1. Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute ulcers.
3. The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and systemic mastocytosis).
4. Short-term treatment of active, benign gastric ulcer. Most patients heal within 6 weeks and the usefulness of further treatment has not been demonstrated.
5. Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers. Placebo-controlled studies have been carried out for 1 year.
6. Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting therapy with Ranitidine 150 mg b.i.d.
7. 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.
8. Maintenance of healing of erosive esophagitis.

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.

CONTRAINDICATIONS:

Ranitidine is contraindicated for patients known to have hypersensitivity to the drug or any of the ingredients.

DESCRIPTION: The active ingredient in Ranitidine 150 Tablets, each Ranitidine 150 Tablet for oral administration contains 168 mg of Ranitidine HCl equivalent to 150 mg of Ranitidine.

CLINICAL PHARMACOLOGY:

Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H ₂ -receptors, including receptors on the gastric cells. Ranitidine does not lower serum Ca ⁺⁺ in hypercalcemic states. Ranitidine is not an anticholinergic agent.

Pharmacokinetics:

Absorption:    Ranitidine is 50% absorbed after oral administration, occurring 2 to 3 hours after a 150-mg dose.

Distribution:    The volume of distribution is about 1.4 L/kg. Serum protein binding averages 15%.

Metabolism:    In humans, the N-oxide is the principal metabolite in the urine; however, this amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the des-methyl Ranitidine (1%). The remainder of the administered dose is found in the stool. Studies in patients with hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically insignificant, alterations in Ranitidine half-life, distribution, clearance, and bioavailability.

Excretion:    The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 hours.

Geriatrics:    The plasma half-life is prolonged and total clearance is reduced in the elderly population due to a decrease in renal function. The elimination half-life is 3 to 4 hours.

Pediatrics:    There are no significant differences in the pharmacokinetic parameter values for Ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when correction is made for body weight.

Pharmacodynamics:    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.

Antisecretory Activity:  

1. Effects on Acid Secretion: Ranitidine inhibits both daytime and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food, betazole, and pentagastrin, as shown in Table 1.

2. Effects on Other Gastrointestinal Secretions:

Pepsin:    Oral Ranitidine does not affect pepsin secretion. Total pepsin output is reduced in proportion to the decrease in volume of gastric juice.

Intrinsic Factor:    Oral Ranitidine has no significant effect on pentagastrin-stimulated intrinsic factor secretion.

Serum Gastrin:    Ranitidine has little or no effect on fasting or postprandial serum gastrin.

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

PRECAUTIONS: General: 1. Symptomatic response to therapy with Ranitidine does not preclude the presence of gastric malignancy.

2. Since Ranitidine is excreted primarily by the kidney, dosage should be adjusted in patients with impaired renal function. Caution should be observed in patients with hepatic dysfunction since Ranitidine is metabolized in the liver.

3. Ranitidine should therefore be avoided in patients with a history of acute porphyria.

Laboratory Tests:    False-positive tests for urine protein may occur during Ranitidine therapy, and therefore testing with sulfosalicylic acid is recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility: 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.

Pregnancy:    Pregnancy Category B.

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

Pediatric Use:   Safety and effectiveness in neonates (less than one month of age) have not been established.

Geriatric Use:  No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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.

Drug Interactions:

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.

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.

In a Ranitidine-triazolam drug-drug interaction study, triazolam plasma concentrations were higher during b.i.d. dosing of Ranitidine than triazolam given alone.

SIDE EFFECTS:

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 H ₂ -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 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.

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

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

OVERDOSAGE:

There has been limited experience with overdosage. Reported acute ingestions of up to 18 g orally have been associated with transient adverse effects. 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.

DOSAGE AND ADMINISTRATION:

 Active Duodenal Ulcer:    The current recommended adult oral dosage of Ranitidine for duodenal ulcer is 150 mg. 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. Antacid should be given as needed for relief of pain.

Maintenance of Healing of Duodenal Ulcers:    The current recommended adult oral dosage is 150 at bedtime.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):    The current recommended adult oral dosage is 150 mg twice a day. 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:  

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 per day twice daily to a maximum of 300 mg/day.

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.

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 two 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/min is 150 mg every 24 hours. 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.

How Supplied: Each pack of Ruz-Ranitidine 150 mg tablets contains 100 tablets in 10 blisters.            

storage: Store between 15° and 30°C in a dry place. Protect from light.

Reference: PDR 2000, page 1310-12

                  USPDI for Professional Health Care, 2004, Page 1539-1550

                  Martindale 2005, Page 1285-1287