ranitidine HCl 150 MG Oral Capsule

Generic Name: RANITIDINE HYDROCHLORIDE
Brand Name: Ranitidine Hydrochloride
  • Substance Name(s):
  • RANITIDINE HYDROCHLORIDE

DRUG INTERACTIONS

Drug Interactions Ranitidine has been reported to affect the bioavailability of other drugs through several different mechanisms such as competition for renal tubular secretion, alteration of gastric pH, and inhibition of cytochrome P450 enzymes.

Procainamide: Ranitidine, a substrate of the renal organic cation transport system, may affect the clearance of other drugs eliminated by this route.

High doses of ranitidine (e.g., such as those used in the treatment of Zollinger-Ellison syndrome) have been shown to reduce the renal excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of these drugs.

Although this interaction is unlikely to be clinically relevant at usual ranitidine doses, it may be prudent to monitor for procainamide toxicity when administered with oral ranitidine at a dose exceeding 300 mg per day.

Warfarin: There have been reports of altered prothrombin time among patients on concomitant warfarin and ranitidine therapy.

Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine.

Ranitidine may alter the absorption of drugs in which gastric pH is an important determinant of bioavailability.

This can result in either an increase in absorption (e.g., triazolam, midazolam, glipizide) or a decrease in absorption (e.g., ketoconazole, atazanavir, delavirdine, gefitinib).

Appropriate clinical monitoring is recommended.

Atazanavir: Atazanavir absorption may be impaired based on known interactions with other agents that increase gastric pH.

Use with caution.

See atazanavir label for specific recommendations.

Delavirdine: Delavirdine absorption may be impaired based on known interactions with other agents that increase gastric pH.

Chronic use of H2-receptor antagonists with delavirdine is not recommended.

Gefitinib: Gefitinib exposure was reduced by 44% with the coadministration of ranitidine and sodium bicarbonate (dosed to maintain gastric pH above 5.0).

Use with caution.

Glipizide: In diabetic patients, glipizide exposure was increased by 34% following a single 150-mg dose of oral ranitidine.

Use appropriate clinical monitoring when initiating or discontinuing ranitidine.

Ketoconazole: Oral ketoconazole exposure was reduced by up to 95% when oral ranitidine was coadministered in a regimen to maintain a gastric pH of 6 or above.

The degree of interaction with usual dose of ranitidine (150 mg twice daily) is unknown.

Midazolam: Oral midazolam exposure in 5 healthy volunteers was increased by up to 65% when administered with oral ranitidine at a dose of 150 mg twice daily.

However, in another interaction study in 8 volunteers receiving IV midazolam, a 300 mg oral dose of ranitidine increased midazolam exposure by about 9%.

Monitor patients for excessive or prolonged sedation when ranitidine is coadministered with oral midazolam.

Triazolam: Triazolam exposure in healthy volunteers was increased by approximately 30% when administered with oral ranitidine at a dose of 150 mg twice daily.

Monitor patients for excessive or prolonged sedation.

OVERDOSAGE

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.

DESCRIPTION

Ranitidine hydrochloride (HCl), is 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, HCl.

It has the following structure: The empirical formula is C13H22N4O3S • HCl, representing a molecular weight of 350.87.

Ranitidine HCl 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 and 300 mg of ranitidine, respectively.

Inactive ingredients: D & C Red #30 Aluminum Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, triethyl citrate, sodium starch glycolate, titanium dioxide and flavoring.

The 300 mg also contains: D & C Yellow #10 Aluminum Lake.

Each capsule, for oral administration contains 168 mg or 336 mg of ranitidine hydrochloride equivalent to 150 mg and 300 mg of ranitidine, respectively.

Inactive ingredients: Ammonium hydroxide, colloidal silicon dioxide, corn starch, FD & C Blue #1, FD & C Red #40, FD & C Yellow #6, gelatin, magnesium stearate, pharmaceutical glaze, propylene glycol, silicon dioxide, simethicone, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide.

ranitidine hydrochloride chemical structure

CLINICAL STUDIES

Clinical Trials 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.

Table 3.

Duodenal Ulcer Patient Healing Rates RanitidineAll patients were permitted antacids as needed for relief of pain.

Placebo Number Entered Healed/ Evaluable Number Entered Healed/ Evaluable OutpatientsWeek 2 69/182 31/164 (38%) P <0.0001.

(19%) 195 188 Week 4 137/187 76/168 (73%) (45%) In these studies, patients treated with ranitidine reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.

Table 4.

Mean Daily Doses of Antacid Ulcer Healed Ulcer Not Healed Ranitidine 0.06 0.71 Placebo 0.71 1.43 Foreign studies have shown that patients heal equally well with 150 mg two times a day and 300 mg at bedtime (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 two times a day as compared to 300 mg at bedtime (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 at bedtime) than in patients treated with placebo over a 12-month period.

Table 5.

Duodenal Ulcer Prevalence Double-blind, Multicenter, Placebo-Controlled Trials Multicenter Trial Drug Duodenal Ulcer Prevalence No.

of Patients 0-4 Months 0-8 Months 0-12 Months RANRAN = ranitidine.

20%% = Life Table estimate.

P<0.05 (Ranitidine versus comparator).

24% 35% 138 USA PLCPLC = placebo.

44% 54% 59% 139 RAN 12% 21% 28% 174 Foreign PLC 56% 64% 68% 165 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.

Table 6.

Gastric Ulcer Patient Healing Rates RanitidineAll patients were permitted antacids as needed for relief of pain.

Placebo Number Entered Healed/ Evaluable Number Entered Healed/ Evaluable OutpatientsWeek 2 92 16/83(19%) 94 10/83(12%) Week 6 50/73(68%) P = 0.009.

35/69(51%) 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 tablets or ranitidine capsules 150 mg at bedtime were 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 hypersecretory 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 two times a day 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 two times a day 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 two times a day was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency and severity of heartburn.

Erosive Esophagitis In two multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, ranitidine 150 mg 4 times daily 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: Table 7.

Erosive Esophagitis Patient Healing Rates Healed/Evaluable PlaceboAll patients were permitted antacids as needed for relief of pain.

(n = 229) Ranitidine 150 mg 4 times daily (n = 215) Week 4 43/198 (22%) 96/206 (47%) p<0.001 versus placebo.

Week 8 63/176 (36%) 142/200 (71%) Week 12 92/159 (58%) 162/192 (84%) No additional benefit in healing of esophagitis or in relief of heartburn was seen with a ranitidine dose of 300 mg 4 times daily.

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 two times a day was significantly more effective than placebo in maintaining healing of erosive esophagitis.

HOW SUPPLIED

Ranitidine Tablets, USP for oral administration, are available as: 150 mg: round, off-white, unscored tablets, film-coated pink, debossed GG 705 on one side and plain on the reverse side.

300 mg: round, off-white, unscored tablets, film-coated orange, debossed GG 706 on one side and plain on the reverse side.

Ranitidine Capsules, for oral administration, are available as: 150 mg: Opaque caramel capsules, imprinted GG 614 in white ink, filled with off-white powder and supplied as: NDC 0615-1354-39 blistercards of 30 capsules 300 mg: Opaque caramel capsules, imprinted GG 615 in white ink, filled with off-white powder.

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature] in a dry place.

Protect from light.

Replace cap securely after each opening.

Dispense in a tight, light-resistant container.

GERIATRIC USE

Geriatric Use Of the total number of subjects enrolled in US and foreign controlled clinical trials of oral formulations of ranitidine, for which there were subgroup analyses, 4,197 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 ).

INDICATIONS AND USAGE

Ranitidine is 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 two times a day.

Treatment of endoscopically diagnosed erosive esophagitis.

Symptomatic relief of heartburn commonly occurs within 24 hours of therapy initiation with ranitidine 150 mg 4 times daily.

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.

PEDIATRIC USE

Pediatric Use The safety and effectiveness of ranitidine has 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 one month of age) have not been established (see CLINICAL PHARMACOLOGY: Pediatrics ).

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to 160 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ranitidine.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

NUSRING MOTHERS

Nursing Mothers Ranitidine is secreted in human milk.

Caution should be exercised when ranitidine is administered to a nursing mother.

DOSAGE AND ADMINISTRATION

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 PHARMACOLOGY: 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 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 ).

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 has 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 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.

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 ).