4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Table 7 summarizes major drug-drug interactions considered clinically relevant for H2RAs. Only those drug-drug interactions identified as severe or those considered life-threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level # |
|---|---|---|---|---|
| cimetidine | clopidogrel (Plavix®) | co-administration may result in decreased clopidogrel active metabolite levels, platelet inhibition, and clopidogrel efficacy; clopidogrel requires metabolism through CYP2C19 to active metabolite and cimetidine is CYP2C19 inhibitor |
cimetidine-clopidogrel combination should be avoided; H2RA alternatives (e.g., famotidine, ranitidine) that are not CYP2C19 inhibitors can be substituted for cimetidine |
major (CP) |
| cimetidine | dofetilide (Tikosyn®) | concurrent use may potentially increase dofetilide serum levels/ enhance pharmacologic effects (e.g., torsades de pointes) as dofetilide metabolized by CYP3A4, eliminated through renal and hepatic mechanisms; cimetidine inhibits dofetilide clearance through interference with active tubular secretion and moderate CYP3A4 inhibition | dofetilide manufacturer states that concurrent administration of dofetilide and cimetidine is contraindicated; medications without effect on dofetilide pharmacokinetics (e.g., omeprazole, ranitidine, antacids) are potential alternatives to cimetidine | severe (CP) |
| cimetidine | theophylline | adjunctive use may cause theophylline toxicity as cimetidine inhibits theophylline hepatic metabolism | adjunctive use possible if proper monitoring and/or dosage adjustments are made; order in which therapy initiated important - adding theophylline to existing cimetidine drug regimen can be safe as theophylline dosage titrated to acceptable serum concentrations, but adding cimetidine to existing theophylline regimen may enhance theophylline pharmacologic/ adverse effects; other available H2RAs do not significantly interact with theophylline and may be appropriate alternatives for cimetidine | major (CP) |
| cimetidine | warfarin | combined use may result in increased INR and moderate to severe bleeding in some patients as cimetidine stereoselectively inhibits hepatic metabolism of warfarin R-isomer | adjunctive use possible if proper monitoring and/or dosage adjustments are made; order in which therapy is initiated is important - adding warfarin to existing cimetidine drug regimen can be safe as warfarin dosage titrated to acceptable monitoring parameter (e.g., INR), but adding cimetidine to existing warfarin regimen may enhance warfarin-induced hypoprothrombinemic response; other H2RAs do not significantly interact with warfarin - may be appropriate alternatives for cimetidine | major (CP) |
| H2RAs | atazanavir (Reyataz®) | concurrent use may cause reduced atazanavir efficacy and increased resistance, as increased gastric pH with H2RAs causes decreased atazanavir solubility/ absorption/plasma levels | administer atazanavir either with and/or at least 10 hours after H2RA dose and monitor for decreased efficacy/increased resistance | major (CP) |
| H2RAs | select azole antifungals (itraconazole (Sporanox®), ketoconazole, posaconazole (Noxafil®) | combined use may result in reduced azole antifungal bioavailability, decreased maximum azole antifungal serum levels, and attenuated azole antifungal pharmacologic effects, as H2RAs increase gastric pH and azole antifungal oral absorption is dependent on acidic environment | posaconazole manufacturer recommends avoiding the posaconazole-cimetidine drug combination unless benefits outweigh risks; if H2RA-azole antifungal combination necessary, monitor patients carefully for reduced antifungal activity | major (CP) |
| H2RAs | drugs pH- dependent for solubility (e.g., dasatinib- Sprycel®; erlotinib – Tarceva®) | adjunctive administration for extended duration may result in reduced exposure and serum levels in select medications dependent on acidic gastric pH for solubility and absorption | combined use not recommended; alternative acid suppressives (e.g., antacids) should be administered 2 hours before or 2 hours after pH-dependent medication for optimal efficacy | major (CP) |
| H2RAs | delavirdine (Rescriptor®) | combined use for extended treatment duration may result in reduced delavirdine absorption, decreased delavirdine serum levels, and attenuated delavirdine efficacy as delavirdine is dependent on an acidic gastric pH for absorption; separating drug doses may not improve delavirdine absorption as H2RAs affect gastric pH for prolonged time | concomitant use not recommended; antacids may be alternative acid suppressive therapy, with antacid and delavirdine doses separated by at least one hour | major (CP) |
Legend:
- *CP = Clinical Pharmacology
- H2RAs = histamine (H2) receptor antagonists
- INR = International Normalized Ratio