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Drug Interactions
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RANITIDINE ORAL
Drug Interactions
Drug-Drug Interactions from First DataBank
These drug interactions are reviewed by an editorial panel at First DataBank and determined to be clinically significant The list does not
include every interaction ever reported.
Contraindicated
None listed
Severe
ITRACONAZOLE; KETOCONAZOLE/H-2
ANTAGONISTS
Moderate
None listed
Drug-Food Interactions from First DataBank
More Significant
None listed
More Significant
None listed
Significant
None listed
Less Significant
None listed
Minor Significance
None listed
Drug Interactions from AHFS DITM
Food and Antacids
Concomitant administration of food or low-dose antacids (neutralizing capacity of 10—15 mEq of hydrochloric acid per 10 mL) does not
appear to substantially decrease the absorption of ranitidine or the mean peak plasma concentration of the drug. However, in one study,
concomitant administration of 30 mL of an aluminum and magnesium hydroxides antacid (Mylanta-II®; neutralizing capacity of 150 mEq of
hydrochloric acid per 30 mL), 30 mL of water, and a single 150-mg dose of ranitidine resulted in a 33% decrease in the absorption of
ranitidine; peak serum ranitidine concentration decreased from 613 to 432 ng/mL and the area under the serum concentration-time curve
(AUC) decreased from 3613 to 2394 g hour/L. The time to reach the peak and the rate of absorption of the drug were not substantially
altered by concurrent administration of the antacid in this study; elimination half-life and renal clearance of ranitidine remained unchanged,
but the fraction of the dose excreted in urine as unchangeddrug and as the desmethyl metabolite was reduced by concomitant administration
of antacid, Concomitant administration of ranitidine bismuth citrate and a high dose (170 mEq) of an antacid results in a 28% reduction in
ranitidine plasma concentrations and also may reduce plasma bismuth concentrations; the manufacturer states that these effects are not
clinically important.
Drug Interactions
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Clarithromycin
Concomitant administration of ranitidine bismuth citrate and clarithromycin increased plasma ranitidine concentrations (57%), plasma
bismuth trough concentrations (48%), and plasma 14-hydroxyclarithromycin concentrations (31%).
Propantheline Bromide
Propantheline bromide appears to delay the absorption and increase the peak serum concentration of ranitidine, probably by delaying gastric
emptying and prolonging transit time; the relative bioavailability of ranitidine reportedly is increased approximately 23% with concomitant
administration ofpropantheline.
Smoking
Cigarette smoking reportedly adversely affects the healing of duodenal ulcers and also appears to decrease the efficacy ofranitidine. In a
controlled study, 62 and 100% of duodenal ulcers in smokers and nonsmokersi respectively, healed following oral administration of 150 mg
of ranitidine twice daily; in the placebo group, 0 and 36% of duodenal ulcers in smokers and nonsmokers, respectively, healed. The number
of cigarettes smoked per day did not appear to influence the ulcer healing rate.
Effects on Hepatic Clearance of Drugs
Since ranitidine interacts with the hepatic cytochrome P-450 (microsomal) enzyme system differently than does cimetidine, ranitidine
appears to only minimally inhibit hepatic metabolism of some drugs (e.g., coumarin anticoagulants, theophylline, diazepam, propranolol).
Ranitidine forms a ligand complex with the cytochrome P-450 enzyme system; however, ranitidine appears to interact with different forms
of cytochrome P-450 than does cimetidine. The affinity of ranitidine for cytochrome P-450 is about 10% that of cimetidine and the extent of
inhibition of the enzyme system is about 2.4 times less than that with cimetidine. Inhibition of hepatic microsomal enzyme activity appears
to be structurally determined rather than associated with H2-receptor blockade, since ranitidine and cimetidine differ substantially in their
effects on this enzyme system. Hepatic microsomal mixed-function oxidase activity appears to be unchanged following concomitant
administration of ranitidine and aminopyrineor antipyrine, since demethylation of aminopyrine and clearance of antipyrine are essentially
unaltered by ranitidine therapy.
Although cimetidine and ranitidine have been reported to reduce hepatic blood flow in some studies, other studies have not confirmed this
finding. Ranitidine does not appear to affect elimination of indocyanine green.
Coumarin Anticoagulants
The manufacturers state that increased or decreased prothrombin time (PT) has been reported during concomitant therapy with ranitidine and
warfarin; however, pharmacokinetic studies of ranitidine at dosages of up to 400 mg daily and warfarin demonstrated no effect on warfarin
clearance and/or PT. Ranitidine dosages exceeding 400 mg daily have not been studied for potential interaction with warfarin. In one study
following concomitant administration of 200 mg of ranitidine twice daily for 14 days and daily warfarin doses (2.5—4.5 mg) designed to
prolong the PT by 2—5 seconds, neither the PT nor plasma warfarin concentration was altered substantially. In another study, although the
effect on PT was not determined, ranitidine (150 mg twice daily orally for 7 days prior to and 5 days after administration of warfarin)
reportedly decreased total body clearance of warfarin (a single 10-mg oral dose) but did not substantially affect warfarin's plasma half-life;
the mechanism of this apparent decrease inwarfarin clearance was not determined.
Theophyllines
In one controlled, crossover study in healthy adults who received 300 mg of ranitidine, 1.2 g of cimetidine, or 2.4 g of cimetidine orally for 4
days prior to and 1 day after an IV aminophylline dose of 6 mg/kg, cimetidine 1.2 or 2.4 g daily decreased plasma theophylline clearance by
22—49 or 11—52%, respectively, while ranitidine did not alter theophylline clearance. Similar results were reported in another controlled,
Drug Interactions
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crossover study in which healthy adults received ranitidine or cimetidine concomitantly with theophylline. Although decreased theophylline
clearance has been reported in at least one patient receiving ranitidine and an extended-release theophylline preparation (Theo-Dur®)
concomitantly, the change in theophylline clearance may have resulted from discontinuance of an aluminum and magnesium hydroxides
antacid rather than from initiation of ranitidine therapyB and documentation of a potential ranitidine/theophylline interaction in this case has
been questioned.
Benzodiazepines
In one study, concomitant administration of diazepam and 150 mg of ranitidine twice daily did not substantially affect the area under the
plasma diazepam concentration-time curve (AUC) or the mean half-life of diazepam. In another study, concomitant administration of a
single 2-mg dose of lorazepam and 150 mg of ranitidine every 12 hours did not affect the elimination half-life, volume of distribution, or
clearance oflorazepam. For information on the potential interaction between midazolam and ranitidine, see Drug Interactions in Midazolam
Hydrochloride 28:24.08.
-
Adrenergic Blocking Agents
Mean serum propranolol concentrations do not appear to differ substantially in individuals receiving ranitidine and propranolol
concomitantly vs those receiving propranolol alone. In one study, combined therapy with 150 mg of ranitidine and 100 mg of atenolol
daily for 7 days did not appear to alter the pharmacokinetics of atenolol; however, in the same study, the pharmacokinetics of 100 mg
of metoprolol were altered by ranitidine. The AUC for metoprolol increased about 80% (1167 vs 2140 ng hour/mL) and the mean peak
serum concentration of metoprolol increased about 50% (177.2 vs 265 ng/mL) during concomitant ranitidine therapy. In the same
study, the elimination half-life of metoprolol increased from 4.4 to 6.5 hours when ranitidine was used concomitantly.
Acetaminophen
Although the clinical importance is not known, ranitidine reportedly produced dose-dependent inhibition of acetaminophen metabolism
in one in vitro study; in another study in which rats were pretreated with 120 mg/kg of ranitidine and then administered 250 mg/kg of
radiolabeled acetaminophen, ranitidine appealed to decrease the oxidation of acetaminophen as determined by liver concentrations of
glutathione and a covalently bound toxic metabolite of acetaminophen.
Phenytoin
Ranitidine does not appear to affect serum concentrations of phenytoin following administration of 150 mg of ranitidine twice daily for
14 days in individuals receiving chronic phenytoin therapy of 180 or 300 mg daily.
Alcohol
Currently available data suggest that consumption of moderate amounts of alcohol (e.g., 0.3 g/kg of body weight) by individuals
receiving H2-receptor antagonists, including ranitidine, is unlikely to result in clinically important alterations in bloodalcohol
concentrations and/or alcohol metabolism, although the possibility of such alterations in predisposed individuals cannot be definitely
excluded. Increases in blood alcohol concentrations have been noted in some studies in healthy individuals receiving ranitidine or some
other H2 antagonists concomitantly with alcohol; however, conflicting data exist, which may be related to the effects of various
patient-specific factors (e.g., gender, ethnic group, hepatic function, chronic alcoholism) on alcohol metabolism and/or to differences in
study design (e.g., alcohol dose and time of administration, fasting vs fed state). Although controversy exists regarding the potential for
psychomotor impairment with increases in alcohol absorption and/or blood alcohol concentration induced by H2-receptor antagonists,)
patients receiving these drugs should observe the usual precautions regarding alcohol intake and performance of hazardous tasks
requiring mental alertness or physical coordination (e.g.,driving, operating machinery).
Other Drugs
The manufacturers state that ranitidine may affect the oral bioavailability of certain drugs by some yet unidentified mechanism (e.g., a pHdependent effect on GI absorption or a change in volume of distribution).
Preliminary evidence indicates that concomitant administration of ranitidine may increase the AUC for nifedipine by about 30%.
Drug Interactions
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Although ranitidine appears to only minimally affect the secretion of gastric intrinsic factor, malabsorption of, and resultant deficiency in,
vitamin B12 may occur during long-term ranitidine therapy.
Ranitidine does not appear to alter peak serum concentration or AUC for ethanol following administration of 0.8 g/kg of ethanol 20% v/v in
individuals pretreated for 7 days with 300 mg of ranitidine daily.
Concomitant administration of ranitidine bismuth citrate and aspirin results in a slight, clinically unimportant reduction in the rate of
salicylate absorption.
Maintenance Therapy from AHFS DITM
Ranitidine is used in reduced dosage as maintenance therapy following healing of active duodenal ulcer to reduce ulcer recurrence.In
placebo-controlled studies, duodenal ulcer recurrence rates after 4 months, 8 months, and 1 year were 12—20,21—24, and 28—35%,
respectively, for 150 mg of ranitidine at bedtime daily vs 44—56,54—64, and 59—68%, respectively, for placebo. In one placebo-controlled
study, the 1-year reduction in recurrence persisted for almost 2 years oftherapy.il Because the efficacyof H2-receptor antagonists in
preventing duodenal ulcer recurrence appears to be substantially reduced in patients who are cigarette smokers compared with nonsmokers,
patients who are cigarette smokers should be advised of the importance of discontinuing smoking in the prevention of ulcer recurrence.
Maintenance therapy with ranitidine has not been studied for longer than 2 years in placebo-controlled studies.
Maintenance Therapy from AHFS DITM
Ranitidine is used in reduced dosage following healing of active, benign gastric ulcer to reduce ulcer recurrence. In 12-month controlled trials
in patients with previously healed gastric ulcers, therapy with ranitidine 150 mg at bedtime each night was more effective than placebo in
maintaining healing of gastric ulcers.
Maintenance Therapy from AHFS DITM
Ranitidine is used as maintenance therapy to prevent recurrence of erosive esophagitis. In controlled trials of 48-weeks duration, ranitidine
150 mg twice daily was more effective than placebo in maintaining healing in patients with previously healed erosive esophagitis.
Food and Antacids from AHFS DITM
Concomitant administration of food or low-dose antacids (neutralizing capacity of 10—15 mEq of hydrochloric acid per 10 mL) does
not appear to substantially decrease the absorption of ranitidine or the mean peak plasma concentration of the drug. However, in one
study, concomitant administration of 30 mL of an aluminum and magnesium hydroxides antacid (Mylanta-n®; neutralizing capacity of
150 mEq of hydrochloric acid per 30 mL), 30 mL of water, and a single 150-mg dose of ranitidine resulted in a 33% decrease in the
absorption of ranitidine; peak serum ranitidine concentration decreased from 613 to 432 ng/mL and the area under the serum
concentration-time curve (AUC) decreased from 3613 to 2394 g hour/L. The time to reach the peak and the rate of absorption of the
drug were not substantially altered by concurrent administration of the antacid in this study; elimination half-life and renal clearance of
ranitidine remained unchanged, but the fraction of the dose excreted in urine as unchangeddrug and as the desmethyl metabolite was
reduced by concomitant administration of antacid.
Concomitant administration of ranitidine bismuth citrate and a high dose (170 mEq) of an antacid results in a 28% reduction in
ranitidine plasma concentrations and also may reduce plasma bismuth concentrations; the manufacturer states that these effects are not
clinically important.
Smoking from AHFS DITM
Cigarette smoking reportedly adversely affects the healing of duodenal ulcers and also appears to decrease the efficacy of
ranitidine. In a controlled study, 62 and 100% of duodenal ulcers in smokers and nonsmokers, respectively, healed
Drug Interactions
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following oral administration of 150 mg of ranitidine twice daily; in the placebo group, 0 and 36% of duodenal ulcers in
smokers and nonsmokers, respectively, healed. The number of cigarettes smoked per day did not appear to influence the
ulcer healing rate.
Effects on Hepatic Clearance of Drugs from AHFS DITM
Since ranitidine interacts with the hepatic cytochrome P-450 (microsomal) enzyme system differently than does cimetidine, ranitidine
appears to only minimally inhibit hepatic metabolism of some drugs (e.g., coumarin anticoagulants, theophylline, diazepam,
propranolol). Ranitidine forms a ligand complex with the cytochrome P-450 enzyme system; however, ranitidine appears to interact
with different forms of cytochrome P-450 than does cimetidine. The affinity of ranitidine for cytochrome P-450 is about 10% that of
cimetidine and the extent of inhibition of the enzyme system is about 2.4 times less than that with cimetidine. Inhibition of hepatic
microsomal enzyme activity appears to be structurally determined rather than associated with H 2-receptor blockade, since ranitidine
and cimetidine differ substantially in their effects on this enzyme system. Hepatic microsomal mixed-function oxidase activity appears
to be unchangedfollowing concomitant administration of ranitidine and aminopyrineor antipyrine, since demethylation of aminopyrine and
clearance of antipyrine are essentially unaltered by ranitidine therapy.
Although cimetidine and ranitidine have been reported to reduce hepatic blood flow in some studies, other studies have not confirmed this
finding. Ranitidine does not appear to affect elimination of indocyanine green.
Coumarin Anticoagulants
The manufacturers state that increased or decreased prothrombin time (PT) has been reported during concomitant therapy with ranitidine and
warfarin; however, pharmacokinetic studies of ranitidine at dosages of up to 400 mg daily and warfarin demonstrated no effect on warfarin
clearance and/or PT. Ranitidine dosages exceeding 400 mg daily have not been studied for potential interaction with warfarin. In one study
following concomitant administration of 200 mg of ranitidine twice daily for 14 days and daily warfarin doses (2.5—4.5 mg) designed to
prolong the PT by 2—5 seconds, neither the PT nor plasma warfarin concentration was altered substantially. In another study, although the
effect on PT was not determined, ranitidine (150 mg twice daily orally for 7 days prior to and 5 days after administration of warfarin)
reportedly decreased total body clearance of warfarin (a single 10-mg oral dose) but did not substantially affect warfarin's plasma half-life; the
mechanism of this apparent decrease inwarfarin clearance was not determined.
Theophyllines
In one controlled, crossover study in healthy adults who received 300 mg of ranitidine, 1.2 g of cimetidine, or 2.4 g of cimetidine orally for 4
days prior to and 1 day after an IV aminophylline dose of 6 mg/kg, cimetidine 1.2 or 2.4 g daily decreased plasma theophylline clearance by
22—49 or 11—52%, respectively, while ranitidine did not alter theophylline clearance. Similar results were reported in another controlled,
crossover study in which healthy adults received ranitidine or cimetidine concomitantly with theophylline. Although decreased theophylline
clearance has been reported in at least one patient receiving ranitidine and an extended-release theophylline preparation (Theo-Dur®)
concomitantly, the change in theophylline clearance may have resulted from discontinuance of an aluminum and magnesium hydroxides
antacid rather than from initiation of ranitidine therapy!} and documentation of a potential ranitidine/theophylline interaction in this case has
been questioned.
Benzodiazepines
In one study, concomitant administration of diazepam and 150 mg of ranitidine twice daily did not substantially affect the area under the
plasma diazepam concentration-time curve (AUC) or the mean half-life of diazepam. In another study, concomitant administration of a
single 2-mg dose of lorazepam and 150 mg of ranitidine every 12 hours did not affect the elimination half-life, volume of distribution, or
clearance of lorazepam. For information on the potential interaction between midazolam and ranitidine, see Drug Interactions in
Midazolam Hydrochloride 28:24.08.
Drug Interactions
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Adrenergic Blocking Agents
Mean serum propranolol concentrations do not appear to differ substantially in individuals receiving ranitidine and propranolol
concomitantly vs those receiving propranolol alone. In one study, combined therapy with 150 mg of ranitidine and 100 mg of atenolol
daily for 7 days did not appear to alter the pharmacokinetics of atenolol; however, in the same study, the pharmacokinetics of 100 mg
of metoprolol were altered by ranitidine. The AUC for metoprolol increased about 80% (1167 vs 2140 ng-hour/mL) and the mean peak
serum concentration of metoprolol increased about 50% (177.2 vs 265 ng/mL) during concomitant ranitidine therapy. In the same
study, the elimination half-life of metoprolol increased from 4.4 to 6.5 hours when ranitidine was used concomitantly.
Acetaminophen
Although the clinical importance is not known, ranitidine reportedly produced dose-dependent inhibition of acetaminophen metabolism
in one in vitro study; in another study in which rats were pretreated with 120 mg/kg of ranitidine and then administered 250 mg/kg of
radiolabeled acetaminophen, ranitidine appeared to decrease the oxidation of acetaminophen as determined by liver concentrations of
glutathione and a covalently bound toxic metabolite of acetaminophen.
Phenytoin
Ranitidine does not appear to affect serum concentrations of phenytoin following administration of 150 mg of ranitidine twice daily for
14 days in individuals receiving chronic phenytoin therapy of 180 or 300 mg daily.
Self-medication. from AHFS DITM
For self-medication for the relief of symptoms of occasional heartburn, acid indigestion, or sour stomach in patients 12
years of age and older, an oral ranitidine dosage of 75 mg once or twice daily is recommended. For self-medication, the
manufacturers recommend that dosage of ranitidine not exceed 150 mg in 24 hours and that such therapy not exceed 2
weeks of continuous use unless otherwise recommended by a clinician. Patients should be instructed to take the tablets with
water and swallow them whole (i.e., they should not be chewed). Persistent symptoms or the development of difficulty in
swallowing should be reported to a clinician since a serious problem requiring alternative therapy may be present.
The manufacturers state that ranitidine should not be used for self-medication in children younger than 12 years of age
unless otherwise directed by their clinician.
Drug Interactions
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