Nizatidine

INDICATIONS AND USAGE Nizatidine capsules are indicated for up to 8 weeks for the treatment of active duodenal ulcer. In most patients, the ulcer will heal within 4 weeks. Nizatidine capsules are 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 capsules are 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 capsules are 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: Active Duodenal Ulcer, GERD, and Benign Gastric Ulcer C cr Dose 20-50 mL/min 150 mg daily less than 20 mL/min 150 mg every other day Maintenance Therapy C cr Dose 20-50 mL/min 150 mg every other day less than 20 mL/min 150 mg every 3 days 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.

CONTRAINDICATION Nizatidine capsules are contraindicated in patients with known hypersensitivity to the drug. Because cross sensitivity in this class of compounds has been observed, H 2 -receptor antagonists, including nizatidine, should not be administered to patients with a history of hypersensitivity to other H 2 -receptor antagonists.

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. Table 5. Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled Clinical Trials In The United States and Canada Percentage of Patients Reporting Event Body System/Adverse Event * Nizatidine (N=2,694) Placebo (N=1,729) Body as a Whole Headache 16.6 15.6 Abdominal pain 7.5 12.5 Pain 4.2 3.8 Asthenia 3.1 2.9 Back pain 2.4 2.6 Chest pain 2.3 2.1 Infection 1.7 1.1 Fever 1.6 2.3 Surgical procedure 1.4 1.5 Injury, accident 1.2 0.9 Digestive Diarrhea 7.2 6.9 Nausea 5.4 7.4 Flatulence 4.9 5.4 Vomiting 3.6 5.6 Dyspepsia 3.6 4.4 Constipation 2.5 3.8 Dry mouth 1.4 1.3 Nausea and vomiting 1.2 1.9 Anorexia 1.2 1.6 Gastrointestinal disorder 1.1 1.2 Tooth disorder 1.0 0.8 Musculoskeletal Myalgia 1.7 1.5 Nervous Dizziness 4.6 3.8 Insomnia 2.7 3.4 Abnormal dreams 1.9 1.9 Somnolence 1.9 1.6 Anxiety 1.6 1.4 Nervousness 1.1 0.8 Respiratory Rhinitis 9.8 9.6 Pharyngitis 3.3 3.1 Sinusitis 2.4 2.1 Cough, increased 2.0 2.0 Skin and Appendages Rash 1.9 2.1 Pruritus 1.7 1.3 Special Senses Amblyopia 1.0 0.9 * Events reported by at least 1% of nizatidine-treated patients are included. 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 H 2 -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- …

Drug Interactions No interactions have been observed between nizatidine and theophylline, chlordiazepoxide, lorazepam, lidocaine, phenytoin, and warfarin. Nizatidine does not inhibit the cytochrome P-450-linked drug-metabolizing enzyme system; therefore, drug interactions mediated by inhibition of hepatic metabolism are not expected to occur. In patients given very high doses (3,900 mg) of aspirin daily, increases in serum salicylate levels were seen when nizatidine, 150 mg b.i.d., was administered concurrently.

DESCRIPTION Nizatidine, USP is a histamine H 2 -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 as follows: Nizatidine, USP has the empirical formula C 12 H 21 N 5 O 2 S 2 representing a molecular weight of 331.46. It is an off white to buff crystalline solid that is soluble in water. Nizatidine has a bitter taste and mild sulfur-like odor. Each capsule for oral administration contains nizatidine, USP, 150 mg (0.45 mmol) or 300 mg (0.91 mmol), croscarmellose sodium, corn starch, dimethicone, partially pregelatinized starch (Corn), povidone, talc. Ingredients for 150 mg capsule shell: gelatin, iron oxide yellow, titanium dioxide. Ingredients for 300 mg capsule shell: D&C red 28, FD&C blue 1, FD&C yellow 6, gelatin, titanium dioxide. Ingredients for 150 mg capsule shell: gelatin, iron oxide yellow, titanium dioxide. Ingredients for 300 mg capsule shell: D&C red 28, FD&C blue 1, FD&C yellow 6, gelatin, titanium dioxide. Ingredients for the ink used in capsule printing are ammonia solution concentrated, butyl alcohol, black iron oxide, dehydrated alcohol, isopropyl alcohol, propylene glycol, potassium hydroxide, shellac. Structure

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.

HOW SUPPLIED Nizatidine capsules, USP 150 mg are off white to buff colored granular powder filled in size '2' hard gelatin capsules with pink opaque cap and yellow opaque body, imprinted "RDY" on cap and "310" on body, with black ink and are supplied in bottles of 30's, 60's, 100's, 500's and unit dose package of 100 (10 × 10). Bottles of 30 NDC 55111-310-30 Bottles of 60 NDC 55111-310-60 Bottles of 100 NDC 55111-310-01 Bottles of 500 NDC 55111-310-05 Unit dose package of 100 (10 × 10 NDC 55111-310-78 Nizatidine capsules, USP 300 mg are off white to buff colored granular powder filled in size '1' hard gelatin capsules with opaque pink cap and white opaque body, imprinted "RDY" on cap and "311" on body, with black ink and are supplied in bottles of 30's, 60's, 100's, 500's and unit dose package of 100 (10 × 10). Bottles of 30 NDC 55111-311-30 Bottles of 60 NDC 55111-311-60 Bottles of 100 NDC 55111-311-01 Bottles of 500 NDC 55111-311-05 Unit dose package of 100 (10 × 10) NDC 55111-311-78 Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature] in a tightly closed light resistant container. The USP defines controlled room temperature as: A temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.