Methods for prevention of ifosfamide-induced encephalopathy include:
- recognising the risk factors
- avoiding concurrent use of opioids, benzodiazepines, sedatives, CYP2B6 and CYP3A4 inhibitors
- prolonging the infusion or fractionating the dose
- alkalinisation to facilitate elimination of chloracetaldehyde
- methylene blue (methylthioninium chloride) prophylaxis, particularly for patients with previous grade 3 or 4 reactions.r,r
In the event of a change in neurological status:
- stop the ifosfamide infusion immediately
- continue mesna infusion as per protocol
- notify the medical officer to perform an immediate assessment of the patient
- ensure a safe environment for the patient (e.g. lower the bed, remove any equipment from patient's reach etc)
- ensure adequate IV hydration with glucose 5%
- if ordered, administer methylene blue or thiamine (particularly in toxicity ≥ grade 2)
- continue hourly neurological observations.
Possible actions of methylene blue include an increase in chloracetaldehyde degradation and inhibition of chloracetaldehyde formation.r
Treatment dose: 50 mg IV/PO as a single dose or every 4 to 8 hours until symptoms resolve.
Prophylaxis dose: 50 mg IV/PO every 6 to 8 hours for the duration of the ifosfamide infusion.
Methylene blue 0.5% or 1% injection can be given intravenously or orally.
Intravenous: Administer undiluted as a slow IV bolus over at least 5 minutes (to prevent local high concentrations with toxic effects) or dilute in 50 mL glucose 5% and infuse over 10 to 15 minutes.
Oral: IV formulation may be given orally (if patient is able to swallow). Dilute dose to 100 to 200mL with water to minimise dysuria and gastrointestinal side effects.
Onset of response may vary from hours to days.
- G6PD deficiency
- known hypersensitivity to methylene blue
- severe renal insufficiency.
Do not administer methylene blue if the patient has:
Precautions when administering methylene blue:
- IV methylene blue may cause falsely low pulse oximetry readings.
- Ensure all patients receiving methylene blue have daily monitoring of haemoglobin (Hb).
- Large doses of methylene blue may cause headaches, dizziness, mental confusion, profuse diaphoresis, hypertension, hypotension, arrhythmias, dysuria, abdominal pain, nausea and vomiting.
- Blue discolouration of urine, stool, skin, saliva and mucous membranes may occur.
- Methylene blue is a potent monoamine oxidase inhibitor (MAOI) and can cause serotonin toxicity if given concomitantly with other serotonergic drugs.
- Do not administer via intrathecal route (can cause neural damage) or subcutaneous route (can cause necrotic abscess).r
The neurological side effects of ifosfamide are similar to Wernicke’s encephalopathy, which is caused by severe thiamine deficiency.r Thiamine is a coenzyme in carbohydrate metabolism and has a function in nerve conduction, leading to improved neuronal function.r
Treatment dose: 100 mg IV every 4 hours.
Administer diluted in 100 mL sodium chloride 0.9% over 10 minutes. Continue until symptoms have resolved or significantly improved.