Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability

In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade name of the administered product should be clearly recorded in the patient file.

Limited clinical data suggest a comparable effect on time to recovery of severe neutropenia for pegfilgrastim to filgrastim in patients with de novo acute myeloid leukemia (AML) (see section 5.1).
However, the long-term effects of pegfilgrastim have not been established in AML; therefore, it should be used with caution in this patient population.

G-CSF can promote growth of myeloid cells in vitro and similar effects may be seen on some non- myeloid cells in vitro.

The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukemia from AML.

The safety and efficacy of pegfilgrastim administration in de novo AML patients aged < 55 years with cytogenetics t (15;17) have not been established.

The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.

Pulmonary adverse events

Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk (see section 4.8).
The onset of pulmonary signs such as cough, fever, and dyspnea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of Acute Respiratory Distress Syndrome (ARDS). In such circumstances pegfilgrastim should be discontinued at the discretion of the physician and the appropriate treatment given (see section 4.8)

Glomerulonephritis

Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim.
Urinalysis monitoring is recommended.

Capillary leak syndrome

Capillary leak syndrome has been reported after G-CSF administration and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care (see section 4.8).

Splenomegaly and splenic rupture

Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see section 4.8). Therefore, spleen size should be carefully monitored (e.g., clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain.

Thrombocytopenia and anemia

Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and hematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.

Myelodysplastic syndrome and acute myeloid leukemia in breast and lung cancer patients 
In the post-marketing observational study setting, pegfilgrastim in conjunction with chemotherapy and/or radiotherapy has been associated with development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in breast and lung cancer patients (see section 4.8). Monitor patients treated in these settings for signs and symptoms of MDS/AML.

Sickle cell anemia

Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease (see section 4.8). Therefore, physicians should use caution when prescribing pegfilgrastim in patients with sickle cell trait or sickle cell disease, should monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of this medicine with splenic enlargement and vaso-occlusive crisis.

Leukocytosis

White blood cell (WBC) counts of 100 × 109/l or greater have been observed in less than 1% of patients receiving pegfilgrastim. No adverse events directly attributable to this degree of leukocytosis have been reported. Such elevation in white blood cells is transient, typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of this medicine. Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 × 109/l after the expected nadir, this medicine should be discontinued immediately.

Hypersensitivity

Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have been reported in patients treated with pegfilgrastim. Permanently discontinue pegfilgrastim in patients with clinically significant hypersensitivity. Do not administer pegfilgrastim to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days.


Stevens-Johnson syndrome
Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against pegfilgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralizing activity at present.

Aortitis

Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF. See section 4.8.

Other warnings

The safety and efficacy of pegfilgrastim for the mobilization of blood progenitor cells in patients or healthy donors has not been adequately evaluated.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging findings. This should be considered when interpreting bone-imaging results.

Sorbitol
Fulphila contains 30 mg sorbitol in each pre-filed syringe which is equivalent to 50 mg/ml. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

Sodium
Fulphila contains less than 1 mmol sodium (23 mg) per 6 mg dose, that is to say, essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Pegfilgrastim has no or negligible influence on the ability to drive and use machines.