NIZATIDINE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-All oral dosage forms: May be administered without regard to meals. Administer with food, water, or milk to minimize gastric irritation. Administer with a full glass of water.
-For non-prescription occasional use for symptom prevention: Administer right before eating or up to 60 minutes before consuming food or beverage that may cause heartburn. Administer with a full glass of water.
Oral Liquid Formulations
-Oral solution: Administer using a calibrated measuring device to assure accurate dosage.

In controlled clinical trials in pediatric patients (age 2 to 18 years), nizatidine was found to be generally safe and well tolerated. The principal adverse experiences (> 5%) included irritability. Most adverse events were mild or moderate in severity. One pediatric subject experienced seizures (diagnosed by EEG) after taking nizatidine 2.5 mg/kg PO twice daily for 23 days. Additional adverse reactions reported in adult populations included headache (16.6% vs 15.6%), dizziness (4.6% vs 3.8%), and drowsiness (1.9% vs 1.6%) and were reported more often in adult patients who received oral nizatidine (n = 2694) compared with placebo (n = 1729) in clinical trials. Anxiety (1.8% vs 1.4%) and nervousness (1.1% vs 0.8%) also occurred more often in adult patients who received oral nizatidine (n = 2694) compared with placebo (n = 1729); mental confusion was reported rarely (< 1%).

In controlled clinical trials in pediatric patients (age 2 to 18 years), nizatidine was found to be generally safe and well tolerated. The principal gastrointestinal (GI) adverse experiences (> 5%) were diarrhea and vomiting. Most adverse events were mild or moderate in severity. Mild elevated hepatic enzymes (elevations in serum transaminases 1-2 times the upper limit of normal) were noted in some patients. Diarrhea (7.2% vs 6.9%), xerostomia (1.4% vs 1.3%), and tooth disorder (1% vs 0.8%) occurred more often in adult patients who received oral nizatidine (n = 2694) compared with placebo (n = 1729) in clinical trials. Reversible hepatocellular injury including elevated hepatic enzymes (e.g., increased AST, ALT, or alkaline phosphatase levels) has been reported in adult patients who received nizatidine in clinical trials, at a rate similar to patients who received placebo. Hepatitis and jaundice have been reported rarely with nizatidine use in post-marketing surveillance. Additionally, reversible cholestatic or mixed hepatocellular and cholestatic injury with jaundice have been reported. Other reported reactions have included nausea.

In controlled clinical trials in pediatric patients (age 2 to 18 years), nizatidine was found to be generally safe and well tolerated. The principal respiratory adverse experiences (> 5%) were nasopharyngitis, nasal congestion, and cough. Most adverse events were mild or moderate in severity. In adult groups, rhinitis (9.8% vs 9.6%), pharyngitis (3.3% vs 3.1%), and sinusitis (2.4% vs 2.1%) occurred more often in those who received oral nizatidine (n = 2694) compared with placebo (n = 1729) in clinical trials.

Infection was reported in 1.7% of adult patients who received oral nizatidine (n = 2694) compared with 1.1% of patients who received placebo (n = 1729) in clinical trials. Pneumonia has been reported with nizatidine use in post-marketing surveillance.

Hypersensitivity reactions such as anaphylactoid reactions, bronchospasm, laryngeal edema, and rash (unspecified) have been reported rarely in patients who received nizatidine in clinical trials. Pruritus was reported in 1.7% of adult patients who received oral nizatidine (n = 2694) compared with 1.3% of patients who received placebo (n = 1729) in clinical trials. Urticaria was reported significantly more often in nizatidine-treated patients compared with patient who received placebo (0.5% vs 0.1%); sweating (hyperhidrosis) was also reported significantly more often with nizatidine therapy. Other dermatologic reactions reported in less than 1% of adult patients include rash (unspecified) and exfoliative dermatitis. Serum sickness like reactions have been reported rarely in patients who received nizatidine. Vasculitis was also reported rarely. Eosinophilia has also been reported.

Fever (pyrexia) was reported in greater than 5% of pediatric patients aged 2-18 years who received oral nizatidine in clinical studies.

Anemia (0.2% vs 0%) occurred significantly more often in adult patients who received oral nizatidine (n = 2694) compared with patients who received placebo (n = 1729) in clinical trials. Thrombocytopenia occurs rarely with the H2-receptor blockers. Fatal thrombocytopenia was reported in 1 patient with a history of drug-induced thrombocytopenia who received nizatidine and another H2-receptor antagonist. Thrombocytopenic purpura has also been reported rarely.

Chest pain (unspecified) was reported in 2.3% of adult patients who received oral nizatidine (n = 2694) compared with 2.1% of patients who received placebo (n = 1729) in clinical trials. There were 2 cases of short episodes of asymptomatic ventricular tachycardia in patients receiving nizatidine in clinical pharmacology studies; however, there were 3 cases of asymptomatic ventricular tachycardia in untreated subjects.

Clinical pharmacology studies and controlled clinical trials showed no evidence of antiandrogenic activity due to nizatidine. Gynecomastia has been reported rarely in adult patients who received nizatidine in clinical trials.

Amblyopia was reported in 1% of adult patients who received oral nizatidine (n = 2694) compared with 0.9% of patients who received placebo (n = 1729) in clinical trials.

Myalgia was reported in 1.7% of adult patients who received oral nizatidine (n = 2694) compared with 1.5% of patients who received placebo (n = 1729) in clinical trials. Pain (4.2% vs 3.8%) and accidental injury (1.2% vs 0.9%) were reported more often in adult patients who received oral nizatidine (n = 2694) compared with patients who received placebo (n = 1729) in clinical trials.

Hyperuricemia unassociated with gout or nephrolithiasis has been reported in less than 1% of adult patients who received nizatidine in clinical trials.

Atrophic gastritis, a precursor for gastric cancer, has been associated with prolonged acid suppression with high dose H2-blockers like nizatidine in patients who are H. pylori positive. A 'test and treat' approach for baseline H. pylori infections is recommended for patients with reflux esophagitis on long term acid suppression therapy. Treatment of baseline infection decreases inflammation and may reverse corpus gastritis.

Long-term (e.g., generally >= 2-3 years) treatment with acid-suppressing agents, such as nizatidine, can lead to malabsorption of vitamin B12 (cyanocobalamin). In a large case-controlled study, adult patients with and without an incident diagnosis of vitamin B12 deficiency (n = 25,956 and 184,199, respectively) were compared, and a correlation between vitamin B12 deficiency and gastric acid-suppression therapy was found. Receipt of >= 2 years of a proton pump inhibitor or H2-receptor antagonist was associated with an increased risk for vitamin B12 deficiency. The precise risk in pediatric patients has not been defined. It may be prudent to monitor patients for signs of pernicious anemia. Neurological manifestations of pernicious anemia can occur in the absence of hematologic changes.

Nizatidine is contraindicated in any patient hypersensitive to the drug or with a history of other H2-blocker hypersensitivity.

Symptomatic response to therapy with famotidine does not preclude the presence of gastric cancer. Patients who have a suboptimal response or early symptomatic relapse after completing therapy should consider evaluation for gastric malignancy. In the patient who is self-medicating with nonprescription (OTC) formulations, the continuation of heartburn, acid indigestion, or dyspepsia beyond 2 weeks signals the need to consult a health care professional for evaluation.

Symptomatic response to therapy with nizatidine does not preclude the presence of H. pylori infection. H2-blockers, as single agents, will not eradicate H. pylori infection, if present.

To avoid accumulation of the drug in individuals with clinically significant renal impairment (i.e., CrCl 50 mL/minute or less) and renal failure, the dosage of nizatidine should be reduced in proportion to the severity of dysfunction.

Chronic use of gastric acid-suppressing agents should be used cautiously and with monitoring in patients who are prone to vitamin B12 deficiency. Daily treatment with a gastric acid-suppressing medication, such as nizatidine, over a long period of time (e.g., generally 2 to 3 years or more) has been associated with malabsorption of cyanocobalamin in adults. Consider the possibility of cyanocobalamin deficiency if clinical symptoms are observed.

A laboratory test interference may occur with nizatidine use. False-positive tests for urobilinogen with Multistix test strips may occur during therapy with nizatidine.

Description: Nizatidine is an oral H2-receptor antagonist. Nizatidine is used for gastroesophageal reflux disease (GERD) and peptic ulcer disease. A non-prescription (OTC) product is also available for self-treatment of pyrosis (heart burn), dyspepsia, and sour stomach. Of note, for the symptomatic acute and chronic treatment of GERD, proton pump inhibitors (PPIs) are considered to be more effective than H2-blockers. Nizatidine use in children and adolescents 12 to 18 years of age is well documented and supported by published literature and controlled trials; the drug is FDA-approved for the treatment of GERD and erosive esophagitis in this age group. Limited data are available for younger children and infants; nizatidine has been used in infants as young as neonates off-label.

NOTE: Globally, as well as in the U.S., some nizatidine products have been recalled from the market since September 2019 because they may contain unacceptable levels of N-nitrosodimethylamine (NDMA), a probable human carcinogen. In April 2020, another H2-receptor antagonist, ranitidine, was withdrawn from the U.S. market after an ongoing investigation of NDMA in ranitidine medications. NDMA has been linked with cancers of the digestive tract, bladder, kidney, and others. The FDA has determined that NDMA in some ranitidine products increases over time and especially when the products are stored at higher than room temperatures, and thus result in consumer exposure to unacceptable levels of this impurity. NDMA has also been found in some nizatidine products. The FDA has required testing of manufactured products. If testing shows NDMA above the acceptable daily intake limit, the manufacturer must inform the FDA and should not release the nizatidine product lot for consumer use. Patients taking prescription nizatidine who wish to stop taking these products should talk to their health care professional about other treatment options. As of April 2020, the FDA's testing has not found NDMA in famotidine, cimetidine, esomeprazole, lansoprazole, or omeprazole.

For self-medication of pyrosis (heartburn), acid dyspepsia (acid indigestion), or sour stomach:
Oral dosage (OTC products):
Neonates, Infants, and Children < 12 years: Do not self-medicate. Use only if advised by qualified health care prescriber.
Children >= 12 years and Adolescents: To prevent heartburn, take 75 mg PO immediately before or up to 60 minutes before consuming food or beverages that are known to cause symptoms. For treatment, take 75 mg PO once or twice daily. Maximum dosage is 150 mg/day PO. Patients should not take for more than 2 weeks without consulting a physician.

For the treatment of gastroesophageal reflux disease (GERD), including endoscopically diagnosed esophagitis (erosive and ulcerative esophagitis), and associated heartburn due to GERD:
Oral dosage (15 mg/mL solution):
Neonates*: 2.5 to 5 mg/kg/dose PO twice daily for 8 weeks has been studied for GERD in an open-label, multiple-dose, randomized, parallel-group, multicenter study. Patients (aged 5 days to 18 years, n = 210) were randomized to receive either of 2 dose levels (2.5 or 5 mg/kg/dose twice daily) for 8 weeks; no clear superiority between doses was observed. Neonatal data were not reported separately. While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.
Infants* and Children* 1 to 11 years: 5 mg/kg/dose PO twice daily is recommended by the American Academy of Pediatrics (AAP). Doses of 2.5 to 10 mg/kg/dose PO twice daily have also been reported. In an open-label, multiple-dose, randomized, parallel-group, multicenter study, patients (aged 5 days to 18 years, n = 210) were randomized to receive either of 2 dose levels (2.5 or 5 mg/kg/dose twice daily) for 8 weeks; no clear superiority between doses was observed. In a separate placebo controlled study, patients (aged 6 months to 8 years, n = 24) with mild to moderate reflux esophagitis received 10 mg/kg/dose PO twice daily for 8 weeks or a matching placebo. Nizatidine therapy was associated with statistically significant improvement in symptoms, reduced esophageal acid exposure, and healed esophagitis. While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.
Children and Adolescents 12 to 17 years: 150 mg PO twice daily for up to 8 weeks. Alternatively, 5 mg/kg/dose PO twice daily is recommended by the American Academy of Pediatrics (AAP); however, a maximum dosage is not specified. While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.
Oral dosage (capsules):
Infants* and Children* 1 to 11 years: 5 mg/kg/dose PO twice daily is recommended by the American Academy of Pediatrics (AAP). Doses of 2.5 to 10 mg/kg/dose PO twice daily have also been reported. In an open-label, multiple-dose, randomized, parallel-group, multicenter study, patients (aged 5 days to 18 years, n = 210) were randomized to receive either of 2 dose levels (2.5 or 5 mg/kg/dose twice daily) for 8 weeks; no clear superiority between doses was observed. In a separate placebo controlled study, patients (aged 6 months to 8 years, n = 24) with mild to moderate reflux esophagitis received 10 mg/kg/dose PO twice daily for 8 weeks or a matching placebo. Nizatidine therapy was associated with statistically significant improvement in symptoms, reduced esophageal acid exposure, and healed esophagitis. While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.
Children* and Adolescents* 12 to 17 years: 150 mg PO twice daily for up to 8 weeks. Alternatively, 5 mg/kg/dose PO twice daily is recommended by the American Academy of Pediatrics (AAP); however, a maximum dosage is not specified. While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.

Maximum Dosage Limits:
-Neonates
10 mg/kg/day PO has been studied.
-Infants
< 6 months: 10 mg/kg/day PO has been studied.
>= 6 months: 10-20 mg/kg/day PO has been studied.
-Children
< 12 years: 10-20 mg/kg/day PO has been studied.
>= 12 years: 300 mg/day PO.
-Adolescents
300 mg/day PO.

Patients with Hepatic Impairment Dosing
Pediatric patients 12 years and older:
Specific dosage adjustments have not been recommended. Use with caution in patients with hepatorenal syndrome as formal studies have not been done and part of the dose of nizatidine is metabolized in the liver. For patients with normal renal function and uncomplicated hepatic dysfunction, the disposition of nizatidine is similar to that of normal subjects.

Patients with Renal Impairment Dosing
Pediatric patients 12 years and older:
CrCl more than 50 mL/minute: No dosage adjustment needed.
CrCl 20 to 50 mL/minute: For those treated for active duodenal ulcer, GERD, or benign gastric ulcer, decrease the dose to 150 mg PO once daily; for maintenance therapy, decrease to 150 mg PO every other day.
CrCl less than 20 mL/minute: For those treated for active duodenal ulcer, GERD, or benign gastric ulcer, decrease the dose to 150 mg PO every other day; for maintenance therapy, decrease to 150 mg PO once every 3 days.

Intermittent Hemodialysis
See dosage recommendations for CrCl less than 20 mL/minute. Nizatidine is not expected to be efficiently removed from the body by dialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Nizatidine competitively inhibits the binding of histamine to the H2-receptors on the gastric basolateral membrane of parietal cells, reducing basal and nocturnal gastric acid secretions. The drug also decreases the gastric acid response to stimuli such as food, caffeine, insulin, betazole, or pentagastrin. Nizatidine reduces the total volume of gastric juice, thus indirectly decreasing pepsin secretion. The drug does not appear to alter gastric motility, gastric emptying, esophageal pressures, biliary secretions, or pancreatic secretions. Nizatidine may aid in gastromucosal healing, and it may protect the mucosa from the irritant effects caused by aspirin and nonsteroidal antiinflammatory agents. H2-blockers, as single agents, do not eradicate H. pylori infection.

Pharmacokinetics: Nizatidine is administered orally. The drug is roughly 35% protein-bound. Approximately 7% of an oral dose is metabolized in the liver to N2-monodesmethylnizatidine, which has H2-antagonist activity. Approximately 60% of unchanged drug and its metabolites is excreted in the urine and approximately 6% in the feces. Nizatidine is eliminated by both glomerular filtration and active tubular secretion. The elimination half-life is 1-2 hours.

Affected cytochrome P450 isoenzymes: none
Nizatidine does not inhibit the cytochrome P450 (CYP450) hepatic oxidative metabolism pathway, and thus is not expected to interact with drugs that are metabolized via this pathway.


-Route-Specific Pharmacokinetics
Oral Route
The oral bioavailability of nizatidine exceeds 70% in adult patients with normal renal function. The presence of food in the GI tract appears to increase the absorption of nizatidine.


-Special Populations
Pediatrics
Neonates and Infants
Elimination of nizatidine and its metabolite is largely dependent on renal excretion. The elimination of nizatidine and N-desmethylnizatidine are reduced in an age-related manner during the first year of life, consistent with immature renal function during this time of development. Preterm neonates would be expected to have longer half-lives than term neonates, consistent with immaturity of renal function associated with pre-term birth.

Children and Adolescents
Elimination of nizatidine and its metabolite is largely dependent on renal excretion. The pharmacokinetics of nizatidine in pediatric patients older than 1 year are comparable with that observed in adults with normal renal function. In children and adolescents 12-18 years of age, the half-life of a 150 mg single dose is 1.2-1.3 hours. The pharmacodynamic response to comparable weight-based dose is equal and potentially greater in children as compared to adults.

Hepatic Impairment
In patients with normal renal function and uncomplicated hepatic impairment, the pharmacokinetics of nizatidine are similar to that of normal subjects. Pharmacokinetic studies in patients with hepatorenal syndrome have not been done; however, nizatidine is partly metabolized in the liver.

Renal Impairment
Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine. The elimination half-life is 3.5-11 hours in functionally anephric adult patients. Those with renal dysfunction require lower dosing rates and/or increased intervals between doses.