How should clozapine be adjusted in a patient starting ciprofloxacin?

Clozapine Dose Adjustment When Adding Ciprofloxacin

When adding ciprofloxacin 500 mg PO BID to a patient on clozapine 250 mg PO QAM and 300 mg PO QHS, the clozapine dose should be reduced to one-third of the current dose (approximately 180 mg total daily dose) due to the strong inhibition of CYP1A2 by ciprofloxacin. 1

Mechanism of Interaction

• Ciprofloxacin is a strong CYP1A2 inhibitor that significantly reduces clozapine metabolism, leading to elevated clozapine plasma levels and potential toxicity 2, 3
• This interaction can cause a 2-3 fold increase in clozapine plasma concentrations, which may result in serious adverse effects including death 3, 4

Recommended Dose Adjustment

• Reduce the total daily clozapine dose to one-third of the current dose (from 550 mg to approximately 180 mg daily) 1
• Consider dividing as 90 mg PO QAM and 90 mg PO QHS to maintain a similar morning/evening distribution 2
• This reduction should be implemented immediately when starting ciprofloxacin 1, 3

Monitoring Requirements

• Obtain a baseline clozapine level before starting ciprofloxacin if possible 2, 3
• Monitor trough clozapine levels on day 2 of ciprofloxacin treatment 2
• Watch closely for signs of clozapine toxicity including:
  • Hypotension or orthostatic changes 2
  • Tachycardia 2
  • Seizures 2
  • Excessive sedation 4
  • Confusion or delirium 4

After Completing Ciprofloxacin

• Do not immediately return to the original clozapine dose after completing the 3-day ciprofloxacin course 1
• Gradually increase the clozapine dose over several days while monitoring for adverse effects 1
• Consider obtaining another clozapine level 3-5 days after ciprofloxacin discontinuation before returning to the full dose 3, 4

Important Cautions

• This interaction has been associated with fatalities due to acute clozapine toxicity 3
• If possible, consider alternative antibiotics without CYP1A2 inhibition properties 4
• If ciprofloxacin is absolutely necessary, the clozapine dose reduction is mandatory 1, 3
• Maintain regular neutrophil monitoring as per standard clozapine protocols 1

Alternative Approach

• If the infection is not severe and alternative antibiotics are available, consider using an antibiotic that does not inhibit CYP1A2 to avoid the need for clozapine dose adjustment 4
• If the patient shows signs of clozapine toxicity despite dose reduction, consider temporarily holding clozapine doses and consulting with a pharmacist 5, 3