Cimetidine Ciclosporin

Omeprazole can inhibit the metabolism of drugs metabolised mainly by the cytochrome P-450 enzyme subfamily 2C (diazepam, phenytoin), but not of those metabolished by subfamilies lA (caffeine, theophylline), 2D (metoprolol, propranolol), and 3A (ciclosporin, lidocaine (lignocaine), quinidine). Since relatively few drugs are metabolised mainly by 2C compared with 2D and 3A, the potential for omeprazole to interfere with the metabolism of other drugs appears to be limited, but the half lives of diazepam and phenytoin are prolonged as much as by cimetidine. 

CICLOSPORIN H2 RECEPTOR BLOCKERS -CIMETIDINE t plasma concentrations of ciclosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity, excessive immunosuppression, with risk of infection and post-transplant lymphoproliferative disease Inhibition of CYP3A4-mediated metabolism of ciclosporin these inhibitors vary in potency. Cimetidine is classified as a potent inhibitor Avoid co-administration with cimetidine. Consider an alternative H2-blocker, but need to monitor plasma ciclosporin levels to prevent toxicity... 

The available data on a possible interaction between histamine H2 receptor antagonists and ciclosporin are inconclusive. Whereas neither cimetidine nor ranitidine significantly altered ciclosporin pharmacokinetics, there was an increase in serum creatinine concentration in patients taking both ciclosporin and cimetidine, but not ranitidine. The clinical significance of this interaction is probably limited, and it has been attributed to competition of cimetidine with creatinine for tubular secretion (251). 

The concurrent use of ranolazine and moderate or potent inhibitors of CYP3A4, such as some azoles, diltiazem, grapefruit juice, macrolides, protease inhibitors, or verapamil will result in increased levels of ranolazine, and can predispose the patient to adverse effects including QT interval prolongation. Cimetidine and paroxetine do not interact to a clinically significant extent. Ranolazine may increase levels of ciclosporin, digoxin or simvastatin. 

The ciclosporin blood levels of a kidney transplant patient rose from 850 to 1930 nanograms/mL when metronidazole 2.25 g daily and cimetidine 800 mg daily were started. The levels fell to about 1500 nanograms/mL when the metronidazole dosage was halved and the eimetidine stopped. Beeause the levels of eielosporin were still so high, the dose of ciclosporin... 

These three cases appear to be the only reports of an interaction, one of which is confused by the presence of cimetidine (see also Ciclosporin + H2-receptor antagonists , p.l035). There is insufficient evidence to advocate monitoring every patient given the combination, but it would be prudent to at least bear tiiis interaction in mind if using metronidazole in patients taking ciclosporin. 

One report (see Cimetidine above), where the eifeets of cimetidine and ranitidine were examined together, suggests that ranitidine raises creatinine levels in patients taking ciclosporin, without affecting ciclosporin levels. Similarly, several other reports say that ranitidine does not alter ciclosporin blood levels. " One also notes that ranitidine does not alter creatinine levels and inulin clearance. ... 

Information about the possible interactions of ciclosporin and cimetidine, famotidine or ranitidine is inconsistent, but there appear to be very few reports of confirmed toxicity. Moreover the reported increases in serum creatinine levels seen with the H2-receptor antagonists may not be a reflection of increased nephrotoxicity (see Mechanism )- Thus there is little to suggest that concurrent use should be avoided, but good initial monitoring is advisable. 

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