Zantac (Ranitidine HCl)

ZANTAC®

Glaxo Wellcome

Ranitidine HCl

Histamine H2 Receptor Antagonist

Action And Clinical Pharmacology: Ranitidine is an antagonist of histamine at gastric H2 receptor sites. Thus ranitidine inhibits both basal gastric secretion and gastric acid secretion induced by histamine, pentagastrin and other secretagogues. On a weight basis, ranitidine is between 4 and 9 times more potent than cimetidine. Inhibition of gastric acid secretion has been observed following i.v., intraduodenal and oral administration of ranitidine and it is dose related, a maximum response being achieved at an oral dose of 300 mg/day.

Pepsin secretion is also inhibited but secretion of gastric mucus is not affected. Ranitidine does not alter the secretion of bicarbonate or enzymes from the pancreas in response to secretin and pancreozymin.

Ranitidine is rapidly absorbed after oral administration, peak plasma concentrations being achieved within 2 to 3 hours. These plasma concentrations are not significantly influenced by the presence of food in the stomach at the time of the oral administration nor by regular doses of antacids.

Bioavailability of oral ranitidine is approximately 50%. Serum protein binding of ranitidine in man is in the range of 10 to 19%. The elimination half-life is approximately 3 hours. The principal route of excretion is the urine (40% recovery of free and metabolized drug in 24 hours).

There is a significant linear correlation between the dose administered and the inhibitory effect upon gastric acid secretion for oral doses up to 300 mg. A plasma ranitidine concentration of 50 ng/mL has an inhibitory effect upon stimulated gastric acid secretion of approximately 50%. Estimates of the IC50 range from 36 to 94 ng/mL. Following the administration of 150 mg ranitidine orally, plasma concentrations in excess of this lasted for more than 8 hours and after 12 hours the plasma concentrations were sufficiently high to have a significant inhibitory effect upon gastric acid secretion. In patients with duodenal ulcer, 150 mg oral ranitidine every 12 hours significantly reduced mean 24-hour hydrogen ion activity by 69% and nocturnal gastric acid output by 90%. 300 mg ranitidine given at night is as effective in reducing 24-hour intragastric acidity as 150 mg ranitidine given twice daily.

Following administration of 50 mg ranitidine injection i.m. plasma concentrations in excess of 100 ng/mL were achieved within 5 minutes and remained above this level for 4 to 6 hours.

I.V. infusion (rate: 0.125 mg/kg/hour) produced a rise of intragastric pH between 5.6 and 7 after 2 hours and maintained this level over the 24 hour period when administered to seriously ill patients. The volume of gastric secretion was reduced by more than 55%. Doubling the infusion rate to 0.25 mg/kg/hour produced no further increase in gastric acid inhibition.

A single 50 mg i.v. bolus dose of ranitidine injection produced significant acid inhibition 8 to 9 hours after administration. When 13 seriously ill patients with 2 or more risk factors (shock, sepsis, respiratory failure, jaundice, renal insufficiency or peritonitis) were treated with a 50 mg i.v. bolus dose of ranitidine followed by a continuous infusion of 0.2 mg/kg/hour, the number of at risk days (gastric pH less than 3.5 at 3 consecutive 4-hour aliquots) was approximately half that of placebo treated patients.

Tablets: In respect of both 24 hours acidity and nocturnal acid output, oral ranitidine 150 mg twice daily was superior to cimetidine 200 mg 3 times daily and 400 mg at night (P
Treatment of volunteers with oral ranitidine 150 mg twice daily for 7 days did not cause bacterial overgrowth in the stomach.

Volunteers treated with an oral dose of ranitidine have reported no significant gastrointestinal or CNS side effects; moreover pulse rate, blood pressure, ECG and electroencephalogram were not significantly affected in man following ranitidine administration.

In healthy human volunteers and patients, ranitidine when administered orally, did not influence plasma levels of the following hormones – cortisol, testosterone, oestrogens, growth hormone, follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, aldosterone or gastrin – although like cimetidine, ranitidine reduced vasopressin output. Treatment for up to 6 weeks with ranitidine 150 mg twice daily by mouth did not affect the human hypothalamic-pituitary-testicular-ovarian or -adrenal axes.

Injection: I.M. ranitidine is fully bioavailable in comparison to i.v. ranitidine. The median elimination half-life of ranitidine injection 50 mg, administered i.v. or i.m. was found to be 2.3 hours (range 120 to 160 minutes). In comparison, the elimination half-life following oral administration is approximately 3 hours. However, the half-life of ranitidine in patients with renal dysfunction is prolonged. In a study of 27 patients with renal dysfunction (plasma creatinine concentration greater than 300 mol/L) therapeutic plasma levels of ranitidine were shown to be achieved without risk of drug accumulation, if half the normal dose of the drug was administered.

Ranitidine injection is well tolerated following i.v. administration at dose levels of up to 100 mg q.i.d. It is evident that these levels are in excess of those recommended for normal clinical use.

At 50 mg i.v. ranitidine injection had no effect on prolactin levels. Only at the 300 mg i.v. dose level was an increase in prolactin secretion, equivalent to that produced by 200 mg of cimetidine i.v., observed.

Indications And Clinical Uses: The treatment of duodenal ulcer, benign gastric ulcer, reflux esophagitis, post-operative peptic ulcer, Zollinger-Ellison syndrome and other conditions where reduction of gastric secretion and acid output is desirable. These include treatment of NSAID-induced lesions (ulcers, erosions) and gastrointestinal symptoms and prevention of their recurrence, prophylaxis of gastrointestinal hemorrhage from stress ulceration in seriously ill patients, the prophylaxis of recurrent hemorrhage from bleeding ulcers, and in the prevention of Acid Aspiration Syndrome (Mendelson’s Syndrome) from general anesthesia in patients considered to be at risk for this, including obstetrical patients in labor, and obese patients.

In addition, ranitidine is indicated for the prophylaxis and maintenance treatment of duodenal or benign gastric ulcer in patients with a history of recurrent ulceration.

Contra-Indications: For patients known to have hypersensitivity to ranitidine.

Manufacturers’ Warnings In Clinical States: Gastric Ulcer: Treatment with a histamine 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 is instituted.

Concomitant NSAID Use: Regular supervision of patients who are taking NSAIDs concomitantly with ranitidine is recommended especially in the elderly and those with a history of peptic ulcer. Baseline endoscopic and histological evaluation is necessary to rule out gastric carcinoma.

Patients with a History of Acute Porphyria: Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks. Therefore, ranitidine should be avoided in patients with a history of acute porphyria.

Pregnancy: The safety of ranitidine in the treatment of conditions where a controlled reduction of gastric secretion is required during pregnancy has not been established. Reproduction studies performed in rats and rabbits have revealed no evidence of ranitidine induced impaired fertility or harm to the fetus. Nevertheless, if the administration of ranitidine is considered to be necessary, its use requires that the potential benefits be weighed against possible hazards to the patient and to the fetus.

Lactation: Ranitidine is secreted in breast milk in lactating mothers but the clinical significance of this has not been fully evaluated.

Children: Experience with ranitidine in children is limited. It has however been used successfully in children aged 8 to 18 years in oral doses up to 150 mg twice daily.

Precautions: Injection: Bradycardia in association with rapid administration of ranitidine injection has been reported rarely, usually in patients with factors predisposing to cardiac rhythm disturbances. Recommended rates of administration should not be exceeded (see Adverse Effects and Dosage).

Use in Impaired Renal Function: Ranitidine is excreted via the kidneys and, in the presence of severe renal impairment, plasma levels of ranitidine are increased and elimination prolonged. Accordingly, it is recommended in such patients, to decrease the dosage of ranitidine by one-half. Accumulation with resulting elevated plasma concentrations will occur in patients with severe renal impairment (plasma creatinine concentration greater than 300 mol/L); a recommended daily dose of oral ranitidine in such patients should be 150 mg. In patients undergoing chronic ambulatory peritoneal dialysis or chronic hemodialysis, a single oral dose of ranitidine 150 mg should be taken immediately after dialysis.

Drug Interactions: Although ranitidine has been reported to bind weakly to cytochrome P450 in vitro, recommended doses of the drug do not inhibit the action of the hepatic cytochrome P450-linked oxygenase enzymes. However, there have been isolated reports of drug interactions which suggest that ranitidine may affect the bioavailability of certain drugs (e.g. ketoconazole) by some mechanism as yet unidentified (e.g. a pH dependant effect on absorption or a change in volume of distribution).

As well, sporadic cases of drug interactions have been reported in elderly patients involving both hypoglycemic drugs and theophylline. The significance of these reports cannot be determined at present, as controlled clinical trials with theophylline and ranitidine have not shown interaction.

If high doses (2 g) of sucralfate are co-administered with ranitidine, the absorption of ranitidine may be reduced. This effect is not seen if sucralfate is taken at least 2 hours after ranitidine administration.

Geriatrics: Since malignancy is more common in the elderly, particular consideration must be given to this before therapy with ranitidine is instituted. Elderly patients receiving NSAIDs concomitantly with ranitidine should be closely supervised.

As with all medication in the elderly, when prescribing ranitidine, consideration should be given to the patient’s concurrent drug therapy. Sporadic cases of drug interaction have been reported in elderly patients involving both hypoglycemic drugs and theophylline. The significance of these reports cannot be determined at present, as controlled clinical trials with theophylline and ranitidine have shown no interaction. Elderly patients may be at increased risk for confusional states and depression.

Adverse Reactions: The following adverse reactions have been reported as events in clinical trials or in the routine management of patients treated with ranitidine. A cause and effect relationship to ranitidine is not always established.

CNS: headache, sometimes severe; malaise; dizziness; somnolence; insomnia; vertigo; and reversible blurred vision suggestive of a change in accommodation. Isolated cases of reversible mental confusion, agitation, depression, hallucinations have been reported, predominantly in severely ill elderly patients.

Cardiovascular: Isolated reports of tachycardia, bradycardia, premature ventricular beats, AV block have been noted. Asystole has been reported in very few individuals with and without predisposing conditions following i.v. administration and has not been reported following oral administration of ranitidine (see Precautions and Dosage).

Gastrointestinal: constipation, diarrhea, nausea/vomiting and abdominal discomfort/pain.

Hepatic: In normal volunteers, transient and reversible ALT and AST values were increased to at least twice the pretreatment levels in 6 of 12 subjects receiving ranitidine 100 mg q.i.d. i.v. for 7 days, and in 4 of 24 subjects receiving 50 mg q.i.d. i.v. for 5 days. Therefore, it may be prudent to monitor AST and ALT in patients receiving i.v. treatment for 5 days or longer and in those with pre-existing liver diseases. With oral administration, there have been occasional reports of hepatitis, hepatocellular or hepatocanalicular or mixed, with or without jaundice. In such circumstances, ranitidine should be discontinued immediately. These are usually reversible, but in exceedingly rare circumstances, death has occurred.

Musculoskeletal: rare reports of arthralgia and myalgia.

Hematologic: Blood count changes (leukopenia, thrombocytopenia) have occurred in a few patients. These are usually reversible. Rare cases of agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or aplasia have been reported.

Endocrine: No clinically significant interference with endocrine or gonadal function has been reported. There have been a few reports of breast symptoms in men taking ranitidine.

Dermatologic: rash, including cases suggestive of mild erythema multiforme.

Other: Rare cases of hypersensitivity reactions (including chest pain, bronchospasm, fever, rash, eosinophilia, anaphylaxis, urticaria, angioneurotic edema, hypotension) and small increases in serum creatinine have occasionally occurred after a single dose. Acute pancreatitis has been reported rarely.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no experience to date with deliberate overdosage. The usual measures to remove unabsorbed drug from the gastrointestinal tract (including activated charcoal or syrup of ipecac), clinical monitoring and supportive therapy should be employed. Also, if need be, the drug can be removed from the plasma by hemodialysis. tag_DosageDosage

Dosage And Administration: Tablets, Oral Solution: Duodenal ulcer and benign gastric ulcer: 300 mg once daily at bedtime or 150 mg twice daily taken in the morning and before retiring. It is not necessary to time the dose in relation to meals. In most cases of duodenal ulcer and benign gastric ulcer, healing will occur in 4 weeks. In the small number of patients whose ulcers may not have fully healed, these are likely to respond to a further 4 week course of treatment. In the treatment of duodenal ulcers, 300 mg twice daily for 4 weeks, may be of benefit when more rapid healing is desired.

Maintenance therapy: Duodenal ulcers, benign gastric ulcers: Patients who have responded to short-term therapy, particularly those with a history of recurrent ulcer, may benefit from chronic maintenance therapy at a reduced oral tablet dosage of 150 mg once daily at bedtime.

In the management of duodenal ulcers, smoking is associated with a higher rate of ulcer relapse (up to 9.2 times higher in one trial), and such patients should be advised to stop smoking. In those patients who fail to comply with such advice, 300 mg nightly provides additional therapeutic benefit over the 150 mg once daily dosage regimen.

Reflux esophagitis: Acute treatment: 300 mg once daily at bedtime, or alternatively 150 mg twice daily, taken in the morning and before retiring for up to 8 weeks. In patients with moderate to severe esophagitis, the dosage of ranitidine may be increased to 150 mg for 4 times daily up to 12 weeks. Long-term management: the recommended adult oral dose is 150 mg twice daily.

Post-operative peptic ulcer: 150 mg twice daily, taken in the morning and before retiring.

Pathological hypersecretory conditions (Zollinger-Ellison Syndrome): 150 mg 3 times daily may be administered initially. In some patients, it may be necessary to administer 150 mg doses more frequently. Doses should be adjusted to individual patient needs. Doses up to 6 g/day have been well tolerated.

Treatment of NSAID-induced lesions (ulcers, erosions) and gastrointestinal symptoms and prevention of their recurrence: In ulcers following NSAID therapy or associated with continued NSAIDs, 150 mg twice daily for 8 to 12 weeks may be necessary. For the prevention of NSAID associated ulcer recurrence, 150 mg twice daily may be given concomitantly with nonsteroidal anti-inflammatory drug therapy.

Prophylaxis of acid aspiration syndrome (AAS): 150 mg the evening prior to anesthesia induction is recommended, however, 150 mg 2 hours before anesthesia induction is also effective. Alternatively, ranitidine injection may be used. For the prevention of AAS in pre-partum patients who elect for anesthesia, 150 mg every 6 hours may be employed, but if general anesthesia is warranted, a nonparticulate oral antacid (e.g., sodium citrate) could supplement ranitidine therapy. In an emergency situation, the use of alkalis, antacids, and meticulous anesthetic technique is still necessary as ranitidine does not affect the pH and volume of the existing gastric content.

Prophylaxis of hemorrhage from stress ulceration in seriously ill patients or prophylaxis of recurrent hemorrhage in patients bleeding from peptic ulceration who are currently managed by i.v. ranitidine: an oral dose of 150 mg twice daily may be substituted for the injection once oral feeding commences.

If necessary ranitidine oral solution may be administered by orogastric or nasogastric tube as an alternative.

Note: A 150 mg dose of ranitidine is equivalent to 10 mL of ranitidine oral solution, and 300 mg ranitidine is equivalent to 20 mL of ranitidine oral solution.

Geriatrics: For all conditions listed above, the drug dosage for the elderly who are seriously ill should start at the lowest recommended dose and be adjusted as necessary with close supervision.

Parenteral Administration: In some hospitalized patients with pathological hypersecretory conditions or intractable duodenal ulcers, or in patients unable to take oral medication, ranitidine may be administered parenterally according to the following recommendations:

I.M. Injection: 50 mg (2 mL) every 6 to 8 hours (no dilution is required).

I.V. Injection: 50 mg (2 mL) every 6 to 8 hours. Dilute ranitidine injection, 50 mg in compatible i.v. solution (see Compatibility of ranitidine injection) to a total volume of 20 mL and inject over a period of not less than 5 minutes (see Precautions). Parenteral administration may continue until oral feeding is commenced and if there is still a risk, oral ranitidine may then commence.

Intermittent I.V. Infusion: 50 mg (2 mL) every 6 to 8 hours. Dilute ranitidine injection 50 mg in 100 mL of compatible i.v. solution (see Dilution of Parenteral Products) and infuse over 15 to 20 minutes. In some patients, it may be necessary to increase dosage. When this is required, the increases should be made by more frequent administration of a 50 mg dose, but generally should not exceed 400 mg/day.

In the prophylaxis of upper gastrointestinal hemorrhage from stress ulceration in seriously ill patients a primary dose of 50 mg as a slow (over a period of not less than 5 minutes) i.v. injection followed by a continuous i.v. infusion of 0.125 to 0.250 mg/kg/hour may be preferred (see Precautions). The higher infusion concentration (0.25 mg/kg/hour) should be reserved for patients who are unresponsive to a lower concentration (0.125 mg/kg/hour).

In the prophylaxis of hemorrhage from stress ulceration in seriously ill patients or prophylaxis of recurrent hemorrhage in patients bleeding from peptic ulceration, parenteral administration may continue until oral feeding is commenced and if there is still a risk, oral ranitidine may then commence.

For patients considered at risk of developing Acid Aspiration Syndrome (Mendelson’s Syndrome); 50 mg by i.m. or slow (over a period of not less than 5 minutes) i.v. injection 45 to 60 minutes before induction of general anesthesia. In an emergency situation, the use of alkalis, antacids, and meticulous anesthetic technique is still necessary as ranitidine does not affect the pH and volume of the existing gastric content.

Dilution of Parenteral Products: I.M. Injection: No dilution is required.

I.V. Injection: Zantac injection for i.v. injection should be diluted to 20 mL (2.5 mg/mL) with one of the recommended diluents listed below.

Intermittent I.V. Infusion: Zantac injection for intermittent i.v. infusion should be diluted to 100 mL (0.5 mg/mL) with one of the recommended diluents listed below. Zantac injection is compatible in polyvinylchloride infusion bags (Viaflex) and in glass with the following i.v. fluids: 0.9% sodium chloride, 5% dextrose, 0.18% sodium chloride and 4% dextrose, 4.2% sodium bicarbonate and Hartmann’s solution. Admixtures of Zantac injection with 0.18% sodium chloride and 4% dextrose or 4.2% sodium bicarbonate or Hartmann’s solution should be discarded after 24 hours. Although i.v. admixtures of Zantac injection with 5% dextrose or 0.9% sodium chloride may often be physically and chemically stable for longer periods, due to microbiological considerations, they are usually recommended for use within the maximum 72 hours when refrigerated (2 to 8°C) followed by 24 hours at room temperature. Hospitals and institutions that have recognized admixture programs and use validated aseptic techniques for preparation of i.v. solutions, may extend the storage time for Zantac injection in admixture with 5% Dextrose Injection or 0.9% Sodium Chloride Injection in Viaflex bags, in concentrations of up to 2 mg/mL, to 35 days when stored under refrigeration at 2 to 8°C. As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate or discoloration or leakage should not be used.

Availability And Storage: Injection: Each mL of solution for i.v. or i.m. injection contains: ranitidine HCl 28 mg (equivalent to ranitidine anhydrous free base 25 mg) in sterile water for injection. Nonmedicinal ingredients: disodium hydrogen orthophosphate, phenol and potassium dihydrogen orthophosphate. Unit dose colorless glass vials of 2 mL. Multidose colorless glass vials of 40 mL. Packages of 10. Protect from light, store between 2 and 25°C. Injection should not be autoclaved.

Oral Solution: Each 5 mL of clear peppermint flavored solution contains: ranitidine HCl 84 mg (equivalent to ranitidine anhydrous free base 75 mg). Nonmedicinal ingredients: alcohol (7.5% w/v), butylparaben, dibasic sodium phosphate, flavor mint, hydroxypropyl methylcellulose, monobasic potassium phosphate, propylparaben, sodium chloride, sodium cyclamate and sorbitol. Bottles of 300 mL. Store at or below 25°C. Protect from light. Keep out of reach of children.

Tablets: 150 mg: Each white, round, biconvex, film-coated tablet engraved ZANTAC 150 on one face and GLAXO on the other contains: ranitidine HCl 168 mg (equivalent to ranitidine anhydrous free base 150 mg). Nonmedicinal ingredients: magnesium stearate and microcrystalline cellulose; film-coating suspension: dichloromethane, hydroxypropyl methylcellulose, isopropyl alcohol and Opaspray K-1-7000. Gluten- and tartrazine-free. Packs of 60. Store between 2 and 30°C. Protect from light.

300 mg: Each white, capsule-shaped, film-coated tablet engraved ZANTAC 300 on one face and GLAXO on the other contains: ranitidine HCl 336 mg (equivalent to ranitidine anhydrous free base 300 mg). Nonmedicinal ingredients: croscarmellose sodium, magnesium stearate and microcrystalline cellulose; film-coating suspension: dichloromethane, hydroxypropyl methylcellulose, isopropyl alcohol and Opaspray K-1-7000. Gluten- and tartrazine-free. Packs of 30. Store between 2 and 30°C. Protect from light. (Shown in Product Recognition Section)

ZANTAC® Glaxo Wellcome Ranitidine HCl Histamine H2 Receptor Antagonist

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