RANITIDINE TABLETS USP
8544
8547

The active ingredient in ranitidine tablets is ranitidine hydrochloride, USP, a histamine H₂-receptor antagonist. Chemically it is N-[2-[[[5-[(dimethylamino)methyl]-2-furanyl] methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine, hydrochloride. It has the following structure:

C₁₃H₂₂N₄O₃S•HCl M.W. 350.87

Ranitidine hydrochloride is a white to pale yellow, granular substance that is soluble in water. It has a slightly bitter taste and sulfur-like odor.

Each tablet for oral administration contains 168 mg or 336 mg of ranitidine hydrochloride equivalent to 150 mg or 300 mg of ranitidine, respectively. In addition, each tablet contains the following inactive ingredients: collodial silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The coating for the tablets contains: hypromellose [135.0 (10% w/w solution in water)], polydextrose, polyethylene glycol, talc, triethyl citrate, and titanium dioxide.

Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H₂-receptors, including receptors on the gastric cells. Ranitidine does not lower serum Ca⁺⁺ in hypercalcemic states. Ranitidine is not an anticholinergic agent.

Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum concentrations of ranitidine are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition.

a. Gastric bacterial flora – increase in nitrate-reducing organisms, significance not known.

b. Prolactin levels – no effect in recommended oral or intravenous (IV) dosage, but small, transient, dose-related increases in serum prolactin have been reported after IV bolus injections of 100 mg or more.

c. Other pituitary hormones – no effect on serum gonadotropins, TSH, or GH. Possible impairment of vasopressin release.

d. No change in cortisol, aldosterone, androgen, or estrogen levels.

e. No antiandrogenic action.

f. No effect on count, motility, or morphology of sperm.

Oral doses of 6 to 10 mg/kg per day in 2 or 3 divided doses maintain gastric pH > 4 throughout most of the dosing interval.

Ranitidine tablets are indicated in:

• Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks. Studies available to date have not assessed the safety of ranitidine in uncomplicated duodenal ulcer for periods of more than 8 weeks.
• Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute ulcers. No placebo-controlled comparative studies have been carried out for periods of longer than 1 year.
• The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and systemic mastocytosis).
• Short-term treatment of active, benign gastric ulcer. Most patients heal within 6 weeks and the usefulness of further treatment has not been demonstrated. Studies available to date have not assessed the safety of ranitidine in uncomplicated, benign gastric ulcer for periods of more than 6 weeks.
• Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers. Placebo-controlled studies have been carried out for 1 year.
• Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting therapy with ranitidine 150 mg b.i.d.
• Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn commonly occurs within 24 hours of therapy initiation with ranitidine 150 mg q.i.d.
• Maintenance of healing of erosive esophagitis. Placebo-controlled trials have been carried out for 48 weeks.

Concomitant antacids should be given as needed for pain relief to patients with active duodenal ulcer; active, benign gastric ulcer; hypersecretory states; GERD; and erosive esophagitis.

Ranitidine tablets are contraindicated for patients known to have hypersensitivity to the drug or any of the ingredients (see PRECAUTIONS).

• Symptomatic response to therapy with ranitidine does not preclude the presence of gastric malignancy.
• Since ranitidine is excreted primarily by the kidney, dosage should be adjusted in patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution should be observed in patients with hepatic dysfunction since ranitidine is metabolized in the liver.
• Rare reports suggest that ranitidine may precipitate acute porphyric attacks in patients with acute porphyria. Ranitidine should therefore be avoided in patients with a history of acute porphyria.

False-positive tests for urine protein with MULTISTIX^® may occur during ranitidine therapy, and therefore testing with sulfosalicylic acid is recommended.

Although ranitidine has been reported to bind weakly to cytochrome P-450 in vitro, recommended doses of the drug do not inhibit the action of the cytochrome P-450-linked oxygenase enzymes in the liver. However, there have been isolated reports of drug interactions that suggest that ranitidine may affect the bioavailability of certain drugs by some mechanism as yet unidentified (e.g., a pH-dependent effect on absorption or a change in volume of distribution).

Increased or decreased prothrombin times have been reported during concurrent use of ranitidine and warfarin. However, in human pharmacokinetic studies with dosages of ranitidine up to 400 mg/day, no interaction occurred; ranitidine had no effect on warfarin clearance or prothrombin time. The possibility of an interaction with warfarin at dosages of ranitidine higher than 400 mg/day has not been investigated.

In a ranitidine-triazolam drug-drug interaction study, triazolam plasma concentrations were higher during b.i.d. dosing of ranitidine than triazolam given alone. The mean area under the triazolam concentration-time curve (AUC) values, in 18 to 60 year old subjects were 10% and 28% higher following administration of 75 mg and 150 mg ranitidine tablets, respectively, than triazolam given alone. In subjects older than 60 years of age, the mean AUC values were approximately 30% higher following administration of 75 mg and 150 mg ranitidine tablets. It appears that there were no changes in pharmacokinetics of triazolam and α-hydroxytriazolam, a major metabolite, and in their elimination. Reduced gastric acidity due to ranitidine may have resulted in an increase in the availability of triazolam. The clinical significance of this triazolam and ranitidine pharmacokinetic interaction is unknown.

There was no indication of tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to 2,000 mg/kg per day.

Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichiacoli) for mutagenicity at concentrations up to the maximum recommended for these assays.

In a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats was without effect on the outcome of 2 matings per week for the next 9 weeks.

Ranitidine is secreted in human milk. Caution should be exercised when ranitidine is administered to a nursing mother.

The safety and effectiveness of ranitidine have been established in the age-group of 1 month to 16 years for the treatment of duodenal and gastric ulcers, gastroesophageal reflux disease and erosive esophagitis, and the maintenance of healed duodenal and gastric ulcer. Use of ranitidine in this age-group is supported by adequate and well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients and an analysis of the published literature (see CLINICAL PHARMACOLOGY, Pediatrics and DOSAGE AND ADMINISTRATION, Pediatric Use).

Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory conditions or the maintenance of healing of erosive esophagitis have not been established.

Safety and effectiveness in neonates (less than 1 month of age) have not been established (see CLINICAL PHARMACOLOGY, Pediatrics).

Of the total number of subjects enrolled in U.S. and foreign controlled clinical trials of oral formulations of ranitidine, for which there were subgroup analyses, 4197 were 65 and over, while 899 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Geriatrics and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Impaired Renal Function).

The following have been reported as events in clinical trials or in the routine management of patients treated with ranitidine. The relationship to therapy with ranitidine has been unclear in many cases. Headache, sometimes severe, seems to be related to administration of ranitidine.

Rarely, malaise, dizziness, somnolence, insomnia, and vertigo. Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been reported, predominantly in severely ill elderly patients. Rare cases of reversible blurred vision suggestive of a change in accommodation have been reported. Rare reports of reversible involuntary motor disturbances have been received.

As with other H₂-blockers, rare reports of arrhythmias such as tachycardia, bradycardia, atrioventricular block, and premature ventricular beats.

Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and rare reports of pancreatitis.

There have been occasional reports of hepatocellular, cholestatic, or mixed hepatitis, with or without jaundice. In such circumstances, ranitidine should be immediately discontinued. These events are usually reversible, but in rare circumstances death has occurred. Rare cases of hepatic failure have also been reported. In normal volunteers, SGPT values were increased to at least twice the pretreatment levels in 6 of 12 subjects receiving 100 mg q.i.d. intravenously for 7 days, and in 4 of 24 subjects receiving 50 mg q.i.d. intravenously for 5 days.

Rare reports of arthralgias and myalgias.

Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia) have occurred in a few patients. These were usually reversible. Rare cases of agranulocytosis, pancytopenia, sometimes with marrow hypoplasia, and aplastic anemia and exceedingly rare cases of acquired immune hemolytic anemia have been reported.

Controlled studies in animals and man have shown no stimulation of any pituitary hormone by ranitidine and no antiandrogenic activity, and cimetidine-induced gynecomastia and impotence in hypersecretory patients have resolved when ranitidine has been substituted. However, occasional cases of gynecomastia, impotence, and loss of libido have been reported in male patients receiving ranitidine, but the incidence did not differ from that in the general population.

Rash, including rare cases of erythema multiforme. Rare cases of alopecia and vasculitis.

Rare cases of hypersensitivity reactions (e.g., bronchospasm, fever, rash, eosinophilia), anaphylaxis, angioneurotic edema, and small increases in serum creatinine.

There has been limited experience with overdosage. Reported acute ingestions of up to 18 g orally have been associated with transient adverse effects similar to those encountered in normal clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and hypotension have been reported.

When overdosage occurs, the usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.

Studies in dogs receiving dosages of ranitidine in excess of 225 mg/kg per day have shown muscular tremors, vomiting, and rapid respiration. Single oral doses of 1,000 mg/kg in mice and rats were not lethal. Intravenous LD₅₀ values in mice and rats were 77 and 83 mg/kg, respectively.

The current recommended adult oral dosage of ranitidine tablets for duodenal ulcer is 150 mg twice daily. An alternative dosage of 300 mg once daily after the evening meal or at bedtime can be used for patients in whom dosing convenience is important. The advantages of one treatment regimen compared to the other in a particular patient population have yet to be demonstrated (see Clinical Trials, Active Duodenal Ulcer). Smaller doses have been shown to be equally effective in inhibiting gastric acid secretion in U.S. studies, and several foreign trials have shown that 100 mg twice daily is as effective as the 150 mg dose.

Antacid should be given as needed for relief of pain (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

The current recommended adult oral dosage is 150 mg at bedtime.

The current recommended adult oral dosage is 150 mg twice a day. In some patients it may be necessary to administer ranitidine 150 mg doses more frequently. Dosages should be adjusted to individual patient needs, and should continue as long as clinically indicated. Dosages up to 6 g/day have been employed in patients with severe disease.

The current recommended adult oral dosage is 150 mg twice a day.

The current recommended adult oral dosage is 150 mg at bedtime.

The current recommended adult oral dosage is 150 mg twice a day.

The current recommended adult oral dosage is 150 mg 4 times a day.

The current recommended adult oral dosage is 150 mg twice a day.

The safety and effectiveness of ranitidine have been established in the age-group of 1 month to 16 years. There is insufficient information about the pharmacokinetics of ranitidine in neonatal patients (less than 1 month of age) to make dosing recommendations.

The following 3 subsections provide dosing information for each of the pediatric indications.

On the basis of experience with a group of subjects with severely impaired renal function treated with ranitidine, the recommended dosage in patients with a creatinine clearance < 50 mL/ min is 150 mg every 24 hours. Should the patient’s condition require, the frequency of dosing may be increased to every 12 hours or even further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.

Elderly patients are more likely to have decreased renal function, therefore caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Geriatrics and PRECAUTIONS, Geriatric Use).

Ranitidine tablets USP, 150 mg (ranitidine hydrochloride equivalent to 150 mg ranitidine) for oral administration are white to off-white, round, bi-convex, film-coated tablets, debossed with N over 544 on one side and 150 on the reverse. They are supplied as follows:

NDC 0093-8544-06 bottles of 60’s

NDC 0093-8544-01 bottles of 100’s

NDC 0093-8544-05 bottles of 500’s

NDC 0093-8544-10 bottles of 1000’s

Ranitidine tablets USP, 300 mg (ranitidine hydrochloride equivalent to 300 mg ranitidine) for oral administration are white to off-white, capsule-shaped, film-coated tablets, debossed with N over 547 on one side and 300 on the reverse. They are supplied as follows:

NDC 0093-8547-56 bottles of 30’s

NDC 0093-8547-01 bottles of 100’s

NDC 0093-8547-52 bottles of 250’s

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light. Dispense in a tight, light-resistant container as defined in the USP. Replace cap securely after each opening.

Manufactured In Canada By:

NOVOPHARM LIMITED

Toronto, Canada M1B 2K9

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. D 5/2005