Pegfilgrastim

Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease. 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 medicinal product with splenic enlargement and vaso-occlusive crisis.

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 leukaemia (AML). However, the long-term effects of pegfilgrastim have not been established in AML; therefore, it should be used with caution in this patient population.

Granulocyte-colony stimulating factor 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 leukaemia, 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 leukaemia 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.

There are no or limited amount of data from the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity. Pegfilgrastim is not recommended during pregnancy and in women of childbearing potential not using contraception.

There is insufficient information on the excretion of pegfilgrastim/metabolites in human milk, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from pegfilgrastim therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 6 to 9 times higher than the recommended human dose (based on body surface area).

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

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, dyspnoea, 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).

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 granulocyte colony-stimulating factors; see 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.

Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly, cases have resulted in respiratory failure or ARDS, which may be fatal.

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

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, adverse reactions are presented in order of decreasing seriousness.

¹ See section "Description of selected adverse reactions" below.
² This adverse reaction was identified through post-marketing surveillance but not observed in randomised, controlled clinical trials in adults. The frequency category was estimated from a statistical calculation based upon 1 576 patients receiving pegfilgrastim in nine randomised clinical trials.

Description of selected adverse reactions

Uncommon cases of Sweet's syndrome have been reported, although in some cases underlying haematological 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.

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 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 pegfilgrastim in conjunction with chemotherapy and/or radiotherapy has been observed in an epidemiological study in breast and lung cancer patients.

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 medicinal products or undergoing apheresis.

Paediatric population

The experience in children and adolescents 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.