Prescriber Update Articles

Omeprazole May Elevate Clozapine Levels

Website: September 2002
Prescriber Update 2002;23(3):39

Dr David Coulter, IMMP Director, 
Centre for Adverse Reactions Monitoring, Dunedin

The IMMP has received three reports of elevation of clozapine levels occurring when omeprazole was co-prescribed in patients already stabilised on clozapine.  In two of the cases, seizures occurred.  The mechanism of the interaction is unknown, but it would be prudent to monitor clozapine levels if concurrent therapy with omeprazole is necessary.

Three reports have been received in the Intensive Medicines Monitoring Programme (IMMP) of problems associated with the combined use of clozapine (Clopine™, Clozaril™) and omeprazole (Losec™).  The dose of omeprazole was unknown in each case.  The reports are summarised as follows:

1. A man aged 73 was well stabilised after titration of clozapine to 200mg daily.  At 150mg daily, he had a blood level of clozapine of 570 nmol/L.  Omeprazole was added to his therapy and about two months later his clozapine blood level was 2700 nmol/L.  This rose to 6420 nmol/L after a further six days (usual therapeutic range 1-2000 nmol/L).  No adverse effects were reported.  The dose of clozapine was reduced and plasma levels fell quite quickly.
2. A man aged 32 had remained well on clozapine 475mg daily, for three years.  Some time after commencing omeprazole, he was found unconscious after a probable seizure.  A high clozapine plasma level (8216 nmol/L) was noted.  Clozapine was withdrawn for four days to reduce plasma levels, and the patient recovered.
3. Another man aged 44 had been well controlled on clozapine 600mg daily for two years, and was then prescribed omeprazole for peptic ulceration and oesophagitis.  Two weeks later he suffered a generalised seizure and had a plasma clozapine level of 1790 nmol/L.  No previous values were available.  The omeprazole was discontinued and the clozapine dose reduced to 300mg daily.  There were no further problems.

These reports suggest that the addition of omeprazole to therapy with clozapine may cause elevated clozapine plasma levels and dose-related adverse effects.  There is no clearly recognisable mechanism for this interaction.  Clozapine and omeprazole have multiple metabolism sites but are both substrates for the CYP 3A4 hepatic enzyme, which may be more important for metabolism in some patients.  In these circumstances, competitive inhibition may come into play.

Prescribers should be aware of the possibility of this interaction and check clozapine levels if concomitant therapy with omeprazole is required.

Competing interests (author): Novartis (sponsor of Clozaril™) has provided research grants for the IMMP.

Correspondence to Dr David Coulter, CARM, PO Box 913, Dunedin.