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GLENMARK PHARMA
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ranitidine 300 mg tablet

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Uses

Ranitidine is used orally for the treatment of active duodenal or gastric ulcer, gastroesophageal reflux disease, or endoscopically diagnosed erosive esophagitis, and as maintenance therapy for duodenal or gastric ulcer. Oral ranitidine also is used for the management of pathologic GI hypersecretory conditions and as maintenance therapy to prevent recurrence of erosive esophagitis. Ranitidine is used parenterally in hospitalized patients with pathologic GI hypersecretory conditions or intractable duodenal ulcer, or for short-term use when oral therapy is not feasible.

Duodenal Ulcer

Acute Therapy

Ranitidine is used orally for the short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer. Ranitidine is used parenterally in hospitalized adults with intractable duodenal ulcer or for short-term use when oral therapy is not feasible. Ranitidine also is used IV in children 1 month to 16 years of age for the treatment of duodenal ulcer. Ranitidine bismuth citrate (no longer commercially available in the US) has been used in combination with clarithromycin for the treatment of Helicobacter pylori infection in adults with active duodenal ulcer. Antacids may be used concomitantly as needed for relief of pain.

In a multicenter, double-blind study in patients with endoscopically diagnosed duodenal ulcers who were receiving supplemental antacids, reported rates of ulcer healing for ranitidine (150 mg twice daily) versus placebo were 38 vs 19% at 2 weeks and 73 vs 45% at 4 weeks. Ranitidine also produced greater reductions in daytime and nocturnal pain and antacid consumption than did placebo. Similar rates of ulcer healing occur following oral ranitidine 150 mg twice daily or 300 mg at bedtime daily; ulcer healing rates of 85-86 or 83-87%, respectively, have been reported at 4 weeks and 92 or 87%, respectively, at 8 weeks. Although there was a trend favoring the twice-daily regimen in a large, multinational study, the differences in healing rates between the regimens were small and might be offset by the benefits derived from once-daily administration of the drug at bedtime.

Ranitidine appears to be as effective as cimetidine for the short-term treatment of active duodenal ulcer. In a multicenter, double-blind study in patients with active duodenal ulcers, 71 or 68% of ulcers were healed following administration of 150 mg of ranitidine twice daily or 300 mg of cimetidine 4 times daily, respectively, for 4 weeks. In another study in patients with endoscopically diagnosed duodenal ulcers, 77 or 84% of ulcers were healed following administration of 150 mg of ranitidine twice daily or 200 mg of cimetidine 3 times daily after meals and 400 mg at bedtime, respectively, for 4 weeks; there appeared to be no difference in healing rates in males or females, the number of episodes of pain was decreased by both drugs during the first 2 weeks of therapy, and fewer antacid tablets were consumed by all individuals as therapy continued. Ranitidine has been effective in some patients whose duodenal ulcers were refractory to cimetidine therapy.

Safety and efficacy of long-term ranitidine therapy for active duodenal ulcer have not been determined. Studies to date have been limited to short-term treatment of active duodenal ulcer, and the safety and efficacy of treatment for active disease beyond 8 weeks have not been determined. Most patients with duodenal ulcer respond to ranitidine therapy during the initial 4-week course of therapy; an additional 4 weeks of therapy may contribute to healing in some patients. However, short-term ranitidine therapy (i.e., up to 8 weeks) for the treatment of active duodenal disease will not prevent recurrence following acute healing and discontinuance of the drug. Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers; long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. For additional information on the association of this infection with these and other GI conditions, .

Conventional antiulcer therapy with H2-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori, and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year). Duodenal ulcers have recurred within 6 months in approximately 50-80% of individuals following discontinuance of ranitidine therapy. In one study in patients who agreed to retreatment, recurring duodenal ulcers rehealed within 8 weeks following an additional course of ranitidine therapy; however, the effect of continued, full-dose ranitidine treatment on the recurrence rate of duodenal ulcers remains to be more fully evaluated. The American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. Although 3-drug regimens consisting of a bismuth salt (e.g., bismuth subsalicylate) and 2 anti-infective agents (e.g., tetracycline or amoxicillin plus metronidazole) administered for 10-14 days have been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori-associated peptic ulcer disease, current evidence principally from studies in Europe suggests that 1 week of such therapy provides comparable H. pylori eradication rates. Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, H2-receptor antagonist) also have been used successfully for H. pylori eradication, and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.

Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti-H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance. Therefore, the ACG and many clinicians currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.

Therapy with an antisecretory drug and a single anti-infective agent (i.e., ''dual therapy'') also has been used successfully for treatment of H. pylori infection. However, while some studies demonstrate that certain 2-drug anti-H. pylori regimens (e.g., clarithromycin-omeprazole, ranitidine bismuth citrate-omeprazole, amoxicillin-omeprazole) can successfully eradicate H. pylori infection and prevent recurrence of duodenal ulcer at least in the short term (e.g., at 6 months following completion of anti-H. pylori therapy), the ACG and some clinicians currently state that anti-H. pylori regimens consisting of at least 3 drugs (e.g., 2 anti-infective agents plus a proton-pump inhibitor) are recommended because of enhanced H. pylori eradication rates, decreased failures due to resistance, and shorter treatment periods compared with those apparently required with 2-drug regimens. Additional randomized, controlled studies comparing various anti-H. pylori regimens are needed to clarify optimum drug combinations, dosages, and durations of treatment for H. pylori infection. For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, .

Maintenance Therapy

Ranitidine is used orally in reduced dosage as maintenance therapy following healing of active duodenal ulcer to reduce ulcer recurrence. In placebo-controlled studies, duodenal ulcer recurrence rates after 4 months, 8 months, and 1 year were 12-20, 21-24, and 28-35%, respectively, for 150 mg of ranitidine at bedtime daily vs 44-56, 54-64, and 59-68%, respectively, for placebo. In one placebo-controlled study, the 1-year reduction in recurrence persisted for almost 2 years of therapy. Because the efficacy of 2-receptor antagonists in preventing duodenal ulcer recurrence appears to be substantially reduced in patients who are cigarette smokers compared with nonsmokers, patients who are cigarette smokers should be advised of the importance of discontinuing smoking in the prevention of ulcer recurrence. Maintenance therapy with ranitidine has not been studied for longer than 2 years in placebo-controlled studies.

Pathologic GI Hypersecretory Conditions

Ranitidine is used orally or parenterally for the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, systemic mastocytosis, postoperative hypersecretion, ''short-gut'' syndrome). Ranitidine reduces gastric acid secretion and associated symptoms (e.g., diarrhea, anorexia, and pain) and promotes healing of intractable ulcers in patients with these conditions. Administration of ranitidine as a continuous IV infusion for up to 15 days in a limited number of patients with Zollinger-Ellison syndrome has resulted in control of gastric acid secretion to 10 mEq/hour or less; no patient developed acid-related disease complications (e.g., bleeding, perforation). Antacids may be used concomitantly as needed for relief of pain. Antimuscarinics (e.g., propantheline bromide, isopropamide iodide) have been used concomitantly with ranitidine to prolong and/or augment ranitidine-induced inhibition of gastric acid secretion in some patients with GI hypersecretory conditions.

The manufacturers state that, in a limited number of patients with GI hypersecretory conditions, ranitidine therapy has resulted in healing of ulcers in 42% of patients who had not responded to previous cimetidine therapy. In one study, patients with Zollinger-Ellison syndrome in whom cimetidine failed to control symptoms of the disease or who did not tolerate cimetidine therapy were successfully treated with 600-900 mg of ranitidine daily for up to 1-12 months. In another study, patients with GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, idiopathic gastric hypersecretion) who were successfully treated with 1.2-12.6 g of cimetidine daily alone or in combination with an antimuscarinic (i.e., propantheline bromide or isopropamide iodide) for up to 60 months were subsequently successfully treated with 450 mg to 6.3 g of ranitidine daily alone or in combination with an antimuscarinic for up to 25 months; both drugs appeared to be equally effective in controlling gastric hypersecretion but lower daily doses of ranitidine were required.

In one study, ranitidine was used successfully IV in the treatment of postoperative hypersecretion in patients whose condition was apparently resistant to cimetidine therapy or in whom adverse effects of cimetidine required discontinuance of the drug.

Gastric Ulcer

Acute Therapy

Ranitidine is used orally for short-term treatment of active, benign gastric ulcer. Antacids may be used concomitantly as needed for relief of pain. The efficacy of ranitidine in the treatment of gastric ulcer appears to be similar to that of cimetidine. Ranitidine promotes healing of ulcers in about 60-70% of patients after 4 weeks of treatment and about 70-80% of patients after 6 weeks of treatment. The usefulness of ranitidine therapy for longer than 6 weeks in the treatment of active, benign gastric ulcer remains to be clearly determined. When ranitidine is used in the treatment of gastric ulcer, it should be kept in mind that symptomatic response does not preclude the presence of a gastric malignancy.

Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of gastric ulcers, and the ACG, NIH, and most clinicians currently recommend that all patients with initial or recurrent gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. The choice of particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.(See Duodenal Ulcer: Acute Therapy, in Uses.) For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, .

Maintenance Therapy

Ranitidine is used orally in reduced dosage following healing of active, benign gastric ulcer to reduce ulcer recurrence. In 12-month controlled trials in patients with previously healed gastric ulcers, therapy with ranitidine 150 mg at bedtime each night was more effective than placebo in maintaining healing of gastric ulcers.

Gastroesophageal Reflux

Ranitidine is used orally in the management of gastroesophageal reflux disease (GERD). Symptomatic relief generally occurs within 24 hours of initiating ranitidine therapy as conventional tablets or within 45 minutes as effervescent tablets. By increasing gastric pH, H2-antagonists have relieved heartburn and other symptoms of reflux and have been associated with somewhat higher healing rates of endoscopically proven esophagitis when compared with placebo and have reduced antacid consumption.

Suppression of gastric acid secretion is considered by the ACG to be the mainstay of treatment for gastroesophageal reflux disease (GERD), and a proton-pump inhibitor or histamine H2-receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease. Because GERD is considered to be a chronic disease, many patients with GERD require long-term, even lifelong, treatment. The ACG states that histamine H2-receptor antagonists administered daily in divided doses are effective in many patients with less severe GERD, and over-the-counter (OTC) antacids and histamine H2-receptor antagonists are appropriate for self-medication as initial therapy in such individuals. A histamine H2-receptor antagonist is particularly useful when taken before certain activities (e.g., heavy meal, exercise) that may result in acid reflux symptoms in some patients. The ACG states that H2-receptor antagonists generally may be used interchangeably, although the drugs may differ in potency and in their onset and duration of action. However, proton-pump inhibitors are more effective (i.e., provide more frequent and more rapid symptomatic relief and healing of esophagitis) than do histamine H2-receptor antagonists in the treatment of GERD, and are effective and appropriate as maintenance therapy in many patients with the disease. Although higher doses and more frequent administration of histamine H2-receptor antagonists appear to increase their efficacy, such dosages are less effective and more expensive than proton-pump inhibitor therapy. Once-daily administration of a histamine H2-receptor antagonist at full dosage is not considered to be appropriate therapy for GERD.

H2-antagonists have also been used in combination with metoclopramide in a limited number of patients who failed to respond to an H2-antagonist alone, but the ACG states that frequent and potentially severe adverse CNS effects of metoclopramide have appropriately decreased regular use of the drug for the treatment of GERD. Although some clinicians have suggested that a histamine H2-receptor antagonist may also be used in combination with bethanechol in patients who fail to respond to a histamine H2-receptor antagonist alone, the ACG states that bethanechol has limited efficacy in the treatment of GERD.

Short-term therapy (i.e., up to 12 weeks) with H2-receptor antagonists for the treatment of GERD will not prevent recurrence following ulcer healing and discontinuance of such therapy. Esophagitis has recurred within 6 months in up to 80% of patients following discontinuance of H2-receptor antagonist therapy. Because GERD is considered to be a chronic disease, many patients with GERD require long-term, even lifelong, treatment. The ACG states that proton-pump inhibitors are effective and appropriate as maintenance therapy in many patients with the disease. Maintenance therapy with an H2-receptor antagonist also has been used to reduce recurrence of GERD. However, many patients initially responding to proton-pump inhibitors experience symptomatic relapse and failure of esophageal healing with subsequent use of a histamine H2-receptor antagonist.

For further information on the treatment of GERD, see Uses: Gastroesophageal Reflux, in Omeprazole 56:40.

Erosive Esophagitis

Acute Therapy

Ranitidine is used orally for the treatment of endoscopically diagnosed erosive esophagitis. In two multicenter, double-blind, placebo-controlled trials of the drug, healing rates of 47, 71, and 84% were reported after 4, 8, and 12 weeks, respectively, of therapy with ranitidine at dosages of 150 mg 4 times daily; concomitant antacids were used as needed for relief of pain. Symptomatic improvement in heartburn generally occurred within 24 hours of initiation of drug therapy. No additional benefit in treatment of esophagitis or relief of heartburn symptoms was observed in patients receiving the drug at dosages of 300 mg 4 times daily.

Maintenance Therapy

Ranitidine is used orally as maintenance therapy to prevent recurrence of erosive esophagitis in adults. In controlled trials of 48-weeks duration, ranitidine 150 mg twice daily was more effective than placebo in maintaining healing in patients with previously healed erosive esophagitis.

Increasing Gastric pH in Neonates Undergoing Extracorporeal Membrane Oxygenation (ECMO)

Limited data suggest that ranitidine administered IV may be useful and safe for increasing gastric pH in neonates younger than 1 month of age receiving ECMO who are at risk of GI hemorrhage. Following a 2 mg/kg IV dose of ranitidine in 5 neonates receiving ECMO, gastric pH was increased from less than 4 to above 4 and remained above 4 for at least 15 hours after administration. (See Cautions: Pediatric Precautions)

Other Uses

Ranitidine may be used for self-medication for relief or prevention of symptoms of occasional heartburn (pyrosis), acid indigestion (hyperchlorhydria), or sour stomach.

Ranitidine has been used for the treatment of recurrent postoperative ulcer and upper GI bleeding (e.g., secondary to gastric ulcer, duodenal ulcer, or hemorrhagic gastritis). Because ranitidine can increase gastric pH, the drug has also been used prophylactically to prevent acid-aspiration pneumonitis during surgery.

Dosage and Administration

Administration

Ranitidine hydrochloride usually is administered orally. The drug also may be given by IM or slow IV injection or by intermittent or continuous slow IV infusion in hospitalized patients with pathologic hypersecretory conditions or intractable duodenal ulcer, or when oral therapy is not feasible. In addition, ranitidine hydrochloride may be given by intermittent slow IV injection or intermittent infusion for the treatment of duodenal ulcer in children 1 month to 16 years of age, and by intermittent slow IV injection, intermittent infusion, or continuous slow IV infusion to decrease gastric pH in neonates younger than 1 month of age receiving extracorporeal membrane oxygenation (ECMO). Because of the risk of inducing bradycardia (see Cautions: Other Adverse Effects), the recommended rates of IV administration should not be exceeded. Antacids may be administered concomitantly as necessary for relief of pain.(See Drug Interactions: Food and Antacids.)

The 1-g pharmacy bulk package of ranitidine hydrochloride is not intended for direct IV infusion; doses of the drug from the bulk package must be further diluted in a compatible IV solution prior to administration.

Oral Administration

Patients receiving 150-mg effervescent tablets of ranitidine hydrochloride should be advised that the preparation must be diluted in 180-240 mL (6-8 ounces) of water as directed prior to ingestion. For pediatric patients receiving the 25-mg effervescent tablets, 1 tablet should be dissolved in at least 5 mL (1 teaspoonful) of water in an appropriate measuring cup. The tablet should be dissolved completely before the solution is administered to the infant or child. For infants, the solution may be administered using a medicine dropper or oral syringe. Effervescent tablets should not be chewed, swallowed whole, or dissolved on the tongue.

IM Injection

For IM administration, ranitidine hydrochloride injection may be given undiluted.

Intermittent Direct IV Injection

Ranitidine hydrochloride injection must be diluted prior to IV administration. For slow IV injection, 50 mg of ranitidine is diluted to a concentration no greater than 2.5 mg/mL (i.e., a total of 20 mL) with 0.9% sodium chloride injection or another compatible IV solution (See Chemistry and Stability: Stability) and injected at a rate not exceeding 4 mL per minute (i.e., over a period of not less than 5 minutes).

Intermittent IV Infusion

For intermittent slow IV infusion, 50 mg of ranitidine is diluted to a concentration no greater than 0.5 mg/mL (i.e., a total of 100 mL) of 5% dextrose injection or another compatible IV solution (See Chemistry and Stability: Stability) and infused at a rate not exceeding 5-7 mL per minute (i.e., over 15-20 minutes). Alternatively, the commercially available IV infusion solution of the drug in 0.45% sodium chloride can be infused IV over 15-20 minutes. The commercially available diluted solution should only be administered by IV infusion. The container should be checked for minute leaks by firmly squeezing the bag. The injection should be discarded if the seal is not intact or leaks are found or if the solution is cloudy or contains a precipitate. Additives should not be introduced into the injection container. The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.

Continuous IV Infusion

For continuous IV infusion, 150 mg of ranitidine injection is diluted in 250 mL of 5% dextrose injection or another compatible IV solution (See Chemistry and Stability: Stability) and infused at a rate of 6.25 mg/hour over a 24-hour period. For use in patients with Zollinger-Ellison syndrome or other hypersecretory conditions, ranitidine injection should be diluted to a concentration no greater than 2.5 mg/mL with 5% dextrose or another compatible IV solution and the infusion initiated at a rate of 1 mg/kg per hour; the rate should be adjusted to individual patient requirements.

Dosage

Although USP currently states that potency of ranitidine hydrochloride preparations should be expressed both in terms of the salt and the base (''active moiety''), dosage currently is expressed in terms of the base.(See Chemistry and Stability: Chemistry.)

Because geriatric patients are more likely to have decreased renal function, caution should be exercised in dosage selection, and it may be useful to monitor renal function. (See Cautions: Geriatric Precautions.)

Oral Dosage

Oral dosages recommended for the treatment of duodenal and gastric ulcers and for maintenance therapy for duodenal and gastric ulcers in children 1 month to 16 years age are extrapolated from clinical adult studies and pharmacokinetic data in children. Dosages of oral ranitidine recommended for the treatment of gastroesophageal reflux disease or erosive esophagitis in children 1 month to 16 years of age or older are based on published medical literature; however, only limited data is available for these conditions in children.

Duodenal Ulcer

For the treatment of active duodenal ulcer, the usual adult oral dosage of ranitidine is 150 mg twice daily. Alternatively, 300 mg daily after the evening meal or at bedtime may be used for patients in whom dosing convenience is considered important for optimum compliance. The advantage of one regimen over another for particular patients with active duodenal ulcer has not been determined to date. Lower dosages have been effective in inhibiting gastric acid secretion in US studies to date; in several foreign studies, 100 mg twice daily was as effective as 150 mg twice daily in healing ulcers.

For the treatment of active duodenal ulcer in children 1 month to 16 years of age, the usual oral dosage of ranitidine is 2-4 mg/kg twice daily up to a maximum daily dosage of 300 mg.

Although the optimum duration of ranitidine therapy has not been established, healing may occur within the first 2 weeks in some patients and within 4 weeks in most patients; some patients may benefit from an additional 4 weeks of therapy. Safety and efficacy of continuing full-dose therapy beyond 8 weeks have not been determined.

Multiple-drug regimens currently recommended by the American College of Gastroenterology (ACG) and many clinicians for the treatment of Helicobacter pylori infection in patients with active duodenal ulcer consist of a proton-pump inhibitor (e.g., omeprazole) and 2 anti-infective agents (e.g., clarithromycin and amoxicillin or metronidazole) or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor.

For maintenance therapy following healing of acute duodenal ulcer to reduce ulcer recurrence, the usual adult oral dosage of ranitidine is 150 mg daily at bedtime. For maintenance therapy following healing of acute duodenal ulcer, the usual oral dosage of ranitidine in children 1 month to 16 years of age is 2-4 mg/kg once daily up to a maximum daily dosage of 150 mg.

Pathologic GI Hypersecretory Conditions

For the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome), the usual adult oral dosage of ranitidine is 150 mg twice daily. It may be necessary to administer 150-mg doses of ranitidine more frequently than twice daily in some patients; dosage should be adjusted according to individual response, and therapy continued as long as clinically necessary. Oral dosages up to 6 g daily have been administered to individuals with severe disease.

Gastric Ulcer

For the treatment of active, benign gastric ulcer, the usual adult oral dosage of ranitidine is 150 mg twice daily. For the treatment of active, benign gastric ulcer in children 1 month to 16 years of age, the usual oral dosage of ranitidine is 2-4 mg/kg twice daily up to a maximum daily dosage of 300 mg. Most patients demonstrate complete healing of gastric ulcers within 6 weeks, and the safety of ranitidine therapy for longer periods in the treatment of gastric ulcer have not been established.

For maintenance therapy following healing of active, benign gastric ulcer to reduce ulcer recurrence, the usual adult oral dosage of ranitidine is 150 mg daily at bedtime. For maintenance therapy following healing of active benign gastric ulcer in children 1 month to 16 years of age, the usual oral dosage of ranitidine is 2-4 mg/kg once daily up to a maximum daily dosage of 150 mg.

Gastroesophageal Reflux

For the management of gastroesophageal reflux disease (GERD), the usual adult oral dosage of ranitidine is 150 mg twice daily. An oral ranitidine dosage of 5-10 mg/kg daily, usually given as 2 equally divided doses, is recommended for the management of GERD in children 1 month to 16 years of age. Symptomatic relief often occurs within 24 hours after initiating therapy with the drug. The optimum duration of acute ranitidine therapy for reflux has not been established.

Erosive Esophagitis

For the treatment of endoscopically diagnosed erosive esophagitis, the usual adult oral dosage of ranitidine is 150 mg 4 times daily. An oral ranitidine dosage of 5-10 mg/kg daily, usually given as 2 equally divided doses, is recommended for the management of erosive esophagitis in children 1 month to 16 years of age.

For maintenance therapy following healing of endoscopically diagnosed erosive esophagitis, the usual adult oral dosage of ranitidine is 150 mg twice daily.

Self-medication

For self-medication for the relief or prevention of symptoms of occasional heartburn, acid indigestion, or sour stomach in patients 12 years of age and older, an oral ranitidine dosage of 75 or 150 mg once or twice daily is recommended; for the prevention of symptoms, the dose should be taken 30-60 minutes before consuming foods or beverages that cause heartburn. For self-medication, the manufacturers recommend that no more than 2 doses be administered in 24 hours and that such therapy not exceed 2 weeks of continuous use unless otherwise recommended by a clinician. Patients should be instructed to take the tablets with water. Use for self-medication should be discontinued and a clinician consulted if stomach pain is persistent, or if heartburn continues or worsens.

The manufacturers state that ranitidine should not be used for self-medication in children younger than 12 years of age unless otherwise directed by their clinician.

Parenteral Dosage

Adult Dosage

The usual adult IM or intermittent IV dosage of ranitidine is 50 mg every 6-8 hours. If necessary, dosage may be increased by increasing the frequency of administration, but dosage should not exceed 400 mg daily.

When ranitidine is administered by continuous slow IV infusion, 150 mg of ranitidine is infused at a rate of 6.25 mg/hour over 24 hours. When the drug is administered by continuous slow IV infusion in adults with Zollinger-Ellison syndrome or other hypersecretory conditions, the infusion is usually started at a rate of 1 mg/kg per hour. If after 4 hours the patient is still symptomatic or if the measured gastric acid secretion is greater than 10 mEq/hour, the dose should be titrated upward in increments of 0.5 mg/kg per hour; the gastric acid secretion should then be redetermined. Doses up to 2.5 mg/kg per hour and infusion rates as high as 220 mg/hour have been used.

Pediatric Dosage

For the treatment of active duodenal ulcer in children 1 month to 16 years of age, the recommended IV dosage of ranitidine is 2-4 mg/kg daily in divided doses administered every 6-8 hours up to a maximum of 50 mg given every 6-8 hours.

Ranitidine IV dosages recommended for the treatment of duodenal ulcers in children 1 month to 16 years of age are extrapolated from clinical adult studies as well as limited pharmacokinetic data in children and published medical literature.

For neonatal patients (less than 1 month of age) receiving ECMO and at risk for GI hemorrhage, doses of 2 mg/kg given IV every 12-24 hours or as a continuous IV infusion should be considered; limited data indicate that a dose of 2 mg/kg usually is sufficient to increase gastric pH above 4 for at least 15 hours.

Dosage in Renal Impairment

In patients with creatinine clearances less than 50 mL/minute, the manufacturer recommends an oral ranitidine dosage of 150 mg once every 24 hours and an IM or IV (intermittent slow infusion or direct injection) dosage of 50 mg every 18-24 hours; the administration of ranitidine as a continuous IV infusion has not been evaluated in patients with impaired renal function. Dosage intervals may be decreased cautiously from every 24 hours to every 12 hours or less, if necessary. Because hemodialysis reduces serum ranitidine concentrations, the dosage regimen should be adjusted so that a scheduled dose of ranitidine is administered at the end of dialysis.

Cautions

Adverse effects of ranitidine are generally infrequent and minor.

Nervous System Effects

Headache (sometimes severe) occurs in approximately 3% of patients receiving ranitidine. Malaise, dizziness, somnolence,insomnia, and vertigo have been reported less frequently with ranitidine therapy. Reversible mental confusion, agitation, mental depression, and hallucinations have occurred, mainly in debilitated geriatric patients. Reversible involuntary motor disturbances have been reported rarely in patients receiving ranitidine. A child who was receiving prolonged, high-dose oral ranitidine therapy (8 mg/kg once daily for 10 months) developed altered consciousness, drowsiness, dysarthria, hyporeflexia, positive Babinski's sign, diaphoresis, and bradycardia, which resolved within 24 hours after discontinuance of the drug.

GI Effects

Constipation, nausea, vomiting, and abdominal discomfort or pain have occurred in patients receiving ranitidine. Pancreatitis has been reported rarely.

Dermatologic and Sensitivity Reactions

Rash, which may be urticarial, maculopapular, and/or pruritic, has been reported during ranitidine therapy. Rash, including rare cases of erythema multiforme, has occurred with ranitidine therapy. Urticaria at the site of injection has occurred following IV administration of ranitidine. Alopecia has occurred rarely.

Hypersensitivity reactions such as bronchospasm, fever, rash, and eosinophilia have occurred rarely in patients receiving ranitidine. Anaphylaxis, characterized by severe urticaria and a decrease in blood pressure in one patient following administration of a single dose of ranitidine, has occurred rarely; exacerbation of asthma and angioedema also has occurred. Mild erythema multiforme-like rash and alopecia also have occurred rarely.

Hematologic Effects

Leukopenia, granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anemia, acquired immune hemolytic anemia, and pancytopenia, which may be accompanied by bone marrow hypoplasia, have been reported rarely in patients receiving ranitidine. Alterations in blood cell counts (leukopenia, granulocytopenia, and thrombocytopenia) usually were reversible. At least one case of leukocytosis has been reported 6-8 days after initiating ranitidine therapy, which resolved following discontinuance of the drug. Although a causal relationship to the drug was not established, aplastic anemia has occurred in at least one patient receiving ranitidine.

Renal and Genitourinary Effects

Small increases in serum creatinine, without concomitant increases in BUN, have been reported during ranitidine therapy; however, the manufacturers state that these increases have occurred less frequently than with cimetidine therapy and may result from competitive inhibition by ranitidine of creatinine secretion into the urine.

Loss of libido has been reported in male patients receiving ranitidine.

Hepatic Effects

Increases in serum aminotransferase (transaminase) (AST [SGOT] and ALT [SGPT]), alkaline phosphatase, LDH, total bilirubin, and γ-glutamyl transferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations have been reported in patients receiving ranitidine. Hepatitis, which may be hepatocellular and/or hepatocanalicular, cholestatic, and may or may not be accompanied by jaundice, has occurred occasionally in individuals receiving ranitidine and usually was reversible; however, death has been reported rarely. Ranitidine should be discontinued immediately in patients with hepatitis. Hepatic failure has been reported rarely. In several multiple-dose studies in healthy individuals, increases in serum AST and ALT concentrations from pretreatment concentrations were greater in individuals receiving IV ranitidine dosages of 100 mg 4 times daily for 7 days than in those receiving 50 mg 4 times daily for 5 days.

Ocular Effects

Reversible blurred vision suggestive of a change in accommodation has occurred rarely in patients receiving ranitidine. Exacerbation of ocular pain and blurred vision associated with increased intraocular pressure and chronic glaucoma have been reported in at least one patient during ranitidine therapy. Loss of color vision, which recurred following rechallenge, also has occurred in at least one patient.

Endocrine Effects

The manufacturers state that ranitidine has not been associated with clinically important effects on endocrine or gonadal function.(See Pharmacology: Endocrine and Gonadal Effects.) Sexual impotence has occurred in at least one male during ranitidine therapy, but disappeared following discontinuance of the drug; impotence recurred upon rechallenge. Painful gynecomastia in men also has occurred during oral administration of ranitidine, but disappeared gradually following discontinuance of the drug; gynecomastia reappeared upon rechallenge.

Cardiovascular Effects

As with other histamine H2-receptor antagonists, cardiac arrhythmias have occurred rarely in patients receiving ranitidine. Bradycardia, sometimes associated with dyspnea, has occurred. Because bradycardia has been associated with rapid IV injection of the drug in some cases, usually in patients with underlying conditions predisposing to cardiac rhythm disturbances, recommended rates of IV administration should not be exceeded. Tachycardia, AV block, asystole, and ventricular premature complexes have also been reported rarely. Vasculitis has been reported rarely.

Respiratory Effects

Community-acquired Pneumonia

Administration of gastric antisecretory agents (e.g., H2-receptor antagonists, proton-pump inhibitors) has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia). A possible association between chronic administration of gastric acid-suppressive drugs and occurrence of community-acquired pneumonia has been evaluated using a large Dutch database (Integrated Primary Care Information [IPCI]) containing information on approximately 500,000 patients, 364,683 of whom (average follow-up: 2.7 years) were selected for evaluating any such association. During the 8-year population-based, case-control study, gastric acid suppressants were first prescribed in 19,459 individuals (10,177 received H2-receptor antagonists [mean duration of use: 2.8 months] and 12,337 received proton-pump inhibitors [mean duration of use: 5 months]; some individuals received both drugs). Most patients did not undergo endoscopy and were treated empirically for upper GI symptoms. In this study, first occurrence of pneumonia (confirmed by radiography or microbiologic testing in 18% of patients) was reported in 5551 individuals; development of pneumonia occurred in 185 individuals while receiving gastric acid suppressants and in 292 individuals who had discontinued such use. The adjusted relative risk for development of pneumonia (or the incidence rate) was 0.6, 2.3 and 2.5 per 100 person-years for individuals not receiving acid-suppressive drugs, for those receiving H2-receptor antagonists, and for those receiving proton-pump inhibitors, respectively. Patients using gastric acid suppressants developed community-acquired pneumonia 4.5 (95% confidence interval of 3.8-5.1) times more often than those who never used such drugs. When evaluating use of all gastric acid suppressants, current use of the drugs was associated with a small (27%) overall increase in the risk of pneumonia (adjusted odds ratio 1.27 and 95% confidence interval of 1.06-1.54). Higher risks were observed for current users of H2-receptor antagonists and proton-pump inhibitors; the adjusted relative risk for developing community-acquired pneumonia was 1.63 (95% confidence interval of 1.07-2.48) or 1.89 (95% confidence interval of 1.36-2.62), respectively, for these classes of drugs compared with those who discontinued using these agents. Estimates for developing pneumonia were higher (1.7 [95% confidence interval of 0.8-2.9] for H2-receptor antagonists and 2.2 [95% confidence interval of 1.4-3.5] for proton-pump inhibitors) when only laboratory-confirmed cases of pneumonia were considered for analysis. Although there was variation among individual H2-receptor antagonists and individual proton-pump inhibitors, the numbers were small and the heterogeneity was not considered significant. For patients currrently receiving proton-pump inhibitors, a dose-response relationship for developing pneumonia was observed; individuals using more than one defined daily dose of these drugs had a 2.3-fold increased risk for developing pneumonia compared with those who discontinued gastric acid suppressants. Such a dose-response relationship for developing pneumonia was not observed in patients receiving H2-receptor antagonists; however, dose variation of these drugs was limited. Among current users of H2-receptor antagonists or proton-pump inhibitors, the risk for developing pneumonia was most pronounced among those who initiated such therapies within the past 30 days.

Although the exact mechanism for development of community-acquired pneumonia in patients receiving gastric acid suppressants has not been fully elucidated, it has been suggested that reduction of gastric acid secretion by acid suppressive therapy and consequent increases of gastric pH may result in a favorable environment for the development of infection. Intragastric acidity constitutes a major nonspecific defense mechanism of the stomach to ingested pathogens; when gastric pH is less than 4, most pathogens are killed, while at higher gastric pH, pathogens may survive. Since for the effective management of upper GI symptoms, intragastric pH should be maintained above 4 for several hours, acid suppressive therapy may lead to insufficient elimination or, even, increased colonization of ingested pathogens. Some evidence indicates that acid-supressive therapy may result in nosocomial infections.

It should be considered that certain patients (e.g., those with pleuritic chest pain, hypothermia, systolic hypotension, tachypnea, diabetes mellitus, neoplastic disease, neurologic disease, bacteremia, leukopenia, multilobar pulmonary infiltrate) are at increased risk for developing infections and in these individuals community-acquired pneumonia may be associated with increased mortality. Some clinicians state that gastric acid-suppressive drugs should be used in patients in whom community-acquired pneumonia may be severe (e.g., those with asthma or chronic obstructive lung disease, immunocompromised patients, pediatric or geriatric individuals) only when clearly needed and the lowest effective dose should be employed.

Other Adverse Effects

Arthralgias and myalgias have been reported rarely with ranitidine therapy. Rare reports suggest that ranitidine may precipitate acute attacks of porphyria in patients with acute porphyria; therefore, the drug should be avoided in patients with a history of acute porphyria.

Precautions and Contraindications

Ranitidine should be used with caution and in reduced dosage in patients with impaired renal function, since ranitidine is excreted principally by the kidneys. Ranitidine should also be used with caution in patients with hepatic dysfunction since the drug is metabolized in the liver.

Limited evidence suggests that ranitidine may precipitate acute porphyria in patients with a history of this condition; therefore, therapy with ranitidine should be avoided in patients with a history of acute porphyria.

Since increases in serum ALT concentrations have occurred in healthy individuals receiving higher than recommended IV dosages of an H2-receptor antagonist for 5 days or longer during clinical trials, the manufacturers suggest that it may be advisable to monitor serum ALT concentrations daily from the fifth day to the remainder of IV therapy in patients receiving IV ranitidine dosages of 400 mg or more daily for 5 days or longer. Hepatotoxicity has also been reported occasionally during oral therapy with the drug.

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that each EFFERdose effervescent tablet (containing 25 or 150 mg of ranitidine) contains aspartame (NutraSweet), which is metabolized in the GI tract to provide about 2.81 or 16.84 mg, respectively, of phenylalanine following oral administration.

Symptomatic response to ranitidine should not be interpreted as precluding the presence of gastric malignancy.

Ranitidine should not be used for self-medication if the patient has difficulty swallowing and should not be used with other drugs that decrease gastric acid secretion. Patients with heartburn that has persisted for more than 3 months or heartburn in conjunction with lightheadedness, sweating, or dizziness should consult their clinician before using ranitidine for self-medication. Patients also should be advised to consult their clinician before using ranitidine for self-medication if they are experiencing chest or shoulder pain with lightheadedness, shortness of breath, sweating, or pain spreading to arms, neck, or shoulders. Those with frequent chest pain, unexplained weight loss, nausea and vomiting, stomach pain, or frequent wheezing (especially with heartburn) also should consult their clinician before using ranitidine for self-medication. Patients should discontinue ranitidine self-medication and consult their clinician if heartburn or stomach pain worsens or persists after 14 days of therapy. Patients with difficulty or pain with swallowing, vomiting with blood, or bloody or blackened stools should not use ranitidine for self-medication; such manifestations should be reported promptly to a clinician, since they may be indicative of a serious condition requiring alternative treatment. Women who are pregnant or breast feeding should consult their clinician before using ranitidine for self-medication.

Ranitidine is contraindicated in patients with known hypersensitivity to the drugs or any of the ingredients in the respective formulation.

Pediatric Precautions

The manufacturer states that safety and efficacy of oral ranitidine for the treatment of active duodenal or gastric ulcer, gastroesophageal reflux disease, or endoscopically diagnosed erosive esophagitis, and as maintenance therapy for duodenal or gastric ulcer in pediatric patients 1 month to 16 years of age have been established. In addition, use of oral ranitidine in pediatric patients is supported by adequate and well-controlled studies in adults, pharmacokinetic data in children, and published reports in the medical literature.

Safety and efficacy of ranitidine administered IV for the treatment of active duodenal ulcer in pediatric patients 1 month to 16 years of age have been established and are supported by adequate and well-controlled studies in adults, pharmacokinetic data in children, and published reports in the medical literature. In a limited study of 20 critically ill pediatric patients receiving IV ranitidine 1 mg/kg every 6 hours, 10 patients with a baseline pH of 4 or higher maintained this baseline throughout the study, and 8 of the remaining patients with a baseline pH of 2 or lower achieved a pH of 4 or higher throughout variable periods after dosing. However, such data should be interpreted with caution when determining dosages for less seriously ill patients. Limited data suggest that ranitidine administered IV may be useful and safe for increasing gastric pH in neonates receiving extracorporeal membrane oxygenation (ECMO) who are at risk of GI hemorrhage.

Safety and efficacy of oral or parenteral ranitidine for the treatment of pathologic GI hypersecretory conditions have not been established in pediatric patients. Safety and efficacy of oral ranitidine as maintenance therapy to prevent recurrence of erosive esophagitis have not been established in pediatric patients. Safety and efficacy of oral ranitidine in neonates younger than 1 month of age have not been established.

Geriatric Precautions

When the total number of patients studied in clinical trials of oral ranitidine is considered, 4197 were 65 years of age or older, while 899 were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. Because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of ranitidine-induced toxicity, dosage should be selected carefully, and it may be useful to monitor renal function in these individuals.

Mutagenicity and Carcinogenicity

It is not known if ranitidine is mutagenic or carcinogenic in humans. In vitro tests have generally not shown ranitidine or its N-oxide, S-oxide, and desmethyl metabolites to be mutagenic. No evidence of carcinogenicity was seen in long-term studies in dogs, mice, or rats receiving ranitidine dosages up to 2 g/kg daily; evidence of gastric neoplasm or premalignant gastric changes was not observed in these studies. Like cimetidine, ranitidine increases nitrate-reducing bacterial flora in the GI tract; however, the clinical importance of this effect is not known.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using oral ranitidine dosages up to 160 times the usual human oral dosage have not revealed evidence of harm to the fetus. There are no adequate and controlled studies to date using ranitidine in pregnant women, and the drug should be used during pregnancy only when clearly needed. Women who are pregnant or nursing should seek the advice of a health professional before using ranitidine for self-medication.

Fertility

Reproduction studies in rats and rabbits using oral ranitidine dosages up to 160 times the usual human oral dosage have not revealed evidence of impaired fertility.

Lactation

Since ranitidine is distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Food and Antacids

Concomitant administration of food or low-dose antacids (neutralizing capacity of 10-15 mEq of hydrochloric acid per 10 mL) does not appear to substantially decrease the absorption of ranitidine or the mean peak plasma concentration of the drug. However, in one study, concomitant administration of 30 mL of an aluminum and magnesium hydroxides antacid (Mylanta-II; neutralizing capacity of 150 mEq of hydrochloric acid per 30 mL), 30 mL of water, and a single 150-mg dose of ranitidine resulted in a 33% decrease in the absorption of ranitidine; peak serum ranitidine concentration decreased from 613 to 432 ng/mL and the area under the serum concentration-time curve (AUC) decreased from 3613 to 2394 mcghour/L. The time to reach the peak and the rate of absorption of the drug were not substantially altered by concurrent administration of the antacid in this study; elimination half-life and renal clearance of ranitidine remained unchanged, but the fraction of the dose excreted in urine as unchanged drug and as the desmethyl metabolite was reduced by concomitant administration of antacid.

Propantheline Bromide

Propantheline bromide appears to delay the absorption and increase the peak serum concentration of ranitidine, probably by delaying gastric emptying and prolonging transit time; the relative bioavailability of ranitidine reportedly is increased approximately 23% with concomitant administration of propantheline.

Smoking

Cigarette smoking reportedly adversely affects the healing of duodenal ulcers and also appears to decrease the efficacy of ranitidine. In a controlled study, 62 and 100% of duodenal ulcers in smokers and nonsmokers, respectively, healed following oral administration of 150 mg of ranitidine twice daily; in the placebo group, 0 and 36% of duodenal ulcers in smokers and nonsmokers, respectively, healed. The number of cigarettes smoked per day did not appear to influence the ulcer healing rate.

Effects on Hepatic Clearance of Drugs

Since ranitidine interacts with the hepatic cytochrome P-450 (microsomal) enzyme system differently than does cimetidine, ranitidine appears to only minimally inhibit hepatic metabolism of some drugs (e.g., coumarin anticoagulants, theophylline, diazepam, propranolol). Ranitidine forms a ligand complex with the cytochrome P-450 enzyme system; however, ranitidine appears to interact with different forms of cytochrome P-450 than does cimetidine. The affinity of ranitidine for cytochrome P-450 is about 10% that of cimetidine and the extent of inhibition of the enzyme system is about 2.4 times less than that with cimetidine. Inhibition of hepatic microsomal enzyme activity appears to be structurally determined rather than associated with H2-receptor blockade, since ranitidine and cimetidine differ substantially in their effects on this enzyme system. Hepatic microsomal mixed-function oxidase activity appears to be unchanged following concomitant administration of ranitidine and aminopyrine or antipyrine, since demethylation of aminopyrine and clearance of antipyrine are essentially unaltered by ranitidine therapy.

Although cimetidine and ranitidine have been reported to reduce hepatic blood flow in some studies, other studies have not confirmed this finding. Ranitidine does not appear to affect elimination of indocyanine green.

Coumarin Anticoagulants

The manufacturers state that increased or decreased prothrombin time (PT) has been reported during concomitant therapy with ranitidine and warfarin; however, pharmacokinetic studies of ranitidine at dosages of up to 400 mg daily and warfarin demonstrated no effect on warfarin clearance and/or PT. Ranitidine dosages exceeding 400 mg daily have not been studied for potential interaction with warfarin. In one study following concomitant administration of 200 mg of ranitidine twice daily for 14 days and daily warfarin doses (2.5-4.5 mg) designed to prolong the PT by 2-5 seconds, neither the PT nor plasma warfarin concentration was altered substantially. In another study, although the effect on PT was not determined, ranitidine (150 mg twice daily orally for 7 days prior to and 5 days after administration of warfarin) reportedly decreased total body clearance of warfarin (a single 10-mg oral dose) but did not substantially affect warfarin's plasma half-life; the mechanism of this apparent decrease in warfarin clearance was not determined.

Theophyllines

In one controlled, crossover study in healthy adults who received 300 mg of ranitidine, 1.2 g of cimetidine, or 2.4 g of cimetidine orally for 4 days prior to and 1 day after an IV aminophylline dose of 6 mg/kg, cimetidine 1.2 or 2.4 g daily decreased plasma theophylline clearance by 22-49 or 11-52%, respectively, while ranitidine did not alter theophylline clearance. Similar results were reported in another controlled, crossover study in which healthy adults received ranitidine or cimetidine concomitantly with theophylline. Although decreased theophylline clearance has been reported in at least one patient receiving ranitidine and an extended-release theophylline preparation (Theo-Dur) concomitantly, the change in theophylline clearance may have resulted from discontinuance of an aluminum and magnesium hydroxides antacid rather than from initiation of ranitidine therapy and documentation of a potential ranitidine/theophylline interaction in this case has been questioned.

Benzodiazepines

In one study, concomitant administration of diazepam and 150 mg of ranitidine twice daily did not substantially affect the area under the plasma diazepam concentration-time curve (AUC) or the mean half-life of diazepam. In another study, concomitant administration of a single 2-mg dose of lorazepam and 150 mg of ranitidine every 12 hours did not affect the elimination half-life, volume of distribution, or clearance of lorazepam.

Administration of oral ranitidine appears to increase the systemic availability of oral triazolam. In healthy adults (18-60 years of age), concomitant administration of triazolam and ranitidine 75 or 150 mg twice daily resulted in a 10 or 28% increase in the AUC of triazolam, respectively, compared with administration of triazolam alone; in individuals older than 60 years of age, such concomitant administration resulted in a 30% increase in the AUC of triazolam compared with administration of triazolam alone. Elimination of triazolam and α-hydroxytriazolam (a major metabolite) were not altered in individuals receiving ranitidine. It has been suggested that increased ranitidine-induced gastric pH may increase bioavailability of triazolam. The clinical importance of this interaction is not known.

For information on the potential interaction between midazolam and ranitidine, .

β-Adrenergic Blocking Agents

Mean serum propranolol concentrations do not appear to differ substantially in individuals receiving ranitidine and propranolol concomitantly vs those receiving propranolol alone. In one study, combined therapy with 150 mg of ranitidine and 100 mg of atenolol daily for 7 days did not appear to alter the pharmacokinetics of atenolol; however, in the same study, the pharmacokinetics of 100 mg of metoprolol were altered by ranitidine. The AUC for metoprolol increased about 80% (1167 vs 2140 nghour/mL) and the mean peak serum concentration of metoprolol increased about 50% (177.2 vs 265 ng/mL) during concomitant ranitidine therapy. In the same study, the elimination half-life of metoprolol increased from 4.4 to 6.5 hours when ranitidine was used concomitantly.

Acetaminophen

Although the clinical importance is not known, ranitidine reportedly produced dose-dependent inhibition of acetaminophen metabolism in one in vitro study; in another study in which rats were pretreated with 120 mg/kg of ranitidine and then administered 250 mg/kg of radiolabeled acetaminophen, ranitidine appeared to decrease the oxidation of acetaminophen as determined by liver concentrations of glutathione and a covalently bound toxic metabolite of acetaminophen.

Phenytoin

Ranitidine does not appear to affect serum concentrations of phenytoin following administration of 150 mg of ranitidine twice daily for 14 days in individuals receiving chronic phenytoin therapy of 180 or 300 mg daily.

Alcohol

Currently available data suggest that consumption of moderate amounts of alcohol (e.g., 0.3 g/kg of body weight) by individuals receiving H2-receptor antagonists, including ranitidine, is unlikely to result in clinically important alterations in blood alcohol concentrations and/or alcohol metabolism, although the possibility of such alterations in predisposed individuals cannot be definitely excluded. Increases in blood alcohol concentrations have been noted in some studies in healthy individuals receiving ranitidine or some other H2 antagonists concomitantly with alcohol; however, conflicting data exist, which may be related to the effects of various patient-specific factors (e.g., gender, ethnic group, hepatic function, chronic alcoholism) on alcohol metabolism and/or to differences in study design (e.g., alcohol dose and time of administration, fasting vs fed state). Although controversy exists regarding the potential for psychomotor impairment with increases in alcohol absorption and/or blood alcohol concentration induced by H2-receptor antagonists, patients receiving these drugs should observe the usual precautions regarding alcohol intake and performance of hazardous tasks requiring mental alertness or physical coordination (e.g., driving, operating machinery).

Other Drugs

The manufacturers state that ranitidine may affect the oral bioavailability of certain drugs by some yet unidentified mechanism (e.g., a pH-dependent effect on GI absorption or a change in volume of distribution).

Preliminary evidence indicates that concomitant administration of ranitidine may increase the AUC for nifedipine by about 30%.

Although ranitidine appears to only minimally affect the secretion of gastric intrinsic factor, malabsorption of, and resultant deficiency in, vitamin B12 may occur during long-term ranitidine therapy.

Ranitidine does not appear to alter peak serum concentration or AUC for ethanol following administration of 0.8 g/kg of ethanol 20% v/v in individuals pretreated for 7 days with 300 mg of ranitidine daily.

Pharmacokinetics

Absorption

Ranitidine is rapidly absorbed from the GI tract following oral administration and from parenteral sites following IM injection; however, following oral administration, the drug undergoes extensive first-pass metabolism.(See Pharmacokinetics: Elimination.) The absolute bioavailability of orally administered ranitidine has been reported to be about 50%, and similar oral bioavailability of the drug has been reported in children 3.5-16 years of age. The manufacturer states that the average bioavailability of orally administered ranitidine is about 48% in pediatric patients. The oral solution and effervescent tablets of ranitidine hydrochloride have been shown to be bioequivalent to conventional tablets of the drug. Following oral administration, area under the plasma concentration-time curve may be substantially increased in geriatric individuals compared with younger adults. Following IM administration, the absolute bioavailability of ranitidine is 90-100%. Following oral administration of 150-mg doses of ranitidine hydrochloride, mean peak serum ranitidine concentrations of 372-545 ng/mL occur within 2-3 hours and may be positively correlated with age in adults. Following oral administration of ranitidine 150 mg twice daily in geriatric patients, average peak plasma concentrations of 526 ng/mL occur in about 3 hours. Following oral administration of single doses of the drug in one study, peak serum concentrations were biphasic in some individuals with an initial peak occurring at 0.5-1.5 hours after administration and a second peak occurring about 3 hours after administration. Following IM administration of a single 50-mg dose of ranitidine hydrochloride, mean peak serum ranitidine concentrations of 576 ng/mL occur within 15 minutes.

Absorption and mean peak plasma concentration of ranitidine are not substantially decreased by concomitant administration of food or low-potency antacids (neutralizing capacity of 10-15 mEq of hydrochloric acid per 10 mL); however, concomitant administration of higher potency antacids may decrease absorption of ranitidine.(See Drug Interactions: Food and Antacids.) Concomitant administration of propantheline appears to increase peak serum concentrations of ranitidine.(See Drug Interactions: Propantheline Bromide.)

The manufacturers state that serum ranitidine concentrations necessary to inhibit 50% of pentagastrin-stimulated gastric acid secretion (IC50) are estimated to be 36-94 ng/mL. However, the manufacturers state that a consistent relationship between serum ranitidine concentrations and a given dose or given therapeutic effect of acid inhibition does not appear to exist. Following administration of a single 150-mg oral or 50-mg IM or IV dose, serum ranitidine concentrations remain in the IC50 range for up to 12 hours and 6-8 hours, respectively. Following chronic oral administration of 150 mg of ranitidine twice daily, trough serum concentrations range between 53-57 ng/mL. In one study following intraduodenal administration of ranitidine in individuals with duodenal ulcers, the IC50 of the drug was estimated to be 100 ng/mL. Substantial inhibition of gastric acid secretion reportedly continues for about 9.5 hours after ingestion of a single 150-mg dose of the drug.

Following oral administration of a single 1- to 2-mg/kg dose of ranitidine as tablets in children 3.5-16 years of age with gastric or duodenal ulcer, peak plasma ranitidine concentrations of 54-492 ng/mL were achieved in 2 hours. Following administration of a single 2-mg/kg dose of ranitidine as the oral solution in otherwise healthy children 8 months to 14 years of age who required ranitidine therapy, peak plasma ranitidine concentrations of 244 ng/mL were achieved in 1.61 hours. Peak plasma concentrations of 320 ng/mL were achieved in 1.7 hours in these children following multiple dosing with 2 mg/kg. The manufacturer states that a serum ranitidine concentration of 40-60 ng/mL has been reported to be required for at least 90% suppression of basal acid secretion in pediatric patients with duodenal or gastric ulcers. In pediatric patients, oral ranitidine dosages of 6-10 mg/kg daily (given in 2 or 3 divided doses) maintain the gastric pH above 4 throughout most of the dosing interval.

Distribution

Ranitidine is widely distributed throughout the body and is 10-19% protein bound. The apparent volume of distribution of ranitidine is reported to be 1.7 (1.2-1.9) L/kg. The apparent volume of distribution in children 3.5-16 years of age is reported to be 2.3-2.5 L/kg (range: 1.1-3.7 L/kg).

Following oral administration, ranitidine is distributed into CSF. In one study in patients undergoing diagnostic lumbar puncture, CSF concentrations of 0.01-0.04 mcg/mL were achieved 2-6 hours after a dose following 6 days of oral ranitidine 150 mg twice daily. In individuals with uninflamed meninges, CSF ranitidine concentrations are reported to be approximately 3-5% of concurrent peak serum concentrations.

Ranitidine is distributed into milk; concentrations in milk reportedly range from 25-100% of concurrent serum concentrations.

Elimination

The elimination half-life of ranitidine in adults averages 1.7-3.2 hours and may be positively correlated with age in adults. The elimination half-life is prolonged in patients with renal impairment. In one study following oral administration of a single 150-mg dose of ranitidine in patients with creatinine clearances averaging 27.2 mL/minute, the terminal elimination half-life of ranitidine was 8.7 hours; a correlation between the degree of impairment and the elimination half-life of the drug was not apparent. However, in another study in patients with GFRs (as determined by inulin clearance) ranging from 3-69 mL/minute per 1.73 m, ranitidine clearance was shown to correlate with GFR and elimination half-life of ranitidine was correlated with degree of renal impairment. In a study in patients with creatinine clearances of 0.5-34 mL/minute, the elimination half-life ranged from 3-10 hours following IV administration of a single 50-mg dose. The manufacturers state that following oral administration of 150 mg of ranitidine twice daily for 4 weeks in patients with renal impairment, mean serum ranitidine concentrations were higher after 24 hours than the concentration observed 12 hours after the same dosage in patients with normal renal function.

There are no substantial differences in pharmacokinetics for ranitidine in pediatric patients 1 month to 16 years of age and healthy adults when correction is made for body weight; however, plasma clearance is decreased and elimination half-life prolonged in neonates younger than 1 month of age. In pharmacokinetic studies of pediatric patients with peptic ulcer disease receiving a 1.25- or 2.5-mg/kg IV dose of ranitidine, plasma clearance averaged 11.41, 8.96, or 9.89 mL/minute per kg, and the elimination half-life averaged 2.2, 2.1, or 1.7 hours in those younger than 6, 6-12, or older than 12 years of age, respectively; in adults receiving 2.5 mg/kg IV, plasma clearance averaged 8.77 mL/minute per kg and elimination half-life averaged 1.9 hours. Following a 0.13-0.8 mg/kg IV dose of ranitidine in pediatric patients 3.5-16 years of age with peptic ulcer disease, plasma clearance averaged 795 mL/minute per 1.73 m, and the elimination half-life averaged 1.8 hours. However, following a 2 mg/kg IV dose of ranitidine in neonatal patients less than 1 month of age receiving ECMO, plasma clearance averaged 4.3 mL/minute per kg and the elimination half-life averaged 6.6 hours. In pediatric patients in an intensive care setting who were 1 day to 12.6 years of age, ranitidine plasma clearance averaged 11.7 mL/minute per kg, and the ranitidine elimination half-life averaged 2.4 hours following a 1-mg/kg IV dose of ranitidine.

In geriatric patients, elimination half-life of ranitidine is prolonged and total clearance is reduced because of a decrease in renal function; although the manufacturer states that the half-life is 3-4 hours in geriatric patients following parenteral or oral administration, the half-life of ranitidine has been reported to be prolonged to about 6 hours in geriatric individuals following oral administration of a 100-mg dose of the drug.

Ranitidine is metabolized in the liver to ranitidine N-oxide, desmethyl ranitidine, and ranitidine S-oxide. Orally administered ranitidine undergoes extensive metabolism on first pass through the liver. Following oral administration of ranitidine to individuals with cirrhosis, the manufacturers state that there are minor but clinically unimportant alterations in the half-life, distribution, clearance, and bioavailability of ranitidine. Peak serum ranitidine concentrations in patients with cirrhosis appear to be higher than those in healthy individuals because of reduced first-pass metabolism of the drug and resultant increased bioavailability; bioavailability of ranitidine appears to average 70% following oral administration in patients with cirrhosis.

Ranitidine is excreted principally in urine via glomerular filtration and tubular secretion. The majority of urinary excretion of ranitidine occurs within the first 6 hours after administration. The portion of an orally administered dose that is excreted unchanged in urine is dose dependent; however, approximately 16-36% of an orally administered dose is excreted unchanged in urine within 24 hours. Approximately 4, 1-2, and 1% are excreted in urine as ranitidine N-oxide, desmethyl ranitidine, and ranitidineS-oxide, respectively, within 24 hours. The remainder of the administered dose is eliminated in feces, apparently via biliary excretion. Approximately 70% of an IV dose of ranitidine is excreted in urine as unchanged drug.

Renal clearance of ranitidine in healthy individuals is reported to average 410-530 mL/minute. In one study following oral administration of 100-mg doses of ranitidine in healthy adults, plasma, renal, and hepatic clearances of the drug were reported to be 20.8, 5.6, and 16.4 mL/minute per kg, respectively. Plasma clearance of ranitidine appears to be decreased in patients with renal dysfunction. In one study following IV administration of a single 50-mg dose of the drug in patients with creatinine clearances of 0.5-34 mL/minute, plasma clearance of the drug correlated with creatinine clearance and ranged from 1.7-10.9 mL/minute per kg. Plasma clearance appears to be reduced in geriatric patients and in patients with cirrhosis.

Ranitidine is removed by hemodialysis. The amount of ranitidine removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate); however, preliminary evidence indicates that a single 6-hour period of hemodialysis removes about 10% of a 120-mg dose of ranitidine into the dialysate.

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