported in some cases with an outcome of respiratory failure or acute respiratory distress syndrome (ARDS), which may be fatal (see section 4.4).

Splenomegaly and splenic rupture

Cases of splenomegaly and splenic rupture have been reported following administration of filgrastim. Some cases of splenic rupture were fatal (see section 4.4).


Capillary leak syndrome

Cases of capillary leak syndrome have been reported with granulocyte-colony stimulating factor use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy medications or undergoing apheresis (see section 4.4).

Cutaneous vasculitis

Cutaneous vasculitis has been reported in patients treated with Neupogen. The mechanism of vasculitis in patients receiving Neupogen is unknown. During long-term use cutaneous vasculitis has been reported in 2% of SCN patients.

Leukocytosis

Leukocytosis (WBC > 50 × 109/l) was observed in 41% of normal donors and transient thrombocytopenia (platelets < 100 × 109/l) following filgrastim and leukapheresis was observed in 35% of donors (see section 4.4).

Sweets syndrome

Cases of Sweets syndrome (acute febrile neutrophilic dermatosis) have been reported in patients treated with Neupogen.

Pseudogout (chondrocalcinosis pyrophosphate)

Pseudogout (chondrocalcinosis pyrophosphate) has been reported in patients with cancer treated with Neupogen.

GvHD

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation (see sections 4.4 and 5.1).
 d.    Pediatric population

Data from clinical studies in pediatric patients indicate that the safety and efficacy of Neupogen are similar in both adults and children receiving cytotoxic chemotherapy suggesting no age-related differences in the pharmacokinetics of filgrastim. The only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.

There is insufficient data to further evaluate Neupogen use in pediatric subjects.
 e.    Other special populations
Geriatric use

No overall differences in safety or effectiveness were observed between subjects over 65 years of age compared to younger adult (> 18 years of age) subjects receiving cytotoxic chemotherapy and clinical experience has not identified differences in the responses between elderly and younger adult patients. There is insufficient data to evaluate Neupogen use in geriatric subjects for other approved Neupogen indications.

Pediatric SCN patients

Cases of decreased bone density and osteoporosis have been reported in pediatric patients with severe chronic neutropenia receiving chronic treatment with Neupogen.


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