Filgrastim and pegfilgrastim: risk of capillary leak syndrome

Capillary leak syndrome (CLS) has been reported in recipients of filgrastim, including patients undergoing chemotherapy and a healthy donor undergoing peripheral blood progenitor-cell mobilisation; it has also been reported in recipients of pegfilgrastim undergoing chemotherapy. Episodes varied in severity and frequency. CLS is characterised by: hypotension and oedema; hypoalbuminaemia; and haemoconcentration, and may be fatal unless promptly diagnosed and managed. Prescribers should monitor patients and healthy donors for signs and symptoms of capillary leak syndrome (CLS), and should give standard symptomatic treatment immediately if symptoms occur.

Article date: September 2013

Background

Filgrastim (Neupogen) and pegfilgrastim (Neulasta) are recombinant granulocyte colony-stimulating factors (G-CSF) used to stimulate the proliferation and differentiation of granulocytes, especially polymorphonuclear, in various forms of neutropenia induced by chemotherapy. Filgrastim is also used to help release blood stem cells from the bone marrow of healthy donors.

A review of filgrastim and pegfilgrastim was triggered by postmarketing reports of capillary leak syndrome (CLS). CLS is characterised by:

  • hypotension and oedema
  • hypoalbuminaemia
  • haemoconcentration

Review of the signal

CLS has been reported in patients with cancer undergoing chemotherapy and a healthy donor undergoing peripheral blood progenitor-cell mobilisation who were receiving filgrastim or pegfilgrastim. Reports have generally involved people with advanced malignant disease, sepsis, those taking multiple chemotherapy medicines, or those undergoing apheresis. The mechanism of CLS remains unclear.

Filgrastim

For filgrastim, 34 postmarketing reports of CLS were received worldwide between April 1991 and August 2012, including five reports received via the Yellow Card Scheme. Of these, one case concerned a healthy donor undergoing stem-cell mobilisation and apheresis. In 12 cases, symptoms of CLS improved or recovered with supportive or corticosteroid treatment and discontinuation of filgrastim. In most cases, CLS symptoms occurred after the first dose of filgrastim. In two cases, symptoms occurred after the first dose and then reoccurred during the second. Six cases of CLS had a fatal outcome.

Pegfilgrastim

For pegfilgrastim, four postmarketing reports of CLS were received worldwide between August 2002 and August 2012. CLS symptoms appeared after the second dose in two cases. In one of these cases, CLS occurred 1 day after pegfilgrastim, suggesting a temporal association. In another case, the patient had a fatal outcome from CLS.

Conclusions

The postmarketing adverse reaction reports provide good evidence of a temporal and causal association between filgrastim or pegfilgrastim treatment and CLS. However, the benefits of filgrastim and pegfilgrastim continue to outweigh the risks. Healthcare professionals should note the following to help manage and minimise the risk of CLS.

Advice for healthcare professionals:

  • closely monitor all patients and healthy donors for CLS symptoms, which commonly have rapid onset. Symptoms include:
    • generalised body swelling
    • puffiness (which may be associated with less-frequent urination)
    • difficulty breathing; abdominal swelling
    • tiredness
  • give standard symptomatic treatment immediately if symptoms occur
  • advise patients and healthy donors to contact their doctor immediately if they develop CLS symptoms
  • any suspected adverse reactions to filgrastim or pegfilgrastim should be reported to us on a Yellow Card

Further information

Minutes from the meeting of the Pharmacovigilance Risk Assessment Committee, October 2012

Letter for healthcare professionals sent August 2013

Article citation: Drug Safety Update August 2013 volume 7, issue 1: A1.

Help us improve GOV.UK

Don’t include personal or financial information like your National Insurance number or credit card details.