Pylorid (Ranitidine Bismuth)

gasPYLORID®

Glaxo Wellcome

Ranitidine Bismuth Citrate

Histamine H2-receptor Antagonist with H. pylori Suppressive Activity

Note: For additional safety information on clarithromycin and ranitidine, consult the individual product monographs.

Action And Clinical Pharmacology: Ranitidine bismuth citrate is a complex of ranitidine, a histamine H2-receptor antagonist, and bismuth citrate, which together produce H. pylori suppressive activity. Following ingestion, ranitidine bismuth citrate dissociates in intragastric fluid, giving rise to ranitidine, and soluble and insoluble forms of bismuth. Histamine H2-receptor antagonists are effective in the treatment of peptic ulcer disease and this therapeutic effect results from their ability to suppress gastric acid secretion. In vitro, bismuth-containing compounds have bactericidal activity against the microorganism H. pylori, in vivo, growth is inhibited and the bactericidal effects of antibiotics (e.g., clarithromycin) greatly enhanced.

Ranitidine bismuth citrate, when used in conjunction with clarithromycin, is effective in the eradication of H. pylori infection. Ranitidine bismuth citrate and clarithromycin have been shown to act synergistically.

Ranitidine bismuth citrate inhibits both daytime and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food. A 400 mg dose of ranitidine bismuth citrate is as effective as a 150 mg dose of ranitidine at inhibiting daytime and nocturnal gastric acidity. Ranitidine bismuth citrate does not alter plasma pepsinogen I and II concentrations or pepsin activity. Ranitidine bismuth citrate has no clinically relevant effects on fasting or postprandial plasma gastrin.

Mucosal penetration and absorption of bismuth from ranitidine bismuth citrate is not affected by the degree of gastritis or the presence of H. pylori.

Ranitidine bismuth citrate has no observed effects on the CNS, cardiovascular system, or respiratory system in rats dosed 50 times, and in dogs and monkeys dosed 6.25 times the human dose. In addition, it has no effects on duodenal bicarbonate secretion, PGE2 output, or transmucosal potential difference.

Pharmacokinetics: Following ingestion, ranitidine bismuth citrate dissociates in intragastric fluid, giving rise to ranitidine and soluble and insoluble forms of bismuth. Approximately 50% of the ranitidine is absorbed with a typical mean peak ranitidine concentration of 433 ng/mL (95%, CI 391, 479 ng/mL) occurring 0.5 to 5 hours after a 400 mg dose. Absorption of ranitidine derived from ranitidine bismuth citrate tablets is not significantly impaired by administration of food. The elimination half life of ranitidine is 3 hours.

The principal route of elimination for ranitidine is in the urine, accounting for 30 to 40% of the dose. Renal clearance (580 to 680 mL/min) is primarily by active tubular secretion. In renally impaired patients, decreases in ranitidine renal clearance are highly correlated with declining renal function, while nonrenal elimination is unaltered by renal impairment, averaging 140 mL/min. Elimination half life may exceed 6 hours in severely impaired patients, e.g., creatinine clearance less than 25 mL/min. The volume of distribution for ranitidine is 0.8 to 1.8 L/kg. Serum protein binding averages 15%.

Although oral absorption of bismuth is variable, less than 1% of bismuth derived from ranitidine bismuth citrate is absorbed after oral administration, with a typical mean peak bismuth concentration of 4.2 ng/mL (95%, CI 3.1, 5.6 ng/mL) occurring 15 to 60 minutes after a 400 mg dose.

Absorption of bismuth derived from ranitidine bismuth citrate is not clinically significantly affected by administration of food or antacids. The absorption of bismuth from ranitidine bismuth citrate is increased when gastric pH exceeds 6 at the time of dosing (AUC increased from a mean of 16 to 48.3 ng.h/mL).

Bismuth accumulates in the plasma/serum in rats and rabbits during once daily dosing, reaching steady-state concentrations in the rat between 1 and 6 months. In the dog, there is no evidence for accumulation of bismuth in the plasma during repeat dosing.

Bismuth accumulates relatively slowly in tissues in animals during once daily dosing, reaching steady-state concentrations between 1 and 6 months. There is slow elimination from tissues and bismuth can still be detected 6 months after cessation of treatment in long-term toxicity studies.

In man, bismuth accumulates in plasma during twice daily dosing with ranitidine bismuth citrate, reaching at least 70% of steady-state concentrations (less than 20 ng/mL) after 4 weeks of dosing at twice the recommended dose. Elimination of bismuth is polyexponential, with a terminal elimination half life of 11 to 28 days.

The principal route of excretion for bismuth is in the urine, with an average renal clearance of 30 to 60 mL/min, indicating net tubular reabsorption. Bismuth concentrations may be elevated in renally impaired and elderly patients as a result of decreased renal elimination. Bismuth also undergoes minor excretion in the bile. Unabsorbed bismuth is excreted in the feces. Bismuth is 98% bound to human plasma proteins, primarily albumin.

Indications And Clinical Uses: Ranitidine bismuth citrate in combination with clarithromycin is indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence.

It is recommended that all patients not eradicated of H. pylori following ranitidine bismuth citrate plus clarithromycin treatment be considered to have H. pylori resistant to clarithromycin. Patients who fail therapy should not be retreated with a regimen containing clarithromycin.

Contra-Indications: The ranitidine bismuth citrate is contraindicated for patients known to have hypersensitivity to the drug or its ingredients.

Ranitidine bismuth citrate should not be used in patients with a history of porphyria.

Renal Impairment: Administration of ranitidine bismuth citrate is not recommended in patients with creatinine clearance less than 25 mL/min.

Manufacturers’ Warnings In Clinical States: Treatment with a H2-antagonist may mask symptoms associated with carcinoma of the stomach and, therefore, may delay diagnosis of that condition. Accordingly, where gastric ulcer is suspected the possibility of malignancy should be excluded before therapy with ranitidine bismuth citrate.

Pregnancy: There are no adequate and well-controlled studies in pregnant women, and therefore, the safety of ranitidine bismuth citrate in human pregnancy has not been established. In animal reproductive studies there was no evidence of teratogenicity. Because animal reproduction studies are not always predictive of human response, administration of ranitidine bismuth citrate is not recommended during pregnancy.

Lactation: It has been demonstrated during repeat dosing of ranitidine bismuth citrate in the lactating rat that low levels of ranitidine and bismuth are excreted in the milk with consequent exposure to the pups. The passage of ranitidine bismuth citrate into human breast milk has not been evaluated, therefore, ranitidine bismuth citrate should not be used by women who are breast-feeding.

Children: Safety and effectiveness of ranitidine bismuth citrate in children (under 18 years) has not been established.

Precautions: Selection of Patients: Whenever possible appropriate tests should be conducted prior to administration of the eradication regimen to determine the presence of H. pylori.

Darkening of the stool was reported in up to 19% of patients treated with ranitidine bismuth citrate in USA placebo-controlled trials. Stool darkening should not be confused with melena (blood in the stool). Adequate followup tests should be conducted if the physician suspects melena.

The doses of ranitidine bismuth citrate should not be taken in close succession repeatedly on consecutive days, since this could result in increased gastric pH to about 6, increased bismuth plasma levels and AUC. It is recommended that ranitidine bismuth citrate be taken in the morning and evening (see Dosage).

Although not seen in clinical trials with ranitidine bismuth citrate, bismuth intoxication from prolonged overdosage or deliberate self poisoning with soluble bismuth compounds can result in neurotoxicity and nephrotoxicity (see Overdose: Symptoms and Treatment).

A plasma bismuth concentration over 77.5 ng/mL (equivalent to 50 ng/mL whole blood) has been reported in the literature as a level of possible clinical concern, however, this value has subsequently been questioned as being too conservative due to a failure to take account of the time elapsed between last ingestion of bismuth and when blood samples were taken for analyses.

Drug Interactions: Although ranitidine has been reported to bind weakly to cytochrome P450 in vitro, the amount contained in 400 mg of ranitidine bismuth citrate does not inhibit the action of the cytochrome P450-linked oxygenase enzymes in the liver. However, there have been isolated reports of drug interactions that suggest ranitidine may affect the bioavailability of certain drugs by some mechanism as yet unidentified (e.g., a pH dependent effect on absorption).

Coadministration with clarithromycin results in a 50% increase in plasma concentrations of ranitidine from ranitidine bismuth citrate, and in 31% increased concentration of 14-hydroxy-clarithromycin.

Coadministration with ASA results in a slight decrease in the rate of salicylate absorption that is clinically unimportant.

Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine, and may decrease plasma concentrations of bismuth from ranitidine bismuth citrate. These effects are not clinically significant.

Geriatrics: Ulcer healing and relapse rates in elderly patients (65 years of age) were no different from those in younger age groups. The incidence of adverse events and laboratory abnormalities were also not different from those seen in other age groups. Serum levels of ranitidine may be increased in elderly patients, however serum bismuth levels were similar to those seen in younger patients.

Renal Impairment: No dosage adjustment is required in patients with mild to moderate renal impairment (see Dosage).

Adverse Reactions: Worldwide clinical trials of ranitidine bismuth citrate tablets included over 4 000 patients given ranitidine bismuth citrate alone or in combination with amoxicillin or clarithromycin.

Incidence of Drug-related Adverse Events in Placebo-controlled Clinical Trials

As with other medicines containing bismuth, ranitidine bismuth citrate may cause blackening of the stools and tongue, these are reversible, usually within 1 month after cessation of treatment.

Although not seen at a frequency of 1%, the following events may also be associated with the use of ranitidine bismuth citrate:

Gastrointestinal: abdominal discomfort, gastric pain.

Hepatic: transient changes in the liver enzymes ALT and AST.

Hypersensitivity: There have been rare reports of hypersensitivity reactions, including pruritus, skin rash and anaphylaxis.

Hematological: There have been rare reports of mild anemia.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There has been limited experience with overdosage. Adverse events related to overdosage with ranitidine are usually reversible, nonspecific, and nonlife threatening and result in no adverse sequelae. Although not seen in clinical trials with ranitidine bismuth citrate, bismuth intoxication from prolonged overdosage or deliberate self poisoning with soluble bismuth compounds can result in neurotoxicity and nephrotoxicity.

Treatment: In the event of an overdose or suspected bismuth toxicity, gastric lavage should be employed to remove unabsorbed material from the gastrointestinal tract, and symptom monitoring and other supportive therapy should be employed, if indicated. The ranitidine and bismuth components may be removed from the plasma by hemodialysis.

Dosage And Administration: The recommended dose should be taken twice daily, in the morning and evening, with or without food.

Eradication of H. pylori Infection: The recommended adult oral dosage is 400 mg twice daily plus clarithromycin (500 mg 3 times daily or 250 mg 4 times daily) for the first 2 weeks followed by ranitidine bismuth citrate 400 mg twice daily for a further 2 weeks to facilitate ulcer healing.

Geriatrics: No dosage adjustment is necessary in elderly patients (see Precautions, Geriatrics).

Renal Impairment: Because the principal route of excretion is renal, care should be exercised when administering ranitidine bismuth citrate to patients with renal impairment. However, for patients with mild to moderate renal impairment (creatinine clearance 25 to 50 mL/min), no dosage adjustment is necessary. Administration of ranitidine bismuth citrate is not recommended in patients with severe renal impairment (creatinine clearance less than 25 mL/min) (see Contraindications).

Availability And Storage: Each light blue, film-coated, elongated octagonal-shaped tablet, identified by a logo on one side, contains: ranitidine bismuth citrate 400 mg, equivalent to ranitidine base 162 mg, trivalent bismuth 128 mg and citrate 110 mg. Nonmedicinal ingredients: indigo carmine aluminum lake, magnesium stearate, methylhydroxypropylcellulose, microcrystalline cellulose, polyvidone K30, sodium carbonate (anhydrous), titanium dioxide and triacetin. Double foil blister packs, cartons of 14 and 28. Store between 2 and 30°C in a dry place.

PYLORID® Glaxo Wellcome Ranitidine Bismuth Citrate Histamine H2-receptor Antagonist with H. pylori Suppressive Activity Note: For additional safety information on clarithromycin and ranitidine, consult the individual product monographs.

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