APPENDIX 5
NOTES ON CYCLOPHOSPHAMIDE THERAPY
Cyclophosphamide therapy is probably the most toxic of the routinely
prescribed
immunosuppressive
agents.
The
provision
of
cyclophosphamide should be in accordance with locally approved
protocols and prescribing guidelines. Intravenous cyclophosphamide
therapy should only be delivered by practitioners appropriately trained in
managing extravasations of chemotherapeutic drugs. These short notes
are designed to provide an overview of cyclophosphamide therapy in the
context of inflammatory interstitial lung disease, most commonly in
association with connective tissue disease or vasculitis and often in
combination with corticosteroid treatment. Cyclophosphamide therapy is
not recommended for the treatment of idiopathic pulmonary fibrosis.
Dose and Mode of Delivery
Oral cyclophosphamide is usually given at a dose of up to 2mg/kg/day,
with a lower dose in those over 60 years and those with renal impairment.
The length of treatment with oral cyclophosphamide is dependent upon the
underlying disease and the response. In clinical trials of systemic
sclerosis-associated ILD, oral therapy has been continued for up to 1
year1.
Intravenous cyclophosphamide therapy is increasingly favoured over oral
therapy due to a significantly better side-effect profile2. Pulsed intravenous
treatment is usually given at a dose of 500-750mg/m2 with adjustments for
age and renal function. The dose interval and duration of treatment is
dependent upon the nature of the underlying inflammatory disease.
Studies of intravenous cyclophosphamide in systemic sclerosis associated
ILD have generally adopted a 3-4-weekly regimen over at least 6 months35.
This regimen exposes the patient to the drug for a prolonged period but
results in a lower cumulative dose than would be achieved with oral
cyclophosphamide.
Side effects and monitoring
Nausea, vomiting and reversible hair loss are common side effects.
Bone marrow suppression is the most common serious side-effect and
regular full blood count monitoring is mandatory. The white blood cell nadir
usually occurs 10-14 days after an intravenous pulse. Prophylactic cotrimoxazole therapy to prevent Pneumocystis jiroveci pneumonia has been
shown to be cost effective in patients with Wegener’s granulamatosis 6, but
there are no equivalent studies in patients with interstitial lung disease
treated with cyclophosphamide.
Haemorrhagic cystitis and bladder cancer are uncommon but serious sideeffects of cyclophosphamide therapy. The incidence of bladder cancer,
after first exposure to cyclophosphamide and a cumulative dose of 100g,
is estimated to be 5% at 10 years and 16% at 15 years7. The risk of
bladder complications is reduced by:
1)
co-administration of sodium 2-mercaptoethanesulfonate (Mesna), a
regional detoxicant of active cyclophosphamide metabolites
2)
good hydration
3)
treatment
in
the
early
morning
to
avoid
overnight
bladder
accumulation.
Individuals receiving cumulative doses of cyclophosphamide exceeding
20g should have 3-6 monthly urinalyses, to detect microscopic
haematuria, for up to 11 years after cessation of the drug8.
Reduced and potentially irreversible infertility in male and females treated
with cyclophosphamide is an important consideration. Counselling and
support from local fertility services is mandatory in appropriate cases.
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