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GLENMARK PHARMA
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68462042560

nizatidine 150 mg capsule

Generic
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Uses

Duodenal Ulcer

Acute Therapy

Nizatidine is used for short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer. Antacids may be used concomitantly as needed for relief of pain. In controlled studies in patients with endoscopically confirmed duodenal ulcers, reported rates of ulcer healing for nizatidine were substantially higher than those for placebo. In multicenter, double-blind studies in patients with endoscopically confirmed duodenal ulcer, ulcer healing with oral nizatidine 300 mg at bedtime daily, nizatidine 150 mg twice daily, or placebo occurred in 23, 27, or 10% of patients at 2 weeks; 67, 68, or 29% at 4 weeks; and 82% for the nizatidine regimens vs 49% for placebo at 8 weeks. Nizatidine also produced greater reductions in daytime and nocturnal pain and antacid consumption than did placebo, with complete relief of pain in most patients usually occurring within 4 weeks after initiation of nizatidine therapy.

Nizatidine appears to be at least as effective as cimetidine or ranitidine for short-term treatment of active duodenal ulcer. An oral nizatidine dosage of 300 mg daily at bedtime reportedly is at least as effective as an oral cimetidine dosage of 800 mg daily at bedtime. Nizatidine also appears to be as effective as ranitidine when the drugs are given in a dosage of 300 mg daily at bedtime. In a multicenter, double-blind study in patients with endoscopically confirmed duodenal ulcers, ulcer healing occurred in 81 or 80% of patients receiving nizatidine or ranitidine, respectively, in a dosage of 300 mg at bedtime for 4 weeks and in 92 or 93%, respectively, of patients receiving such therapy for 8 weeks. Patient age did not influence ulcer healing in this study; ulcers were healed in 77 or 78% of geriatric patients (i.e., those 61 years of age or older) receiving nizatidine or ranitidine, respectively, in a dosage of 300 mg daily at bedtime for 4 weeks and in 92 or 93%, respectively, of these patients following 8 weeks of such therapy. In several studies, there appeared to be little difference between nizatidine and cimetidine or ranitidine in reductions of daytime and nocturnal pain and antacid consumption.

Administration of a single daily dose of nizatidine at bedtime appears to be as effective in healing active duodenal ulcer as twice-daily administration of the drug. With an oral nizatidine dosage of 300 mg at bedtime daily or 150 mg twice daily, ulcer healing occurred in 23 or 27% of patients, respectively, at 2 weeks and 67 or 68% of patients, respectively, at 4 weeks. In several studies, ulcer healing occurred less frequently in patients who were smokers and in those with large ulcers.

Safety and efficacy of long-term nizatidine therapy (i.e., longer than 8 weeks) for active duodenal ulcer have not been determined. Most patients with duodenal ulcer respond to nizatidine therapy during the initial 4-week course of therapy; an additional 4 weeks of therapy may contribute to healing in some patients. Short-term nizatidine 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 Helicobacter 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 12 months in about 60-80% of patients following discontinuance of H2-receptor antagonist therapy. 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. For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, .

Maintenance Therapy

Nizatidine is used in reduced dosage as maintenance therapy following healing of active duodenal ulcer to reduce ulcer recurrence. In a placebo-controlled study, cumulative duodenal ulcer recurrence rates after 3, 6, and 12 months were 13, 24, and 34%, respectively, for 150 mg of nizatidine at bedtime daily vs 40, 57, and 64%, respectively, for placebo. Nizatidine appears to be at least as effective as ranitidine in preventing duodenal ulcer recurrence. Cumulative duodenal ulcer recurrence rates following therapy with nizatidine or ranitidine 150 mg at bedtime were 18.8 or 13.2%, respectively, at 6 months and 27.5 or 22.3%, respectively, at 12 months. Because the efficacy of H2-receptor antagonists in preventing duodenal ulcer recurrence appears to be reduced substantially in patients who are cigarette smokers compared with that in nonsmokers, patients who are smokers should be advised of the importance of discontinuing smoking in the prevention of ulcer recurrence. Safety and efficacy of nizatidine for maintenance therapy beyond 1 year have not been determined.

Gastric Ulcer

Nizatidine is used for short-term treatment of active, benign gastric ulcer. Antacids may be used concomitantly as needed for relief of pain. In a multicenter, double-blind study in patients with endoscopically confirmed benign gastric ulcer, reported rates of ulcer healing with oral nizatidine 300 mg at bedtime daily, nizatidine 150 mg twice daily, or placebo were 34, 43, or 32%, respectively, at 4 weeks and 65, 70, or 52%, respectively, at 8 weeks. The efficacy of nizatidine in the treatment of gastric ulcer appears to be similar to that of ranitidine, with ulcer healing rates of about 65% at 4 weeks and 83-96% at 8 weeks following therapy with either agent. Nizatidine also has produced greater reductions in epigastric pain, dyspepsia, and heartburn than placebo. Response of gastric ulcers to nizatidine therapy does not appear to be affected by patient age or gender or by cigarette smoking. Safety and efficacy of nizatidine in the treatment of gastric ulcer have not been established for periods exceeding 8 weeks. When H2-receptor antagonists are 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 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.(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, .

Gastroesophageal Reflux

Nizatidine is used to provide short-term, symptomatic relief of gastroesophageal reflux. In addition, nizatidine is used for short-term (up to 12 weeks) treatment of esophagitis associated with gastroesophageal reflux, including endoscopically proven erosive or ulcerative disease. By increasing gastric pH, H2-receptor antagonists have relieved heartburn and other symptoms of reflux, and therapy with these agents has been associated with higher rates of endoscopically proven healing in patients with esophagitis when compared to those of placebo.

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. The ACG states that a histamine H2-receptor antagonist administered daily in divided doses is 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, the ACG states that proton-pump inhibitors are more effective (i.e., provide more frequent and more rapid symptomatic relief and healing of esophagitis) than histamine H2-receptor antagonists in the treatment of GERD. 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.

Reported rates of ulcer healing with a nizatidine dosage of 150 mg twice daily generally are higher than those with placebo or a nizatidine dosage of 300 mg at bedtime in patients with endoscopically evaluated GERD. In controlled studies, healing rates with nizatidine 150 mg twice daily or placebo were, respectively, 16 or 7% at 3 weeks, 21-32 or 11-16% at 6 weeks, and 29 or 13% at 12 weeks. Patients receiving nizatidine reported faster relief of daytime and nocturnal heartburn and greater reduction in antacid consumption than those receiving placebo. H2-receptor antagonists also have been used in combination with metoclopramide in a limited number of patients who failed to respond to an H2-receptor 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 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 will 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 gastroesophageal reflux disease. 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,

Other Uses

Nizatidine may be used for self-medication for prevention of symptoms of occasional heartburn (pyrosis), acid indigestion (hyperchlorhydria), or sour stomach caused by food and beverages.

Dosage and Administration

Administration

Nizatidine is administered orally. Concomitant administration of nizatidine and food increases area under the plasma concentration-time curve (AUC) and peak plasma concentrations of the drug by 10% or less. Therefore, nizatidine generally can be given orally without regard to meals. Antacids may be administered concomitantly as necessary for relief of pain.(See Drug Interactions: Food and Antacids.)

Dosage

The manufacturer states that nizatidine dosage adjustment based solely on age is not necessary in geriatric patients; however, dosage adjustment is required in the presence of moderate to severe renal impairment.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Duodenal Ulcer

For the treatment of active duodenal ulcer, the usual dosage of nizatidine in adults is 300 mg daily at bedtime. Alternatively, 150 mg twice daily may be administered in adults. The advantage of one regimen over another for particular patients with active duodenal ulcer has not been determined to date, although a once-daily bedtime dosage may be used for patients in whom dosing convenience is considered important for compliance. Healing may occur within 2 weeks in some patients and within 4 weeks in most patients. Some patients may benefit from an additional 4 weeks of therapy. It occasionally may be necessary to continue full-dose nizatidine therapy for longer than 6-8 weeks; however, safety and efficacy of continuing full-dose therapy beyond 8 weeks have not been determined.

For maintenance therapy to reduce ulcer recurrence following healing of acute duodenal ulcer, the usual adult dosage of nizatidine is 150 mg at bedtime daily. Some clinicians recommend continuing maintenance therapy for at least 1 year; however, safety and efficacy of continuing nizatidine maintenance therapy beyond 1 year have not been determined.

Gastric Ulcer

For the short-term treatment of active, benign gastric ulcer, the usual dosage of nizatidine in adults is 150 mg twice daily or 300 mg once daily at bedtime. Most patients demonstrate complete healing of gastric ulcers within 8 weeks; the safety and efficacy of continuing nizatidine therapy beyond 8 weeks have not been determined.

Gastroesophageal Reflux

For the management of esophagitis associated with gastroesophageal reflux, including endoscopically proven erosive or ulcerative disease, the usual dosage of nizatidine in adults is 150 mg twice daily for up to 12 weeks. Nizatidine dosages of 300 mg at bedtime also have been used for the symptomatic management of gastroesophageal reflux disease (GERD); however, twice-daily administration of nizatidine appears to be more effective in the management of GERD than administration just at bedtime. In addition, the American College of Gastroenterology (ACG) states that once-daily administration of a histamine H2-receptor antagonist at full dosage is not considered to be appropriate therapy for GERD.

Pediatric Dosage

The usual pediatric dosage of nizatidine in children and adolescents is 150 mg twice daily. Dosage should not exceed 300 mg daily.

The duration of pediatric nizatidine therapy for gastroesophageal reflux disease or erosive esophagitis may extend up to 8 weeks.

See Dosage: Self-medication under Dosage and Administration for additional pediatric dosage information.

Self-medication

For self-medication for the prevention of symptoms of occasional heartburn, acid indigestion, or sour stomach caused by food and beverages in patients 12 years of age and older, an oral nizatidine dosage of 75 mg once or twice daily, to be taken 30-60 minutes before consuming food (e.g., rich, spicy, fried foods; chocolate) or beverages (e.g., those containing caffeine or alcohol), is recommended. For self-medication, the manufacturer recommends that dosage of nizatidine not exceed 150 mg in 24 hours and that such therapy not exceed 2 weeks of continuous use unless otherwise recommended by a clinician. Persistent symptoms or the development of difficulty in swallowing should be reported to a clinician since a serious problem requiring alternative therapy may be present.

The manufacturer states that nizatidine should not be used for self-medication in children younger than 12 years of age unless otherwise directed by a clinician.

Dosage in Renal and Hepatic Impairment

In patients with moderate to severe renal impairment, doses and/or frequency of administration of nizatidine should be modified in response to the degree of renal impairment. Modification of dosage in these patients may avoid excess accumulation of the drug; however, clinical efficacy of the following dosage regimens has not been systematically evaluated. For the treatment of acute duodenal ulcer, benign gastric ulcer, or gastroesophageal reflux disease in patients with creatinine clearances of 20-50 mL/minute, the manufacturer recommends a nizatidine dosage of 150 mg daily; in patients with creatinine clearances less than 20 mL/minute, a dosage of 150 mg every other day is recommended. For maintenance therapy in patients with duodenal ulcer, the manufacturer recommends a nizatidine dosage of 150 mg every other day in patients with creatinine clearances of 20-50 mL/minute; a dosage of 150 mg every 3 days is recommended in patients with creatinine clearances less than 20 mL/minute.

Reduction of nizatidine dosage in patients with hepatic impairment does not appear to be necessary.

Cautions

Nizatidine generally is well tolerated. A causal relationship between many adverse reactions and the drug has not been established but cannot be excluded. In some studies, the incidence of reported adverse effects was similar in patients receiving nizatidine or placebo; however, the incidences of anemia and urticaria were higher in patients receiving nizatidine. In controlled clinical trials in the US, discontinuance of nizatidine therapy has been necessary in less than 4.5% of patients receiving the drug.

Overall, the frequency of adverse effects produced by nizatidine is similar to that with ranitidine. Nizatidine does not appear to exhibit antiandrogenic activity nor does it affect prolactin concentrations, and the drug does not appear to affect hepatic clearance of other drugs.

Nervous System Effects

Headache or dizziness has been reported in about 17 or 5% of patients, respectively; however, these adverse effects have not been directly attributed to the drug. Insomnia, abnormal dreams, somnolence, asthenia, anxiety, or nervousness has been reported in approximately 3% or less of patients receiving nizatidine; the incidence of these adverse effects was similar in patients receiving nizatidine or placebo. Reversible mental confusion has been reported rarely.

GI Effects

Diarrhea, nausea and/or vomiting, abdominal pain/discomfort, constipation, flatulence, dyspepsia, dry mouth, anorexia, GI disorder, or tooth disorder has been reported in 1-7% of patients receiving nizatidine in clinical trials, but these effects have occurred with similar frequency in patients receiving placebo.

Dermatologic and Sensitivity Reactions

Urticaria occurred more often with nizatidine therapy (0.5% of patients) than with placebo (0.1% of patients) in placebo-controlled clinical studies. Rash, pruritus, or exfoliative dermatitis has occurred in up to 2% of patients receiving nizatidine. Serum sickness-like reactions, anaphylaxis, bronchospasm, laryngeal edema, eosinophilia, vasculitis, and erythema multiforme also have been reported rarely.

Hematologic Effects

Anemia was reported more often with nizatidine therapy (0.2% of patients receiving the drug) than with placebo (0% of patients) in placebo-controlled clinical studies. Thrombocytopenic purpura has occurred rarely in patients receiving nizatidine. Fatal thrombocytopenia occurred in a patient with a history of thrombotic thrombocytopenic purpura and drug-induced thrombocytopenia who received 2 doses of nizatidine before results of hematologic tests performed prior to nizatidine administration revealed anemia and thrombocytopenia. This patient also had been treated with another2-receptor antagonist, and a causal relationship to nizatidine has not been established.

Hepatic Effects

Reversible hepatocellular injury, evidenced by increases (occasionally marked) in serum aminotransferase (transaminase) (AST [SGOT] and ALT [SGPT]) and/or alkaline phosphatase concentration, has occurred in patients receiving nizatidine. Hepatitis and jaundice also have been reported with nizatidine therapy. Reversible cholestatic or mixed cholestatic-hepatocellular injury with jaundice has occurred rarely.

Respiratory Effects

Rhinitis, pharyngitis, sinusitis, or increased cough has occurred in about 2-10% of patients receiving nizatidine.

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

Diaphoresisoccurred more often with nizatidine therapy than with placebo but was not considered drug related because of its association with other concurrent adverse events (e.g., fever, anxiety). Pain, including back or chest pain, has been reported in approximately 2-4% of patients receiving nizatidine. Other adverse events reported in patients receiving nizatidine include myalgia, fever, infection, amblyopia, hyperuricemia, and impotence. In most studies, the incidence of these adverse effects, and of surgical procedures or accidental injuries, was similar in patients receiving nizatidine or placebo. Asymptomatic ventricular tachycardia, decreased libido, and gynecomastia have been reported rarely.

Precautions and Contraindications

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

The possibility that gastric acid-suppressive therapy may increase the risk of community-acquired pneumonia should be considered. (See Respiratory Effects: Community-acquired Pneumonia, in Cautions.)

Nizatidine should be used with caution and the dose and/or frequency of administration reduced in patients with renal impairment (i.e., creatinine clearance less than 50 mL/minute), since the drug is excreted principally by the kidneys.

Nizatidine is contraindicated in patients with known hypersensitivity to the drug, other H2-receptor antagonists, or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of nizatidine in children younger than 12 years of age have not been established.

Geriatric Precautions

Clinically important differences in the pharmacokinetic profile of nizatidine have not been observed in studies in geriatric patients. Therefore, dosage adjustment solely on the basis of age generally is not required in such patients. However, in geriatric patients with renal impairment, the dose and frequency of administration of nizatidine should be modified in response to the degree of renal impairment.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was observed with nizatidine in various in vitro and in vivo test systems, including bacterial mutation tests, unscheduled DNA synthesis, sister chromatid exchange, mouse lymphoma assay, chromosome aberration tests, and a micronucleus test.

No evidence of carcinogenicity was seen in rats, male mice, or female mice receiving oral nizatidine dosages up to 500 mg/kg daily (about 80 times the usual human dosage), 2 g/kg daily (about 330 times the usual human dosage), or 360 mg/kg daily, respectively, for 2 years. Although hepatic carcinoma and hepatic nodular hyperplasia were found in female mice following long-term (2 years) administration of nizatidine 2 g/kg daily, the incidence of hepatic carcinoma was similar to that of historical controls for this strain of mice and this finding alone is not considered indicative of carcinogenic potential. A dose-related increase in the density of enterochromaffin-like cells (ECL) in the gastric oxyntic mucosa was observed in rats but not in mice.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproductive studies in rats and rabbits using oral nizatidine dosages up to 1500 and 275 mg/kg daily (40.5 and 14.6 times the recommended human dose based on body surface area), respectively, have not revealed evidence of harm to the fetus. However, there are no adequate and controlled studies using nizatidine 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 nizatidine for self-medication.

Fertility

Reproductive studies in rats and rabbits using oral nizatidine dosages up to 1500 and 275 mg/kg daily (40.5 and 14.6 times the recommended human dose based on body surface area), respectively, have not revealed evidence of impaired fertility.

Lactation

Nizatidine is distributed into milk in rats, and growth depression has occurred in the offspring of lactating rats treated with the drug. Nizatidine also is distributed into milk in humans. Because of the potential for serious adverse reactions to nizatidine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Food and Antacids

Food appears to slightly enhance, and antacids appear to slightly decrease, the bioavailability of nizatidine, but these effects do not appear to be clinically important. Nizatidine may be administered concomitantly with food.

In a limited number of studies, concomitant administration of single or multiple doses of nizatidine and food did not affect pharmacokinetic parameters compared with values obtained following oral administration of the drug in fasting individuals. Concomitant administration of an aluminum and magnesium hydroxides antacid and oral nizatidine tends to decrease the mean peak plasma concentration and the mean AUC of nizatidine.

Propantheline Bromide

Concurrent administration of propantheline bromide 15 mg and nizatidine does not appear to alter the oral bioavailability of nizatidine.

Effects on Hepatic Clearance of Drugs

Unlike cimetidine, nizatidine does not inhibit the hepatic cytochrome P-450 (microsomal) enzyme system; therefore, drug interactions mediated by inhibition of hepatic metabolism are unlikely. No drug interactions have been observed between nizatidine and chlordiazepoxide, diazepam, lidocaine, lorazepam, metoprolol, phenytoin, theophylline, or warfarin.

Salicylate

Nizatidine may increase serum salicylate concentrations in patients receiving high-dose aspirin, presumably by inhibiting renal salicylate excretion. In a limited number of healthy men receiving nizatidine 150 mg twice daily in a placebo-controlled, randomized study, plasma salicylate concentrations and salicylate AUC increased with concurrent administration of high-dose (3.9 g daily) aspirin.

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 nizatidine, 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 nizatidine or 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 nizatidine should observe the usual precautions regarding alcohol intake and performance of hazardous tasks requiring mental alertness or physical coordination (e.g., driving, operating machinery).

Pharmacokinetics

Absorption

Nizatidine is rapidly and well absorbed following oral administration. A small portion of an orally administered dose of nizatidine is metabolized during first pass through the liver, resulting in a bioavailability averaging about 70% compared with that following IV injection. Food may slightly enhance and antacids may slightly decrease the bioavailability of nizatidine capsules, but these alterations do not appear to be clinically important.(See Drug Interactions: Food and Antacids.)

Following oral administration of a single 150- or 300-mg dose of nizatidine capsules, peak plasma concentrations average approximately 700-1800 or 1400-3600 ng/mL, respectively, within 0.5-3 hours. Little, if any, accumulation of nizatidine appears to occur during repeated administration of the drug in patients with normal renal function. The oral bioavailability of nizatidine capsules and solution is equivalent at a 150-mg dose.

In a study in healthy men, nizatidine inhibited basal gastric acid secretion by about 50 or 90% at a steady-state plasma concentration averaging 60 or 430 ng/mL, respectively; meal-stimulated acid secretion was inhibited by about 50 or 90% at a mean plasma concentration of 75 or 490 ng/mL, respectively. Inhibition of gastric acid secretion is apparent within 30 minutes following IV administration of nizatidine. The duration and degree of inhibition of gastric acid secretion produced by nizatidine are dose dependent, with maximum inhibition produced by an oral dose of 300 mg. The duration of inhibition of nocturnal acid secretion following a single 300-mg dose of the drug is 10-12 hours. Inhibition of food-stimulated acid secretion generally persists for up to 4 hours following a 150- or 300-mg dose of nizatidine.

Distribution

Distribution of nizatidine into human body tissues and fluids has not been fully characterized. The apparent volume of distribution of the drug is reported to be 0.8-1.5 L/kg in adults and does not appear to be altered substantially in patients with renal dysfunction.

Nizatidine is about 35% bound to plasma proteins, mainly α1-acid glycoprotein.

Most histamine H2-receptor antagonists, including cimetidine, ranitidine, and famotidine, cross the blood-brain barrier; it is not known whether nizatidine is distributed into the CNS. Nizatidine crosses the placenta and is distributed into milk in humans.

Elimination

The elimination half-life of nizatidine averages 1-2 hours in adults with normal renal function. The elimination of nizatidine in adults does not appear to be affected substantially by age but is prolonged in patients with renal impairment. In a limited number of adults with creatinine clearances of 50-75 mL/minute, the elimination half-life of nizatidine averaged 2.1 hours; with creatinine clearances of 10-49 mL/minute, the elimination half-life of the drug averaged 4.1 hours. In anuric patients, the elimination half-life of nizatidine ranges from 3.5-11 hours.

Nizatidine is metabolized in the liver to N-desmethylnizatidine, nizatidine N-oxide, and nizatidine sulfoxide. Of these metabolites, only N-desmethylnizatidine has histamine H2-receptor blocking activity; studies in animals indicate that this metabolite is approximately 60% as active as nizatidine in blocking gastric acid secretion. Orally administered nizatidine undergoes minimal metabolism on first pass through the liver.

Nizatidine is excreted principally in urine via glomerular filtration and tubular secretion. More than 90% of a dose is excreted in urine within 12-16 hours following oral administration; approximately 60-65% of a dose is excreted as unchanged drug in patients with normal renal function. About 8% of an orally administered dose of nizatidine is excreted in urine as N-desmethylnizatidine, 6% as nizatidine sulfoxide, 6% as nizatidine N-oxide, and about 15% as unidentified metabolites. Less than 6% of an orally administered dose of nizatidine is eliminated in feces.

Total body clearance of nizatidine from plasma averages 660-1000 mL/minute, and renal clearance averages 500 mL/minute.

The rate of nizatidine elimination is prolonged, and the drug's clearance decreased, in patients with renal impairment; these changes result from decreased renal elimination of the drug. While about 60% of a dose is excreted in urine unchanged in patients with normal renal function, only 25% of a dose is recovered from urine as unchanged drug in patients with renal impairment (e.g., at a creatinine clearance of 10-49 mL/minute). Unlike with famotidine, nonrenal excretion of nizatidine is not decreased in patients with severe renal impairment. Decreased renal elimination of nizatidine results in increased formation of the N-desmethyl metabolite, N-desmethylnizatidine. In addition, N-desmethylnizatidine is excreted more slowly in patients with renal failure, resulting in a 4-fold increase in its elimination half-life and a 5-fold increase in AUC compared with values from patients with normal renal function.

Nizatidine does not appear to be removed appreciably by hemodialysis.

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