Adverse reactions : תופעות לוואי

4.8    Undesirable effects
 a. Summary of the safety profile

The most serious adverse reactions that may occur during Filgrastim 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 tables 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                                              Adverse reactions system organ       Very common               Common            Uncommon                     Rare class                 (≥1/10)           (≥ 1/100 to < 1/10)   (≥ 1/1,000 to <           (1/10,000 to < 1/100)                   1/1,000)

Infections                             Sepsis and                                    Bronchitis infestations                           Upper respiratory tract infection
Urinary tract infection
MedDRA                                        Adverse reactions system organ     Very common           Common            Uncommon                   Rare class               (≥1/10)       (≥ 1/100 to < 1/10)   (≥ 1/1,000 to <         (1/10,000 to < 1/100)                 1/1,000)

Blood and       Thrombocytopeni   Splenomegalya         Leukocytosisa        Splenic rupturea lymphatic       a                 Haemoglobin                                Sickle cell anemia system          Anemiae           decreasede                                 with crisis disorders
Immune                                                  Hypersensitivity     Anaphylactic system                                                  Drug                 reaction disorders                                               hypersensitivitya Graft versus Host
Diseaseb


Metabolism                        Decreased             Hyperuricaemia       Blood glucose and nutrition                     Appetitee             Blood uric acid      decreased disorders                         Blood lactate         increased            Pseudogouta dehydrogenase                              (Chondrocalcinosis increased                                  Pyrophosphate)
Fluid volume disturbances
Psychiatric                       Insomnia disorders
Nervous         Headachea         Dizziness,
system                            Hypoaesthesia disorders                         Paraesthesia
Vascular                          Hypotension           Veno-occlusive       Capillary leak Disorders                         Hypertension          diseased             syndromea Aortitis
Respiratory,                      Haemoptysis           Acute respiratory thoracic and                      Dyspnoea              distress mediastinal                       Cougha                syndromea disorders                         Oropharyngeal         Respiratory paina,e               failurea
Epistaxis             Pulmonary edemaa
Pulmonary hemorrhage
Interstitial lung diseasea
Lung infiltrationa
Hypoxia
Gastrointesti   Diarrhoeaa,e      Oral Pain nal disorders   Vomitinga,e       Constipatione
Nauseaa
Hepatobiliary                     Hepatomegaly          Aspartate disorders                         Blood alkaline        aminotransferase phosphatase           increased increased             Gamma-glutamyl transferase increased


MedDRA                                             Adverse reactions system organ       Very common              Common            Uncommon                   Rare class                 (≥1/10)          (≥ 1/100 to < 1/10)   (≥ 1/1,000 to <         (1/10,000 to < 1/100)                 1/1,000)


Skin and                              Rasha                  Rash                 Cutaneous a subcutaneous     Alopecia                                    maculopapular        vasculitisa tissue                                Erythema                                    Sweets syndrome disorders                                                                         (acute febrile neutrophilic dermatosis)


Musculoskele     Musculoskeletal      Muscle spasms          Osteoporosis         Bone density tal and          painc                                                            decreased connective                                                                        Exacerbation of tissue                                                                            rheumatoid arthritis disorders
Renal and                             Dysuria                                     Glomerulonephritis urinary                               Haematuria             Proteinuria          Urine abnormality disorders
General          Fatiguea             Chest paina            Injection site disorders and    Mucosal                                     reaction administratio    inflammationa        Paina n site           Pyrexia              Astheniaa conditions                            Malaisee
Edema peripherale
Injury,                               Transfusion poisoning and                         reactione procedural 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 Filgrastim 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, dyspnoea 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. Filgrastim 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 Filgrastim. The mechanism of vasculitis in patients receiving Filgrastim is unknown. During long term use cutaneous vasculitis has been reported in 2% of SCN patients.

Leukocytosis
Leukocytosis (WBC > 50 x 109/L) was observed in 41% of normal donors and transient thrombocytopenia (platelets < 100 x 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 filgrastim.

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

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 filgrastim 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 filgrastim 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 StimoFil use in geriatric subjects for other approved StimoFil 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 filgrastim.

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