Managing interactions with omeprazole

A 30-year-old man comes into the pharmacy complaining of recurrent attacks of heartburn. He tells you that the symptoms are worse after large meals, and especially bad when he lies down. He has no history of other gastrointestinal conditions. He says he has seen an advertisement for Zanprol (omeprazole) and he asks you if he can buy a box. On further questioning he tells you he takes citalopram 20mg daily for depression.
Is there an interaction with citalopram? Omeprazole is a moderate inhibitor of CYP2C19 and citalopram is a substrate of this isoenzyme. A crossover study in healthy subjects has shown that omeprazole approximately doubled the area under the concentration-time curve (AUC) of plasma S-citalopram (escitalopram), but did not affect the AUC of R-citalopram to a statistically significant extent.[1] Any patient taking citalopram (or escitalopram) would, therefore, be expected to have a moderate increase in its exposure on concurrent use with omeprazole.However, because CYP2C19 is subject to genetic polymorphism (see PJ 2013;291:350–51), the extent to which citalopram is metabolised via this route could depend on the individual. Furthermore, determining the metaboliser status of an individual is currently a research tool rather than a clinical one.

The clinical relevance of the interaction between omeprazole and citalopram is unclear. Until more is known, patients should be advised to be alert for an increase in citalopram adverse effects (such as dry mouth, increased sweating, or insomnia) when taking omeprazole. If patients experience an increase in citalopram adverse effects, they should be advised to stop taking it and to see their GP if the effects are severe, or switched to an alternative treatment for heartburn. For patients on longer-term treatment with omeprazole, consideration should be given to decreasing the dose of the SSRI if citalopram adverse effects become troublesome.

Pantoprazole, another proton pump inhibitor available for OTC sale, does not inhibit CYP2C19 to a clinically relevant extent, and would be a more suitable alternative for this patient. Some H2 receptor antagonists, such as famotidine and ranitidine (but not cimetidine) also do not inhibit cytochrome P450 isoenzymes to a clinically relevant extent, and could also be sold to this patient for his heartburn.

After you have explained the possible outcome of taking omeprazole with citalopram, and suggested alternatives, the patient decides he would still like to “give omeprazole a try”. After ensuring that he is aware of potential interaction effects and what to do if he experiences any, you sell it to him. You also explain that OTC omeprazole should only be used for up to two weeks and, if his symptoms persist, he should see his GP.

A week later, the man returns to the pharmacy with a prescription for itraconazole capsules for a persistent ringworm infection. You ask him how his heartburn is. He tells you that it is still causing him problems, but the omeprazole is helping and he has been taking it on most days.

On checking the prescription, you see there is an interaction between itraconazole and omeprazole.

How significant is this interaction with itraconazole? Itraconazole is a poorly soluble base that must be converted by acid in the stomach into the soluble hydrochloride salt. Drugs that reduce acidity, such as proton pump inhibitors, H2 receptor antagonists, or antacids, therefore reduce the dissolution and absorption of itraconazole when given in capsule form.

In a study in healthy subjects, the AUC and maximum plasma concentration of itraconazole given as a capsule were both reduced by about 65 per cent by omeprazole.[2] In contrast, another study in healthy subjects found that omeprazole did not affect the pharmacokinetics of single doses of itraconazole given as an oral solution.[3]

The above studies indicate the possibility of an interaction between omeprazole and itraconazole capsules, but not between omeprazole and itraconazole solution. Therefore one option is to contact the man’s GP and suggest that he prescribes itraconazole solution to reduce the possibility of an interaction.

It is interesting to note that studies have shown that giving itraconazole with acidic drinks can increase its dissolution and absorption. For example, a study in eight healthy subjects given itraconazole 100mg with either 325ml of water or Coca-Cola (pH 2.5) found that the maximum plasma concentration of itraconazole was more than doubled by Coca-Cola and the AUC of itraconazole was increased by 80 per cent, although two of the subjects did not show this effect.[4]

Although their effects on itraconazole absorption have not been studied, diet carbonated drinks are less acidic and are therefore expected to be less effective at reducing the stomach pH.9

In theory, you could consider recommending that patients prescribed a combination of omeprazole with itraconazole take the latter with an acidic drink, such as non-diet cola, to increase gastric acidity and absorption of the antifungal, but this may not be such a good idea since acidic carbonated drinks might make heartburn worse.

You decide to call the patient’s GP and explain that he is taking OTC omeprazole. You suggest that it would be a good idea to prescribe itraconazole liquid instead of the capsules. The GP agrees.

Several months later the man returns with a prescription for fluoxetine 20mg daily, omeprazole 10mg daily, and a seven-day course of clarithromycin 250mg bd for an upper respiratory tract infection. He tells you that he did not respond particularly well to the citalopram, so his GP changed him to a different SSRI. Remembering your previous advice about potential drug interactions with omeprazole, the patient asks you if there will be any problems taking clarithromycin with his other prescribed medicines.

What are the potential interactions with clarithromycin? CYP3A4 is one of the isoenzymes involved in the metabolism of omeprazole, and clarithromycin is a potent inhibitor of this isoenzyme. It would, therefore, be expected to increase the exposure of omeprazole, leading to an increase in omeprazole’s adverse effects.

Studies have shown that clarithromycin moderately increases the AUC of omeprazole, but because omeprazole has a wide therapeutic range, the increase in exposure reported is unlikely to be clinically relevant.[5],6  In addition, omeprazole might slightly increase the AUC of clarithromycin and its active metabolite, but this is also not expected to be clinically relevant.6

An isolated case report describes a man who developed apparent acute fluoxetine toxicity while taking clarithromycin, but the clinical significance of this case report is unknown. It has been suggested that clarithromycin (a potent inhibitor of CYP3A4), reduced the metabolism of fluoxetine, thereby increasing its serum concentration and precipitating the observed toxicity.7 However, fluoxetine does not appear to be primarily metabolised by CYP3A4.

The Stockley’s team is not aware of an interaction between fluoxetine and omeprazole and the book contains no data for an interaction with this drug pair. The patient can be advised that no additional precautions or dose adjustments appear necessary on the concurrent use of omeprazole, clarithromycin, and fluoxetine.

This case serves to illustrate some of the drug interactions that should be considered when omeprazole is sold over the counter and how they can be managed. It also highlights that not all potential drug interactions will be clinically relevant because of omeprazole’s wide therapeutic range. Panel 1 lists some more drug interactions that could occur with omeprazole.

Other omeprazole interactions
Cilostazol Omeprazole increases the exposure to cilostazol. Cilostazol dose reduction might be required.

Clopidogrel Omeprazole might reduce the antiplatelet effects of clopidogrel. Consider giving an H2 receptor antagonist (not cimetidine) or pantoprazole instead.

Clozapine Omeprazole possibly reduces clozapine concentrations. Monitor for reduced clozapine efficacy.

Methotrexate Reduced methotrexate elimination has been reported in

patients given proton pump inhibitors with high-dose methotrexate. Routine methotrexate monitoring should detect any toxicity; some advise against concurrent use and suggest that omeprazole should be stopped five days before starting methotrexate.

Phenytoin Phenytoin exposure might be increased or not affected by omeprazole. Any interaction seems unlikely to be clinically significant, but be alert for signs of phenytoin toxicity.

Tacrolimus Omeprazole might affect tacrolimus exposure; consider monitoring tacrolimus concentrations when either drug is started or stopped.

Voriconazole Voriconazole increases the exposure to omeprazole. Omeprazole might increase the exposure to voriconazole and serious neurological adverse effects have been seen in some patients. Voriconazole dose reduction is recommended.

Key points
Omeprazole might increase exposure to citalopram but the clinical relevance is unclear. Patients should be alerted to the possibility of an increase in citalopram adverse effects.

No additional precautions or dose adjustments appear to be necessary with the concurrent use of omeprazole and clarithromycin.

Omeprazole reduces the exposure to itraconazole given as capsules, but not when given as itraconazole solution.

Taking itraconazole capsules with an acidic drink, such as non-diet cola, can increase gastric acidity and therefore increase the absorption of the drug.

About Stockley
This article has been produced by Stephanie Jones, Sonia Khan and Claire L. Preston on behalf of the ‘Stockley’s drug interactions’ editorial team.

The book is available in print through Pharmaceutical Press (www.pharmpress.com) or electronically with quarterly updates through MedicinesComplete (www.medicinescomplete.com).

References:

[1]Rocha, A, Coelho EB, Sampaio SA, et al. Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers. Br J Clin Pharmacol (2010) 70, 43–51.

[2]Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol (1998) 54, 159–61.

[3]Johnson MD, Hamilton CD, Drew RH, et al. A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution. J Antimicrob Chemother (2003) 51, 453–7.

[4]Jaruratanasirikul S, Kleepkaew A. Influence of an acidic beverage (Coca-Cola) on absorption of itraconazole. Eur J Clin Pharmacol (1997) 52, 235–7.

[5]Pollak PT, Sketris IS, MacKenzie SL. Delirium probably induced by clarithromycin in a patient receiving fluoxetine. Ann Pharmacother (1995) 29, 486–8.

Source:
The Pharmaceutical Journal 5 APR 2014 By
Stephanie Jones
Sonia Khan
Claire L. Preston
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