Ranitidine hydrochloride (HCl), USP, is a histamine H 2-receptor antagonist. Chemically it is

N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]- N′-methyl-2-nitro-1,1-ethene-diamine, HCl. It has the following structural formula:

The molecular formula is C 13H22N4O3S•HCl, representing a molecular weight of 350.87.

Ranitidine HCl is a white to pale yellow, crystalline substance that is soluble in water. It has a slightly bitter taste and sulfurlike 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: FD&C Yellow No. 6 Aluminum Lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, synthetic yellow iron oxide, titanium dioxide and triethyl citrate.

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.

Active Duodenal Ulcer:In a multicenter, double-blind, controlled, US study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients treated with ranitidine as shown in Table 3.

In these studies, patients treated with rantidine reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.

Foreign studies have shown that patients heal equally well with 150 mg b.i.d. and 300 mg h.s. (85% versus 84%, respectively) during a usual 4-week course of therapy. If patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg b.i.d. as compared to 300 mg h.s. (92% versus 87%, respectively).

Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose ulcers healed during therapy had recurrences of ulcers at the usual rates.

Maintenance therapy in Duodenal Ulcer: Ranitidine has been found to be effective as maintenance therapy for patients following healing of acute duodenal ulcers. In two independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with ranitidine (150 mg h.s.) than in patients treated with placebo over a 12 month period.

As with other H2-antagonists, the factors responsible for the significant reduction in the prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of ulcers that may occur during maintenance therapy, or both.

Gastric Ulcer:In a multicenter, double-blind, controlled, US study of endoscopically diagnosed gastric ulcers, earlier healing was seen in the patients treated with ranitidine as shown in Table 6.

In this multicenter trial, significantly more patients treated with ranitidine became pain-free during therapy.

Maintenance of Healing of Gastric Ulcers:In two multicenter, double-blind, randomized, placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been previously healed, ranitidine 150 mg h.s. was significantly more effective than placebo in maintaining healing of gastric ulcers.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome): Ranitidine inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome, systemic mastocytosis, and other pathological hyper-secretory conditions (e.g., postoperative, “short-gut” syndrome idiopathic). Use of ranitidine was followed by healing of ulcers in 8 of 19 (42%) patients who were intractable to previous therapy.

Gastroesophageal Reflux disease (GERD):In two multicenter, double-blind, placebo-controlled, 6-week trials performed in the United States and Europe, ranitidine 150 mg b.i.d. was more effective than placebo for the relief of heartburn and other symptoms associated with GERD. Ranitidine-treated patients consumed significantly less antacid than did placebo-treated patients.

The US trial indicated that ranitidine 150 mg b.i.d. significantly reduced the frequency of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The improvement was maintained throughout the 6-week trial period. Moreover, patient response rates demonstrated that the effect on heartburn extends through both the day and night time periods.

In two additional US multicenter, double-blind, placebo-controlled, 2-week trials, ranitidine 150 mg b.i.d. was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency of severity of heartburn.

Erosive Esophagitis:In two multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, ranitidine 150 mg q.i.d. was significantly more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving associated heartburn. The erosive esophagitis healing rates were as follows:

No additional benefit in healing of esophagitis or in relief of heartburn was seen with a ranitidine dose of 300 mg q.i.d.

Maintenance of Healing of Erosive Esophagitis:In two multicenter, double-blind, randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis had been previously healed, ranitidine 150 mg b.i.d. was significantly more effective than placebo in maintaining healing of erosive esophagitis.

Ranitidine tablets are indicated in:

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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.

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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.

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The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and systemic mastocytosis).

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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.

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Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers. Placebo-controlled studies have been carried out for 1 year.

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Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting therapy with ranitidine 150 mg b.i.d.

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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; hyper-secretory 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).

General:

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Symptomatic response to therapy with ranitidine does not preclude the presence of gastric malignancy.

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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.

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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.

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.

Central Nervous System:

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.

Cardiovascular:

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

Gastrointestinal:

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

Hepatic:

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.

Musculoskeletal:

Rare reports of arthralgias and myalgias.

Hematologic:

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.

Endocrine:

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 hyper-secretory 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.

Integumentary:

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

Respiratory:

A large epidemiological study suggested an increased risk of developing pneumonia in current users of histamine-2-receptor antagonists (H2RAs) compared to patients who had stopped H2RA treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07 – 2.48). However, a causal relationship between use of H2RAs and pneumonia has not been established.

Other:

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 1000 mg/kg in mice and rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg, respectively.

Active Duodenal Ulcer:

The current recommended adult oral dosage of ranitidine 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 US studies, and several foreign trials have been shown that 100 mg twice is as effective as the 150 mg dose.

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

Maintenance of Healing of Duodenal Ulcers:

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

Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):

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.

Benign Gastric Ulcer:

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

Maintenance of Healing of Gastric Ulcers:

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

GERD:

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

Erosive Esophagitis:

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

Maintenance of Healing of Erosive Esophagitis:

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

Pediatric Use: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.

Treatment of Duodenal and Gastric Ulcers:The recommended oral dose for the treatment of active duodenal and gastric ulcers is 2 to 4 mg/kg twice daily to a maximum of 300 mg/day. This recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric patients.

Maintenance of Healing of Duodenal and Gastric Ulcers:The recommended oral dose for the maintenance of healing of duodenal and gastric ulcers is 2 to 4 mg/kg once daily to a maximum of 150 mg/day. This recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric patients.

Treatment of GERD and Erosive Esophagitis: Although limited data exist for these conditions in pediatric patients, published literature supports a dosage of 5 to 10 mg/kg per day, usually given as 2 divided doses.

Dosage Adjustment for Patients With Impaired Renal Function:

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 per minute 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).

150 mg tablets: peach to light-brown colored, round unscored tablets debossed“Par 544” on one side and plain on the other, supplied in bottles of 60 (NDC 49884-544-02), 100 (NDC 49884-544-01), 500 (NDC 49884-544-05), and 1000 (NDC 49884-544-10).

300 mg tablets: peach to light-brown colored, oval unscored tablets debossed “Par 545” on one side and plain on the other, supplied in bottles of 30 (NDC 49884-545-11), 100 (NDC 49884-545-01), 250 (NDC 49884-545-04).

Store at 15°-30°C (59°-86°F) in a dry place. Protect from light. Replace cap securely after opening.

Dispense in a tight, light-resistant container as defined in the USP.

Manufactured by:

PAR PHARMACEUTICAL COMPANIES, INC.

Spring Valley, NY 10977