SSRIs + H2-receptor antagonists - Drug Interactions

Citalopram, escitalopram, paroxetine and sertraline levels aremoderately increased by cimetidine but only clinically relevant effect appears to be a slight increase in adverse effects withsertraline.

Twelve healthy subjects were given citalopram 40mg daily for 21 days and then for next 8 days they were also given cimetidine 400mg twice daily. The cimetidine caused a 29 % decrease in oral clearance of citalopram, a 39 % rise in its maximum serum levels and a 43 % increase in its AUC. Some changes in renal clearance of citalopram metabolites were also seen (See reference number 1).

Cimetidine 400mg twice daily increased mean plasma level of escitalopram by about 70%. There was also a 22 % increase in maximum plasma level of citalopram, but this was not considered to be clinically significant (See reference number 2).

Cimetidine 200mg four times daily for 8 days did not affect mean pharmacokinetic values or bioavailability of a single 30mg dose of paroxetine in 10 healthy subjects. However,2 subjects had AUC increases of 55 % and 81%, respectively, while taking cimetidine and 4 others also had some minor increases (See reference number 3). Another study in 11 healthy subjects found that cimetidine 300mg three times a day increased AUC of paroxetine 30mg daily by 50 % after 1 week of concurrent use (See reference number 4).

In a randomised,two-way, crossover study, 12 healthy subjects were given a single 100mg oral dose of sertraline after taking either cimetidine 800mg or a placebo at bedtime for 7 days. Cimetidine increased AUC of sertraline by 50%, maximum serum levels of sertraline by 24%, and half-life by 26 % (See reference number 5,6). There was a small increase in sertraline adverse effects (not specified) while taking cimetidine (See reference number 5).

The apparent reason for all these changes is that cimetidine inhibits activity of cytochrome P450 so that metabolism of SSRIs is reduced, and as a result their serum levels rise.

The authors of citalopram study say that while cimetidine certainly causes an increase in serum levels of citalopram, extent is only moderate and because drug is well tolerated and there are very considerable pharmacokinetic variations between individual subjects, they consider that there is no need to reduce citalopram dosage (See reference number 1). This advice is most likely applicable to escitalopram, S-isomer of citalopram. However, manufacturer of escitalopram suggests caution, and advises that a reduction in dose of escitalopram may be necessary (based on monitoring of adverse effects) during concurrent treatment (See reference number 7).

Information on concurrent use of cimetidine and paroxetine or sertraline seems to be limited and clinical significance of changes in clearance is not known. However, it would be prudent to monitor outcome for excessive adverse effects (dry mouth, nausea, diarrhoea, dyspepsia, tremor, ejaculatory delay, sweating) if cimetidine is used with either of these SSRIs and reduce sertraline or paroxetine dosage if necessary. If suggested mechanism of interaction is true, one of other H2-re

ceptor antagonists that lack enzyme inhibitory activity,such as ranitidine or famotidine, might be a non-interacting alternative for cimetidine. This needs confirmation.

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Cipralex (Escitalopram oxalate). Lundbeck Ltd. UK Summary of product characteristics,December 2005.