Professional Information — Nizatidine

Indications and Usage

Nizatidine is indicated for up to 8 weeks for the treatment of active duodenal ulcer. In most patients, the ulcer will heal within 4 weeks.

Nizatidine is indicated for maintenance therapy for duodenal ulcer patients, at a reduced dosage of 150 mg h.s. after healing of an active duodenal ulcer. The consequences of continuous therapy with nizatidine for longer than 1 year are not known.

Nizatidine is indicated for up to 12 weeks for the treatment of endoscopically diagnosed esophagitis, including erosive and ulcerative esophagitis, and associated heartburn due to GERD.

Nizatidine is indicated for up to 8 weeks for the treatment of active benign gastric ulcer. Before initiating therapy, care should be taken to exclude the possibility of malignant gastric ulceration.

Dosage and Administration

Active Duodenal Ulcer – The recommended oral dosage for adults is 300 mg once daily at bedtime. An alternative dosage regimen is 150 mg twice daily.

Maintenance of Healed Duodenal Ulcer – The recommended oral dosage for adults is 150 mg once daily at bedtime.

Gastroesophageal Reflux Disease – The recommended oral dosage in adults for the treatment of erosions, ulcerations, and associated heartburn is 150 mg twice daily.

Active Benign Gastric Ulcer – The recommended oral dosage is 300 mg given either as 150 mg twice daily or 300 mg once daily at bedtime. Prior to treatment, care should be taken to exclude the possibility of malignant gastric ulceration.

Dosage Adjustment for Patients With Moderate to Severe Renal Insufficiency – The dose for patients with renal dysfunction should be reduced as follows:

Some elderly patients may have creatinine clearances of less than 50 mL/min, and based on pharmacokinetic data in patients with renal impairment, the dose for such patients should be reduced accordingly. The clinical effects of this dosage reduction in patients with renal failure have not been evaluated.

Adverse Reactions

Worldwide, controlled clinical trials of nizatidine included over 6,000 patients given nizatidine in studies of varying durations. Placebo-controlled trials in the United States and Canada included over 2,600 patients given nizatidine and over 1,700 given placebo. Among the adverse events in these placebo-controlled trials, anemia (0.2% vs 0%) and urticaria (0.5% vs 0.1%) were significantly more common in the nizatidine group.

Incidence in Placebo-Controlled Clinical Trials in the United States and Canada – Table 5 lists adverse events that occurred at a frequency of 1% or more among nizatidine-treated patients who participated in placebo-controlled trials. The cited figures provide some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

A variety of less common events were also reported; it was not possible to determine whether these were caused by nizatidine.

Hepatic – Hepatocellular injury, evidenced by elevated liver enzyme tests (SGOT [AST], SGPT [ALT], or alkaline phosphatase), occurred in some patients and was possibly or probably related to nizatidine. In some cases there was marked elevation of SGOT, SGPT enzymes (greater than 500 IU/L) and, in a single instance, SGPT was greater than 2,000 IU/L. The overall rate of occurrences of elevated liver enzymes and elevations to 3 times the upper limit of normal, however, did not significantly differ from the rate of liver enzyme abnormalities in placebo-treated patients. All abnormalities were reversible after discontinuation of nizatidine. Since market introduction, hepatitis and jaundice have been reported. Rare cases of cholestatic or mixed hepatocellular and cholestatic injury with jaundice have been reported with reversal of the abnormalities after discontinuation of nizatidine.

Cardiovascular – In clinical pharmacology studies, short episodes of asymptomatic ventricular tachycardia occurred in 2 individuals administered nizatidine and in 3 untreated subjects.

CNS – Rare cases of reversible mental confusion have been reported.

Endocrine – Clinical pharmacology studies and controlled clinical trials showed no evidence of anti-androgenic activity due to nizatidine. Impotence and decreased libido were reported with similar frequency by patients who received nizatidine and by those given placebo. Rare reports of gynecomastia occurred.

Hematologic – Anemia was reported significantly more frequently in nizatidine- than in placebo-treated patients. Fatal thrombocytopenia was reported in a patient who was treated with nizatidine and another H₂-receptor antagonist. On previous occasions, this patient had experienced thrombocytopenia while taking other drugs. Rare cases of thrombocytopenic purpura have been reported.

Integumental – Sweating and urticaria were reported significantly more frequently in nizatidine- than in placebo-treated patients. Rash and exfoliative dermatitis were also reported. Vasculitis has been reported rarely.

Hypersensitivity – As with other H₂-receptor antagonists, rare cases of anaphylaxis following administration of nizatidine have been reported. Rare episodes of hypersensitivity reactions (e.g., bronchospasm, laryngeal edema, rash, and eosinophilia) have been reported.

Body as a Whole – Serum sickness-like reactions have occurred rarely in conjunction with nizatidine use.

Genitourinary – Reports of impotence have occurred.

Other – Hyperuricemia unassociated with gout or nephrolithiasis was reported. Eosinophilia, fever, and nausea related to nizatidine administration have been reported.

To report SUSPECTED ADVERSE EVENTS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Overdosage

Overdoses of nizatidine have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.

Signs and Symptoms – There is little clinical experience with overdosage of nizatidine in humans. Test animals that received large doses of nizatidine have exhibited cholinergic-type effects, including lacrimation, salivation, emesis, miosis, and diarrhea. Single oral doses of 800 mg/kg in dogs and of 1,200 mg/kg in monkeys were not lethal. Intravenous median lethal doses in the rat and mouse were 301 mg/kg and 232 mg/kg respectively.

Treatment – To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

If overdosage occurs, use of activated charcoal, emesis, or lavage should be considered along with clinical monitoring and supportive therapy. The ability of hemodialysis to remove nizatidine from the body has not been conclusively demonstrated; however, due to its large volume of distribution, nizatidine is not expected to be efficiently removed from the body by this method.

Description

Nizatidine, USP is a histamine H₂-receptor antagonist. Chemically, it is N-[2-[[[2-[(Dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine. The structural formula is represented below:

It is an off-white to buff crystalline solid that is soluble in water. Nizatidine, USP has a bitter taste and mild sulfur-like odor. Nizatidine capsules USP, for oral administration, contain 150 mg or 300 mg nizatidine, USP and the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, magnesium stearate and pregelatinized starch. The capsule shells contain: ammonium hydroxide, black iron oxide, gelatin, potassium hydroxide, propylene glycol, shellac, silicon dioxide, sodium lauryl sulfate and titanium dioxide.

The 150 mg capsule shell also contains D&C Yellow No. 10 and FD&C Yellow No. 6.

The 300 mg capsule shell also contains black iron oxide, red iron oxide and yellow iron oxide.

Clinical Pharmacology

Nizatidine is a competitive, reversible inhibitor of histamine at the histamine H2-receptors, particularly those in the gastric parietal cells.

Antisecretory Activity – 1. Effects on Acid Secretion: Nizatidine significantly inhibited nocturnal gastric acid secretion for up to 12 hours. Nizatidine also significantly inhibited gastric acid secretion stimulated by food, caffeine, betazole, and pentagastrin (Table 1).

2. Effects on Other Gastrointestinal Secretions – Pepsin: Oral administration of 75 to 300 mg of nizatidine did not affect pepsin activity in gastric secretions. Total pepsin output was reduced in proportion to the reduced volume of gastric secretions.

Intrinsic Factor: Oral administration of 75 to 300 mg of nizatidine increased betazole-stimulated secretion of intrinsic factor.

Serum Gastrin: Nizatidine had no effect on basal serum gastrin. No rebound of gastrin secretion was observed when food was ingested 12 hours after administration of nizatidine.

3. Other Pharmacologic Actions 

1. Hormones: Nizatidine was not shown to affect the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodothyronine, thyroxin, testosterone, 5α-dihydrotestosterone, androstenedione, or estradiol.
2. Nizatidine had no demonstrable antiandrogenic action.

4. Pharmacokinetics – The absolute oral bioavailability of nizatidine exceeds 70%. Peak plasma concentrations (700 to 1,800 mcg/L for a 150 mg dose and 1,400 to 3,600 mcg/L for a 300 mg dose) occur from 0.5 to 3 hours following the dose. A concentration of 1,000 mcg/L is equivalent to 3 mcmol/L; a dose of 300 mg is equivalent to 905 mcmoles. Plasma concentrations 12 hours after administration are less than 10 mcg/L. The elimination half-life is 1 to 2 hours, plasma clearance is 40 to 60 L/h, and the volume of distribution is 0.8 to 1.5 L/kg. Because of the short half-life and rapid clearance of nizatidine, accumulation of the drug would not be expected in individuals with normal renal function who take either 300 mg once daily at bedtime or 150 mg twice daily. Nizatidine exhibits dose proportionality over the recommended dose range.

The oral bioavailability of nizatidine is unaffected by concomitant ingestion of propantheline. Antacids consisting of aluminum and magnesium hydroxides with simethicone decrease the absorption of nizatidine by about 10%. With food, the AUC and C_max increase by approximately 10%.

In humans, less than 7% of an oral dose is metabolized as N2-monodesmethylnizatidine, an H₂-receptor antagonist, which is the principal metabolite excreted in the urine. Other likely metabolites are the N2-oxide (less than 5% of the dose) and the S-oxide (less than 6% of the dose).

More than 90% of an oral dose of nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose is excreted as unchanged drug. Renal clearance is about 500 mL/min, which indicates excretion by active tubular secretion. Less than 6% of an administered dose is eliminated in the feces.

Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine. In individuals who are functionally anephric, the half-life is 3.5 to 11 hours, and the plasma clearance is 7 to 14 L/h. To avoid accumulation of the drug in individuals with clinically significant renal impairment, the amount and/or frequency of doses of nizatidine should be reduced in proportion to the severity of dysfunction (see DOSAGE AND ADMINISTRATION ).

Approximately 35% of nizatidine is bound to plasma protein, mainly to α₁-acid glycoprotein. Warfarin, diazepam, acetaminophen, propantheline, phenobarbital, and propranolol did not affect plasma protein binding of nizatidine in vitro.

Clinical Trials – 1. Active Duodenal Ulcer: In multicenter, double-blind, placebo-controlled studies in the United States, endoscopically diagnosed duodenal ulcers healed more rapidly following administration of nizatidine, 300 mg h.s. or 150 mg b.i.d., than with placebo (Table 2). Lower doses, such as 100 mg h.s., had slightly lower effectiveness.

2. Maintenance of Healed Duodenal Ulcer: Treatment with a reduced dose of nizatidine has been shown to be effective as maintenance therapy following healing of active duodenal ulcers. In multicenter, double-blind, placebo-controlled studies conducted in the United States, 150 mg of nizatidine taken at bedtime resulted in a significantly lower incidence of duodenal ulcer recurrence in patients treated for up to 1 year (Table 3).

3. Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind, placebo-controlled clinical trials performed in the United States and Canada, nizatidine was more effective than placebo in improving endoscopically diagnosed esophagitis and in healing erosive and ulcerative esophagitis.

In patients with erosive or ulcerative esophagitis, 150 mg b.i.d. of nizatidine given to 88 patients compared with placebo in 98 patients in Study 1 yielded a higher healing rate at 3 weeks (16% vs 7%) and at 6 weeks (32% vs 16%, P<0.05). Of 99 patients on nizatidine and 94 patients on placebo, Study 2 at the same dosage yielded similar results at 6 weeks (21% vs 11%, P <0.05) and at 12 weeks (29% vs 13%, P<0.01).

In addition, relief of associated heartburn was greater in patients treated with nizatidine. Patients treated with nizatidine consumed fewer antacids than did patients treated with placebo.

4. Active Benign Gastric Ulcer: In a multicenter, double-blind, placebo-controlled study conducted in the United States and Canada, endoscopically diagnosed benign gastric ulcers healed significantly more rapidly following administration of nizatidine than of placebo (Table 4).

* P-values are one-sided, obtained by Chi-square test, and not adjusted for multiple comparisons.

In a multicenter, double-blind, comparator-controlled study in Europe, healing rates for patients receiving nizatidine (300 mg h.s. or 150 mg b.i.d.) were equivalent to rates for patients receiving a comparator drug, and statistically superior to historical placebo control rates.

How Supplied / Storage and Handling

Nizatidine capsules, USP are available as follows:

150 mg - Size #2, two-piece hard-gelatin buff opaque capsules imprinted “3137” on cap and “WPI” on body. Capsules are supplied in bottles of 60 (NDC 0591-3137-60).

300 mg - Size #0, two-piece hard-gelatin light brown opaque capsules imprinted with “3138” on cap and “WPI” on body. Capsules are supplied in bottles of 30 (NDC 0591-3138-30).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].  

Dispense in a tight, light-resistant container as defined in the USP. 

Manufactured In India By:
Watson Pharma Private Limited
Verna, Salcette Goa 403 722 INDIA

Manufactured For:
Teva Pharmaceuticals
Parsippany, NJ 07054

Rev. A 6/2022