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Interactions with Ranitidine

If you are currently being treated with any of the following medications, you should not use Ranitidine without reading these interactions.

Atazanavir (oral)

ADJUST DOSING INTERVAL: Concurrent administration of H2-receptor antagonists may decrease the oral bioavailability of atazanavir and substantially reduce its concentrations in plasma. Atazanavir solubility decreases with increasing pH, thus inhibition of gastric acid secretion may interfere with dissolution of the drug. Subtherapeutic antiretroviral drug levels may lead to reduced viral susceptibility and development of resistance.

MANAGEMENT: To lessen the effect of H2-receptor antagonists on atazanavir systemic exposure, the medications should be administered as far apart as possible, preferably 12 hours apart.

Itraconazole

ADJUST DOSING INTERVAL: Oral H2 antagonists may significantly decrease the plasma concentration of oral itraconazole. The mechanism is related to an increase in gastric pH resulting in a decrease in absorption of the antifungal. Clinical monitoring of patient response is recommended.

MANAGEMENT: H2 antagonists should be taken at least 2 hours after itraconazole. If necessary, an acidic pH may be produced by administration with an acidic beverage such as Coca-Cola(R) or Pepsi(R). However, clinicians should still consider the possibility of a reduced or subtherapeutic antifungal effect. It may be appropriate to switch to an agent like fluconazole or terbinafine whose absorption is not affected by stomach pH.

Acetaminophen (oral/rectal)

Animal studies have suggested that ranitidine may potentiate the hepatotoxicity of acetaminophen, however, a double-blind placebo-controlled crossover study has failed to confirm this finding in humans. Acetaminophen dosage adjustments are not indicated.

Cyanocobalamin

By reducing or suppressing gastric acid secretion, H2-receptor antagonists and proton pump inhibitors may interfere with the gastrointestinal absorption of vitamin B12, a process that is dependent on the presence of gastric acid and pepsin. Clinical studies have shown that dietary (i.e., protein-bound) vitamin B12 malabsorption can occur during treatment with these agents, particularly the proton pump inhibitors, although the likelihood of developing clinically significant deficiency over time is unknown. There has been one reported case of vitamin B12 deficiency with megaloblastic anemia in a patient who received omeprazole at a minimum of 40 mg/day for 4 years. Also uncertain is whether acid reduction or suppression can affect the absorption of vitamin B12 ingested in the form of oral supplements such as cyanocobalamin and mecobalamin. Parenteral or intranasal administration is generally the preferred route in the treatment of B12 deficiency-related anemia.

Alendronate

Coadministration of alendronate and intravenous ranitidine has been shown to double the bioavailability of alendronate. The clinical significance of this increased bioavailability is unknown, as are the effects of oral and other intravenous H2-antagonists.

Duloxetine

Coadministration of enteric-coated duloxetine with substances that raise gastrointestinal pH may result in earlier release of duloxetine from the formulation. The enteric coating is intended to resist drug dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. However, coadministration with aluminum- and magnesium-containing antacids (51 mEq) or famotidine has been shown to have no significant effect on the rate or extent of duloxetine absorption following administration of a 40 mg oral dose. It is unknown whether concomitant administration of proton pump inhibitors would affect duloxetine absorption.

Enoxacin

Depending on the route of administration, enoxacin effects may be altered by certain histamine-2 (H2) receptor antagonists. Oral enoxacin effects may be decreased due to reduced gastrointestinal solubility and absorption as a result of H2 antagonist-induced reductions in gastric pH. Reports of this interaction exist for parenteral ranitidine. On the other hand, pharmacologic effects of parenteral enoxacin may be increased by cimetidine. The mechanism of action is speculated to be competition for active renal secretion. Reports of enoxacin interactivity with other H2 antagonists do not exist, although theoretically, all H2 antagonists may produce a similar effect on oral enoxacin. Close clinical monitoring for altered enoxacin effect is recommended in patients receiving concomitant enoxacin and an H2 antagonist.

Pramipexole (oral)

Drugs that are secreted by the renal tubules via the cationic transport system may decrease the oral clearance of pramipexole by approximately 20%. The mechanism of action is competitive inhibition of tubular secretion of pramipexole. This interaction is not likely to be of clinical importance, although it may be prudent to monitor the patient for increased adverse effects due to pramipexole.

Cisapride (oral)

During coadministration, cisapride may accelerate but slightly decrease the extent of gastrointestinal absorption of ranitidine. These effects are thought to be secondary to the increased gastrointestinal transit induced by cisapride. In twelve healthy volunteers given cisapride (10 mg single dose) and ranitidine (150 mg single dose), median time to reach peak plasma concentration (Tmax) of ranitidine was one hour less than when ranitidine was taken alone, and area under the concentration-time curve (AUC) was decreased by 24%. Theoretically, the reduced Tmax may translate to a quicker onset of action of ranitidine. The reduction in bioavailability is unlikely to be of clinical significance during regular administration, although the duration of action of a single dose of oral ranitidine may be shortened.

Phenytoin (oral), Mephenytoin, Ethotoin

GENERALLY AVOID: Cimetidine and ranitidine may significantly increase plasma phenytoin concentrations and toxicity has been reported. Increased phenytoin concentrations of up to 141% have been reported with cimetidine. The mechanism is related to inhibition of CYP450 enzymes responsible for hydantoin metabolism. This interaction may be expected with other hydantoins. This interaction has not been reported with famotidine or nizatidine.

MANAGEMENT: Concomitant use of cimetidine or ranitidine and phenytoin is not recommended. If no alternatives exist, clinical monitoring of patient response, tolerance, and serum phenytoin concentrations is recommended, especially during the first month of therapy. Patients should be advised to notify their physician if they experience symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia. The hydantoin dose may need to be decreased.

Bacampicillin

GENERALLY AVOID: Coadministration with antacids, H2-receptor antagonists, proton pump inhibitors, or other agents with acid neutralizing or reducing effects may decrease the oral bioavailability and plasma concentrations of ampicillin from bacampicillin. The exact mechanism of interaction is unknown but may be related to degradation of the prodrug when gastric pH is increased.

MANAGEMENT: The possibility of a reduced or subtherapeutic response to bacampicillin should be considered during coadministration with antacids, H2-receptor antagonists, proton pump inhibitors, or other agents that can increase gastric pH. Preferably, these agents should be avoided during therapy with bacampicillin, or an alternative antibiotic be prescribed if these medications cannot be discontinued. Patients treated with antacids (or oral medications that contain antacids such as didanosine buffered tablets or pediatric oral solution) may minimize the effects of the interaction with bacampicillin by separating the times of administration by at least 2 hours.

Tacrine, Donepezil (oral), Rivastigmine, Galantamine

GENERALLY AVOID: Due to opposing effects, agents that possess anticholinergic activity (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; class IA antiarrhythmics especially disopyramide; carbamazepine; cimetidine; ranitidine) may negate the already small pharmacologic benefits of acetylcholinesterase inhibitors in the treatment of dementia. These agents may also adversely affect elderly patients in general. Clinically significant mental status changes associated with anticholinergic agents can range from mild cognitive impairment to delirium, and patients with Alzheimer's disease and other dementia are especially sensitive.

MANAGEMENT: Drugs that possess anticholinergic activity should generally be avoided in patients with Alzheimer's disease or other cognitive impairment, regardless of whether they are receiving an acetylcholinesterase inhibitor. For patients requiring treatment for adverse effects of acetylcholinesterase inhibitor therapy (e.g., gastrointestinal intolerance, urinary problems), an agent without anticholinergic properties should be used whenever possible. Otherwise, a dosage reduction, slower titration, or even discontinuation of the acetylcholinesterase inhibitor should be considered. In patients who are already receiving an acetylcholinesterase inhibitor with anticholinergic agents, every attempt should be made to discontinue the latter or substitute them with less anticholinergic alternatives. Caution is required, however, since anticholinergic withdrawal may occur. Seizures have been reported following abrupt discontinuation of anticholinergics during acetylcholinesterase inhibitor therapy.

Ketoconazole

GENERALLY AVOID: H2 antagonists may reduce the bioavailability of ketoconazole by 75% to 80% resulting in decreased plasma ketoconazole concentrations and possible therapeutic failure. The mechanism is related to an increase in gastric pH and a decrease in absorption of the antifungal agent.

MANAGEMENT: Concomitant use is not recommended. Fluconazole absorption is not significantly affected.

Dasatinib

GENERALLY AVOID: Nonclinical data indicate that the solubility of dasatinib is pH-dependent. Therefore, long-term suppression of gastric acid secretion by H2-receptor antagonists or proton pump inhibitors is likely to reduce dasatinib systemic exposure. In a pharmacokinetic study of 24 healthy subjects, administration of a 50 mg dose of dasatinib 10 hours after famotidine was associated with a 61% reduction in systemic exposure (AUC) and a 63% reduction in peak plasma concentration (Cmax) of dasatinib.

MANAGEMENT: The concomitant use of H2-receptor antagonists or proton pump inhibitors with dasatinib is not recommended. If gastric acidity management is necessary, antacids should be considered in place of these agents. However, patients treated with dasatinib should avoid taking antacids or oral medications that contain antacids (e.g., didanosine buffered tablets or pediatric oral solution) for at least two hours before and two hours after administration of dasatinib.

Cefditoren

GENERALLY AVOID: The coadministration with H2-receptor antagonists or other agents that reduce stomach acid (e.g., proton pump inhibitors) may reduce the oral absorption and plasma concentrations of cefditoren pivoxil. According to the manufacturer, a single intravenous dose of famotidine (20 mg) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single dose of cefditoren pivoxil (400 mg, administered following a meal) by 27% and 22%, respectively. The clinical significance of these alterations is unknown.

MANAGEMENT: The manufacturer recommends that cefditoren pivoxil not be administered concomitantly with H2-receptor antagonists or other agents that reduce stomach acid.

Cefuroxime, Cefpodoxime

GENERALLY AVOID: The coadministration with H2-receptor antagonists, proton pump inhibitors, or other agents that can increase gastric pH may reduce the oral bioavailability of cefpodoxime proxetil and cefuroxime axetil. The proposed mechanism is a pH-dependent reduction in drug dissolution and absorption. In ten healthy volunteers, famotidine 40 mg administered one hour before the ingestion of cefpodoxime proxetil 200 mg led to an approximately 40% reduction in the cefpodoxime peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) compared to when the drug was given alone. Similar results were reported with ranitidine in another study, where cefpodoxime Cmax and AUC decreased by approximately 30%. Likewise, pre-treatment with ranitidine plus sodium bicarbonate decreased the Cmax and AUC of cefuroxime by over 40% in six healthy volunteers. The clinical significance of these effects is unknown, but potentially reduced antibiotic efficacy should be considered.

MANAGEMENT: Until further data are available, patients treated with cefpodoxime proxetil or cefuroxime axetil may want to avoid using H2-receptor antagonists, proton pump inhibitors, or other agents that can increase gastric pH. An alternative antibiotic may be considered if these medications cannot be discontinued.

Delavirdine

GENERALLY AVOID: Theoretically, H2 antagonists and proton pump inhibitors may decrease the gastrointestinal absorption of delavirdine. The proposed mechanism is a pH-dependent reduction in drug dissolution or absorption.

MANAGEMENT: While the clinical significance of this potential interaction is unknown, the manufacturer recommends against the chronic use of these drugs with delavirdine due to the risk of treatment failure and emergence of drug resistance associated with subtherapeutic levels of delavirdine.

Fenoprofen, Ketoprofen, Sulindac, Indomethacin, Tolmetin, Ketorolac, Mefenamic acid, Nabumetone, Piroxicam, Diclofenac, Etodolac, Oxaprozin, Meclofenamate

H2 antagonists may alter the disposition of nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased or decreased plasma concentrations. Data are varied, even for the same NSAID. The mechanism may be related to inhibition of metabolism, changes in gastric pH that decrease absorption, and/or reduced urinary elimination. Statistically significant changes have been small and of limited clinical significance. Clinical monitoring of patient response and tolerance is recommended.

Nicotine (oral/patches/nasal)

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.

Cyclosporine

Increases in serum creatinine have been reported during concomitant use of ranitidine and cyclosporine by kidney transplant patients. Data have been conflicting; no changes in creatinine have also been reported. The mechanism and clinical significance are unknown.

Miglitol

Miglitol may reduce the bioavailability of ranitidine by 60%. The mechanism of action and clinical significance are unknown. If both drugs must be given together, the patient should be monitored for altered clinical response when either drug is started, stopped or changed in dosage.

Theophylline, Oxtriphylline, Aminophylline

MONITOR: Cimetidine may increase theophylline plasma concentrations by as much as 70%. The mechanism is related to inhibition of liver CYP450 enzymes responsible for theophylline metabolism. Although controlled studies have not demonstrated an interaction with ranitidine, famotidine, or nizatidine, and they do not have enzyme-inhibiting properties, there have been rare case reports of increased theophylline concentrations and/or toxicity with each of these agents. Patients with chronic obstructive pulmonary disease, congestive heart failure, or cirrhosis may have slower theophylline clearance rates; therefore, they may be at greater risk of developing theophylline toxicity.

MANAGEMENT: Clinical monitoring of patient response, tolerance, and laboratory theophylline serum concentrations is recommended. Patients should be advised to report any signs of theophylline toxicity including nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat to their physician.

Gefitinib

MONITOR: Coadministration with drugs that cause significant, sustained elevations in gastric pH such as H2-receptor antagonists and proton pump inhibitors may decrease the plasma concentrations of gefitinib. The exact mechanism of interaction is unknown. According to the manufacturer, coadministration with high dosages of ranitidine and sodium bicarbonate (to maintain the gastric pH above 5.0) reduced the mean area under the plasma concentration-time curve of gefitinib by 44% in healthy male volunteers.

MANAGEMENT: The possibility of a diminished therapeutic response to gefitinib should be considered during coadministration with H2-receptor antagonists or proton pump inhibitors. Pharmacologic response to gefitinib should be monitored more closely whenever one of these agents is added to or withdrawn from therapy.

Fosamprenavir

MONITOR: Coadministration with H2-receptor antagonists or proton pump inhibitors may decrease the oral bioavailability of amprenavir from its prodrug, fosamprenavir. In 30 study subjects, ranitidine (300 mg single oral dose) decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir from fosamprenavir (1400 mg single oral dose) by 51% and 30%, respectively, compared to administration of fosamprenavir alone. The mechanism of interaction has not been described. It is possible that fosamprenavir solubility decreases with increasing pH, thus inhibition of gastric acid secretion may interfere with dissolution of the drug. Subtherapeutic antiretroviral drug levels may lead to reduced viral susceptibility and development of resistance.

MANAGEMENT: Caution is advised if fosamprenavir is prescribed with H2-receptor antagonists or proton pump inhibitors. Antiretroviral response should be monitored closely during coadministration.

Chlorpropamide, Acetohexamide, Glipizide, Glyburide, Tolazamide, Tolbutamide, Glimepiride

MONITOR: H2 antagonists such as cimetidine and ranitidine may increase plasma concentrations of sulfonylureas and enhance hypoglycemic effects. The mechanism may be related to inhibition of liver cytochrome P450 enzymes responsible for sulfonylurea metabolism or increased absorption due to altered gastric pH. Cimetidine may also inhibit glucose metabolism. Other H2 antagonists may interact in a similar manner, particularly if increased pH is involved.

MANAGEMENT: Clinical monitoring of patient response, tolerance, and glycemic control is recommended. Patients receiving this combination should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations) and to notify their physician if it occurs. The sulfonylurea dosage may require reduction in affected patients.

Metformin

MONITOR: Ranitidine is a cationic drug and theoretically could decrease the excretion of metformin by competing for renal tubular transport. Although this interaction has not been specifically reported for ranitidine, cimetidine (also a cationic drug) has been reported to interact with metformin in this manner. Increased metformin levels may increase the risk of lactic acidosis.

MANAGEMENT: If ranitidine and metformin must be used together, particularly slow and cautious titration of metformin dosage is recommended. The maximal dose of metformin probably also should be reduced until further information about this interaction is available. Patients should be advised to monitor their blood glucose and to promptly notify their physician if they experience possible signs of lactic acidosis such as malaise, myalgia, respiratory distress, hyperventilation, slow or irregular heartbeat, somnolence, abdominal upset, or other unusual symptoms.

Tenofovir

MONITOR: Theoretically, coadministration of tenofovir disoproxil fumarate with other drugs that are eliminated by active tubular secretion may result in increased plasma concentrations of tenofovir and/or the coadministered drug(s). The mechanism is competitive inhibition of renal excretion. Drugs that are thought to undergo active tubular secretion include metformin, cimetidine, ranitidine, procainamide, flecainide, quinidine, triamterene, midodrine, cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir.

MANAGEMENT: Patients receiving tenofovir disoproxil fumarate in combination with other drugs that undergo active tubular secretion should be monitored for excessive pharmacologic effects of one or both drugs, and the dosages of the drugs adjusted if necessary.

Trospium

MONITOR: Theoretically, coadministration of trospium chloride with other drugs that are eliminated by active tubular secretion may result in increased plasma concentrations of trospium and/or the coadministered drug(s). The mechanism is competitive inhibition of renal excretion. Drugs that are thought to undergo active tubular secretion include acyclovir/valacyclovir, cidofovir, cimetidine, digoxin, flecainide, ganciclovir/valganciclovir, metformin, midodrine, morphine, pancuronium, procainamide, quinidine, ranitidine, tenofovir, triamterene, and vancomycin.

MANAGEMENT: Patients receiving trospium chloride in combination with other drugs that undergo active tubular secretion should be monitored for excessive pharmacologic effects of one or both drugs, and the dosages of the drugs adjusted if necessary.

Adefovir

MONITOR: Theoretically, the coadministration of adefovir dipivoxil with other drugs that are eliminated by active tubular secretion may result in increased plasma concentrations of adefovir and/or the coadministered drug(s). The mechanism is competitive inhibition of renal excretion. Drugs that are thought to undergo active tubular secretion include metformin, cimetidine, ranitidine, procainamide, flecainide, quinidine, triamterene, midodrine, cidofovir, acyclovir, valacyclovir, tenofovir, ganciclovir, and valganciclovir.

MANAGEMENT: Patients receiving adefovir dipivoxil in combination with other drugs that undergo active tubular secretion should be monitored for excessive pharmacologic effects of one or both drugs, and the dosages of the drugs adjusted if necessary.

Entecavir

MONITOR: Theoretically, the coadministration of entecavir with other drugs that are eliminated by active tubular secretion may result in increased plasma concentrations of entecavir and/or the coadministered drug(s). The mechanism is competitive inhibition of renal excretion. Drugs that are thought to undergo active tubular secretion include metformin, cimetidine, ranitidine, procainamide, flecainide, quinidine, triamterene, midodrine, cidofovir, acyclovir, tenofovir, valacyclovir, ganciclovir, and valganciclovir.

MANAGEMENT: Patients receiving entecavir in combination with other drugs that undergo active tubular secretion should be monitored for excessive pharmacologic effects of one or both drugs, and the dosages of the drugs adjusted if necessary.

Calcium carbonate, Sodium bicarbonate, Aluminum hydroxide, Aluminum carbonate, Magnesium hydroxide, Magnesium oxide

Oral antacids and some aluminum, calcium, and magnesium salts may decrease oral H2 blocker plasma concentrations. The mechanism may be related to reduced gastric absorption and bioavailability due to acid-neutralizing effects. Data vary and the clinical significance has not been clearly established. It is recommended that H2 blocker be administered one to two hours before one of these preparations.

Triamterene

Ranitidine, famotidine, and nizatidine may interfere with the absorption of triamterene. The diuretic effect of triamterene may be decreased when it is taken with any of these drugs. No special precaution appears necessary.

Procainamide

Ranitidine may slightly increase plasma concentrations of procainamide and its active metabolite, NAPA. However, some studies have failed to confirm this finding. The mechanism may be related to decreased renal tubular secretion of procainamide and NAPA. Famotidine and nizatidine do not appear to interact in this manner.
Clinical monitoring of patient response and tolerance is recommended and procainamide dosage adjustments may be indicated.

Didanosine

Ranitidine may slightly increase the bioavailability of didanosine by increasing gastric pH. This interaction is unlikely to be clinically significant.

Midodrine

Theoretically, the coadministration with midodrine may result in decreased clearance of drugs that are primarily eliminated by active tubular secretion such as metformin, cimetidine, ranitidine, procainamide, flecainide, quinidine, and triamterene. The proposed mechanism is competitive inhibition of renal excretion by desglymidodrine, the active metabolite of midodrine. However, clinical data are lacking and no supportive experimental evidence exists. Patients receiving midodrine in combination with drugs that undergo active tubular secretion should be monitored for excessive effects of one or both drugs.

Memantine

Theoretically, the concomitant administration of memantine and other drugs that undergo active renal tubular secretion may result in altered plasma levels of both drugs. The clinical significance is unknown. When hydrochlorothiazide/triamterene and memantine were coadministered in a clinical study, the bioavailability of
hydrochlorothiazide decreased by 20% and there was no change in memantine or triamterene bioavailability.

Nifedipine

The plasma concentration of some calcium channel blockers may be increased by H2 blockers such as cimetidine and ranitidine. The mechanism is related to inhibition of liver cytochrome P450 enzymes responsible for metabolism and/or increased gastric pH. Ranitidine is a much weaker inhibitor of the cytochrome P450 system and effects are not expected to be clinically significant. Other H2 blockers, antacids, and proton pump inhibitors that notably increase gastric pH would be expected to have a similar effect. Clinical monitoring of patient response and tolerance is recommended and calcium channel blocker dosage adjustments may be indicated.

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