ZANTAC® 75
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. Inhibition of gastric acid secretion has been observed following i.v., intraduodenal and oral administration of ranitidine. This response 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 single oral doses up to 300 mg. In healthy subjects a single 75 mg dose of ranitidine significantly reduced meal-stimulated intragastric acidity ([H AUC) compared with placebo. The effect of ranitidine on intragastric acidity and pH is also dose-related.
A single 75 mg dose, compared to placebo, has an early onset of action; significantly elevating gastric pH within 1 hour and lasting for up to 13 hours postdosing. After correcting for onset of action (within 1 hour), the duration of acid suppression for ranitidine 75 mg is up to 12 hours (i.e., all day or all night). In the same multicentre, randomized, crossover study, the onset of acid suppression effect for ranitidine 75 mg was statistically superior to famotidine 10 mg at only 1 and 2 hours postdosing. The duration and degree of acid suppression of ranitidine 75 mg (63.1%, n=75) were superior to cimetidine 200 mg (37.8%, n=52) over the 10-hour daytime evaluation period.
In a large, multicentre, dose-ranging, placebo-controlled trial in patients with episodic heartburn, a single 75 mg dose relieved symptoms within 30 minutes and provided relief for the duration of the 4-hour evaluation period.
Volunteers treated with an oral dose of ranitidine have reported no significant gastrointestinal or CNS side effects; moreover, pulse rate, blood pressure, ECG and EEG are 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, estrogens, 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.
The safety and efficacy of 75 mg ranitidine for treatment of episodic heartburn were established in 2 large replicate Phase III studies involving 2 985 patients. These 2 pivotal studies showed that 1 ranitidine 75 mg tablet was statistically and clinically superior to placebo in providing relief of episodic heartburn beginning at 30 minutes.
Indications And Clinical Uses: For fast and effective relief, treatment and prevention, day or night, of the burning and discomfort of acid indigestion (dyspepsia), heartburn, hyperacidity, sour stomach and upset stomach associated with excess stomach acid. These symptoms may be brought on by consuming food and beverages.
Contra-Indications: For patients known to have hypersensitivity to any component of the preparation.
Manufacturers’ Warnings In Clinical States: Gastric Carcinoma: Treatment with a histamine H2-antagonist may mask symptoms associated with carcinoma of the stomach and, therefore, may delay diagnosis of that condition. Accordingly, patients should be advised to consult a physician if they have difficulty swallowing or persistent abdominal discomfort or if symptoms get worse or persist for more than 2 weeks.
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 and Lactation: 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 at higher doses 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.
Ranitidine is secreted in breast milk in lactating mothers, but the clinical significance of this has not been fully evaluated. Women who are breast-feeding are advised to speak with their doctor before taking ranitidine.
Precautions: 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, ranitidine should be used under physician supervision for these patients.
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. A review of selected publications of controlled clinical drug interaction studies at the level of hepatic elimination has indicated ranitidine is unlikely to cause clinically significant potentiation of actions of drugs which are inactivated by the hepatic cytochrome P450 enzyme system; these drugs may include: diazepam, lidocaine, phenytoin, propranolol, theophylline and warfarin. Sporadic cases (approximately 1 case per 4 million patient treatments) 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 have not shown interactions. These reports are based on use for prescription indications and dosage.
Antacids: Concurrent administration of antacid of medium to high potency (75 mEq) with ranitidine is not recommended. The absorption of ranitidine may be decreased. Patients should be cautioned not to take antacids within 1/2 to 1 hour of ranitidine ingestion.
Ketoconazole: Simultaneous administration of ketoconazole and ranitidine may result in reduction of the absorption of ketoconazole by some mechanism as yet unidentified (e.g., a pH-dependent effect on absorption or a change of volume of distribution). Patients should be cautioned not to take ranitidine for at least 2 hours after ketoconazole. These reports are based on use of prescription indications and dosage.
Sucralfate: If high doses of sucralfate (2 g) are coadministered 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. These reports are based on use of prescription indications and dosage.
Procainamide: Some evidence of interactions with ranitidine at the level of renal elimination have been reported, but the clinical importance is unknown/questionable. These reports are based on use for prescription indications and dosage.
Ethanol: The coadministration of a single oral dose of ranitidine 75 mg and ethanol 0.15 g/kg has no clinically relevant effect on ethanol pharmacokinetics as shown in a double-blind, placebo-controlled, crossover study in 25 healthy subjects.
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 nonsteroidal anti-inflammatory drugs concomitantly with ranitidine should be closely supervised. As with all medication in the elderly, consideration should be given to concurrent drug therapy.
Adverse Reactions: In clinical trials with ranitidine the most frequently reported adverse events included: headache (4%), nausea and vomiting (3%) and diarrhea (2%). There was no statistical difference in reported events between the ranitidine- and placebo-treated groups.
The following adverse reactions have been reported as events in clinical trials, in postmarketing surveillance, or in the routine management of patients treated with prescription doses of ranitidine. The majority of these events have been observed following oral administration of higher prescription doses of ranitidine and a cause and effect relationship to ranitidine has not always been 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: As with other H2-receptor antagonists, there have been rare reports of tachycardia, premature ventricular beats, bradycardia, and atrioventricular block.
Gastrointestinal: constipation, diarrhea, nausea/vomiting and abdominal discomfort/pain.
Hepatic: Transient and reversible changes in liver function tests can occur (increase in ALT and AST values). With oral administration, there have been occasional reports of hepatitis, hepatocellular or hepatocanalicular, 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. Up to 6 g/day has been administered without untoward effect.
Dosage And Administration: Adults and Children 16 Years of Age and Older: 1 tablet should be taken when symptoms appear, day or night. If symptoms persist for more than 1 hour or return after 1 hour, a second tablet may be taken. The maximum dosage is 2 tablets in a 24-hour period. Patients are advised to consult their physician if symptoms get worse or continue after 14 days of treatment.
For prevention of symptoms brought on by consuming food or beverages, 1 tablet should be taken 30 to 60 minutes before eating a meal expected to cause symptoms.
Children Under 16 Years: Children under 16 years of age should be supervised by a physician.
Availability And Storage: Each pink, five-sided, biconvex, film-coated tablet, with “Z” engraved on one side and 75 on the other, contains: ranitidine HCl 84 mg equivalent to ranitidine anhydrous free base 75 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, iron oxide, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin. Packs of 2, 4, 10, 30, 40 and 60. Store between 2 and 30°C.
ZANTAC® 75 Glaxo Wellcome Ranitidine HCl Histamine H2-receptor Antagonist
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