Warfarin
Ranitidine (Zantac) Interactions
NOTE: Although ranitidine has been reported to bind weakly to cytochrome P-450 in vitro, recommended doses of the drug do not inhibit the action of the cytochrome P-450 enzyme system. However, there have been isolated reports of drug interactions that suggest that ranitidine may affect the bioavailability of certain drugs by some mechanism as yet unidentified (e.g., a pH-dependent effect on absorption or a change in volume of distribution).
Reports in the literature have suggested ranitidine increases theophylline serum concentrations, but clinical studies in healthy subjects have failed to identify this effect. Furthermore, a clinical study in 12 healthy subjects demonstrated a lack of effect of ranitidine doses up to 4200 mg/day on theophylline metabolism. However, caution should be exercised when using even larger doses, such as in the treatment of Zollinger-Ellison syndrome (see dosage), since the occurrence of cimetidine-like drug interactions at these doses is unknown.
Ranitidine appears to have less of an effect on hepatic metabolism of warfarin than cimetidine. Most studies have found that in oral dosages of 300 mg/day or less or equivalent, ranitidine is not likely to have any effect on warfarin pharmacodynamics or pharmacokinetics. However, variable effects on INR’s have been reported. Excessive hypoprothrombinemia has occurred when ranitidine, in dosages > 300 mg/day, was added to an established warfarin regimen in rare instances. One extensive review has concluded that adequate evidence of an interaction between ranitidine and warfarin has yet to be reported.
Ketoconazole and itraconazole are weak bases. Both require an acidic environment for oral absorption and therapy with ranitidine can reduce their bioavailability. The mechanism involves decreased ionization and dissolution of the antifungals. Due to the sustained action of H2-blockers, a clinically-significant drug interaction with these azole antifungals may still occur even if administration times are adjusted. When possible, concurrent use of H2-blockers with either ketoconazole or itraconazole should be avoided.
H2-blockers appear to increase the systemic absorption of bismuth from bismuth-containing compounds like bismuth subsalicylate. The clinical significance of this finding is uncertain.
H2-blockers can affect the pharmacokinetics of some orally-administered cephalosporins. Ranitidine has been shown to reduce oral cefuroxime axetil AUC by more than 40% and reduce the AUC of oral cefpodoxime by 29%. The interactions are probably due to increased gastric pH and subsequent pH-induced changes in the oral absorption of these cephalosporins. Clinicians should watch for antibiotic failure in patients receiving cefpodoxime or cefuroxime who are concurrently receiving H2-blockers. Conversely, the oral bioavailability of ceftibuten was reported to be increased by the administration of 150 mg of ranitidine PO every 12 hours for 3 days, but this interaction is of unknown clinical relevance. Furthermore, co-administration of a single dose of an intravenous H2-blocker (famotidine) reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered after a meal. There was a 27% and 22% decrease in mean Cmax and AUC, respectively. Although the clinical significance is not known, it is recommended that cefditoren pivoxil not be taken concomitantly with any H2-blockers.
Although some studies have suggested that H2-receptor antagonists inhibit gastric alcohol dehydrogenase and thus decrease the first pass metabolism of ethanol, a small study of patients receiving treatment for duodenal ulcer with either famotidine or ranitidine did not demonstrate altered ethanol pharmacokinetics. A meta-analysis evaluating the effects of H2-blockers on blood ethanol concentrations reported that only cimetidine and ranitidine, but not other H2-blockers, caused small elevations in serum ethanol levels. However, it was reported that larger studies were less likely to show an effect and that these elevations were not likely to be clinically relevant.
Propantheline bromide increases the bioavailability of ranitidine by 23% when the drugs are administered concomitantly. Propantheline bromide is believed to delay gastric emptying, increase transit time, and thereby increase the peak plasma concentration of ranitidine.
Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas, notably, glipizide and glyburide. In one placebo controlled study, diabetic patients stabilized on glipizide were given ranitidine 3 hours before a meal. Ranitidine significantly reduced the rise in blood glucose after a meal by a mean of 25% and also increased plasma glipizide AUC by approximately 20%. Similar effects have been reported with glyburide. The mechanism of the interaction is not clear, but asymptomatic hypoglycemia has been observed as a result of this interaction. Animal studies to date have not noted pharmacokinetic interactions between ranitidine and other sulfonylureas (e.g., tolbutamide), but caution is advised. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued.
Cationic medications, like ranitidine, may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when ranitidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin because of less tubular excretion.
Ranitidine has been shown to decrease the bioavailability of orally-administered enoxacin by up to 40%, and this interaction is thought to be due to decreased gastric acidity. Patients taking the two medications concurrently should be observed for antibiotic failures. Ranitidine appears to have variable effects on the pharmacokinetics of other quinolone antibiotics. Ranitidine does not appear to decrease the oral absorption of ciprofloxacin. The renal tubular secretion of lomefloxacin has been shown to be decreased by ranitidine, and is probably due to competition for renal tubular secretion.
Sucralfate may slightly decrease ranitidine bioavailability. Sucralfate does not appear to reduce the bioavailability of other orally-administered H2-antagonists to a clinically significant degree. Drugs that reduce gastric acidity (e.g. H2-blockers) were formerly thought to decrease the ability of sucralfate to bind to ulcerated tissues in the GI tract; however, in vitro animal studies have not supported an interaction between the H2-antagonists and sucralfate. The concurrent use of H2-blockers does not appear to interfere with the appropriate action of sucralfate.
Ranitidine has been reported to increase the plasma concentrations of oral triazolam when administered concurrently. Mean triazolam AUCs were 10 - 28% higher following the use of ranitidine versus those occurring with triazolam alone in patients under the age of 60 years. In the elderly, mean triazolam AUC values increased by 30%. Ranitidine does not alter the AUC of intravenous triazolam. It is postulated by the manufacturer of ranitidine that reduced gastric acidity may increase triazolam bioavailability, as no changes in triazolam half-life or metabolic pathways were observed.
The absorption of dirithromycin is slightly enhanced when administered immediately following antacids or H2-blockers. The clinical significance of this interaction is unclear.
The bioavailability of oral iron salts is influenced by gastric pH, and concomitant administration of H2-blockers may decrease iron absorption. Limited data suggest cimetidine decreases gastric, non-heme iron absorption. However, the clinical significance of this interaction is unclear since it is not a well recognized complication of cimetidine therapy. Iron salts provide non-heme iron which requires an acidic intragastric pH to be reduced to ferrous and to be absorbed. At higher pH values iron is more readily ionized to its ferric state, which is more poorly absorbed. Since H2-blockers have long-lasting effects, adjusting administration times may not alleviate the possible interaction. Although significant data are lacking, It is likely that other H2-blockers, including ranitidine, can also reduce the oral absorption of iron supplements.
Cimetidine can increase nifedipine area-under-the-curve by inhibiting hepatic metabolism of nifedipine. Ranitidine has been shown to have a similar, but lesser effect on nifedipine pharmacokinetics. Clinicians should be alert for exaggerated nifedipine effects if ranitidine is added to the regimen. Although data are lacking, similar precautions may apply to the addition of ranitidine to isradipine or nicardipine. Ranitidine does not appear to interact with amlodipine or felodipine.
Drugs that cause a significant sustained elevation in gastric pH (e.g., H2-blockers, gastric acid-pump inhibitors) may reduce plasma concentrations of gefitinib and thus potentially may reduce gefitinib efficacy. Concurrent administration of high doses of ranitidine with sodium bicarbonate to maintain the gastric pH > 5 reduced the mean gefitinib AUC by 44%.
Memantine is excreted in part by renal tubular secretion. Cationic drugs that are eliminated by renal tubular secretion (e.g., ranitidine) may decrease memantine elimination by competing for common renal tubular transport systems. Careful patient monitoring and dose adjustment of memantine and/or ranitidine is recommended. Of the H2-antagonists, cimetidine is most likely to interact with memantine in this manner; famotidine and nizatidine may be less likely to interact with memantine because of less tubular excretion.
Coadministration of delavirdine with antacids results in decreased absorption of delavirdine. When given in combination with an antacid (Maalox TC®), the Cmax of delavirdine was decreased by 52% and the delavirdine AUC was decreased by 44%. Administration of delavirdine and antacids should be separated by at least 1 hour. H2-blockers and proton pump inhibitors (PPIs), which increase gastric pH, may also reduce the absorption of delavirdine. However, since these agents affect gastric pH for an extended period, separation of doses may not eliminate the interaction. Chronic use of H2-blockers and proton pump inhibitors (PPIs) with delavirdine is not recommended.
Atazanavir solubility decreases as gastric pH increases. The coadministration of atazanavir (400 mg once daily) with famotidine (40 mg twice daily) resulted in substantially decreased atazanavir plasma concentrations. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. However, H2-blockers (famotidine, nizatidine, ranitidine, and cimetidine) can be used during treatment with atazanavir under specific administration restrictions. In treatment-naive patients 2 regimens may be used: 1) atazanavir 400 mg once daily with food given at least 2 hours before and at least 10 hours after the H2-blocker or 2) atazanavir 300 mg boosted with ritonavir 100 mg given once dialy with food without the need for separation from the H2-blocker. Treatment-experienced patients should receive atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food at least 2 hours before and at least 10 hours after the H2-blocker.
Both trospium and ranitidine are eliminated by active renal tubular secretion; coadministration has the potential to increase serum concentrations of trospium or ranitidine due to competition for the drug elimination pathway. Careful patient monitoring and dosage adjustment of trospium and/or ranitidine is recommended.
Although the clinical significance has not been determined, the bioavailability of oral alendronate is doubled by concomitant administration of intravenous ranitidine. Investigations have not been undertaken to determine if other H2-antagonists have a similar effect on bioavailability. Patients should be closely monitored when antiulcer medications, such as proton pump inhibitors (PPIs), gastric mucosal agents, and H2-blockers, or other medications for GI disorders, are coadministered as they may affect the bioavailability of alendronate, leading to a higher likelihood of developing GI adverse effects while taking alendronate.
Ranitidine does not have a significant in vivo drug interaction with voriconazole. An open-label, placebo-controlled, three-way crossover study evaluated the effects of cimetidine and ranitidine on the pharmacokinetics of voriconazole. Twenty healthy male subjects received voriconazole alone, voriconazole plus cimetidine, and voriconazole plus ranitidine; treatment periods were separated by at least 7 days. The AUC of voriconazole was increased 22% by cimetidine and 4% by ranitidine; neither cimetidine nor ranitidine altered the half-life of voriconazole. According to manufacturer recommendations, these interactions are not clinically significant and dose adjustment of voriconazole is not required with these agents.
Both entecavir and ranitidine are secreted by active tubular secretion. In theory, coadministration of entecavir with ranitidine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
The effects of gastrointestinal pH alterations on the absorption of methylphenidate extended release capsules (Ritalin® LA) and dexmethylphenidate extended-release tablets (Focalin™ XR) have not been studied. Although the SODAS® system (drug delivery system utilized in Ritalin® LA and Focalin™ XR) is thought to be minimally affected by changes in pH, per the manufacturer, the modified release characteristics of both extended-release formulations are pH-dependent. It is possible that the administration of H2-blockers or other acid suppressants could alter the release of dexmethylphenidate or methylphenidate. Patients receiving these extended-release products (Focalin™ XR or Ritalin® LA) with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
[ Last revised: 3/23/2006 12:40:00 PM ]
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