Axid (Nizatidine)

AXID®

Lilly

Nizatidine

Histamine H2 Receptor Antagonist

Action And Clinical Pharmacology: Nizatidine is a competitive, reversible inhibitor of the histamine H2 receptor of gastric-acid secreting cells. Nizatidine is not an anticholinergic agent. It inhibits nocturnal gastric-acid secretion and gastric-acid secretion stimulated by food, caffeine, betazole and pentagastrin. Pepsin output is reduced in proportion to the reduced volume of gastric secretions. Nizatidine has little or no effect on basal serum gastrin or food induced hypergastrinemia.

In man nizatidine is absorbed rapidly, peak plasma concentrations occur from 0.5 to 3 hours after an oral dose. Absorption is unaffected by food or propantheline; however, antacids consisting of aluminum and magnesium hydroxide with simethicone decrease the absorption of nizatidine by about 10%. The absolute oral bioavailability of nizatidine is 70.9% ± 6.4. Approximately 35% of nizatidine is bound to plasma protein, primarily a1-glycoprotein. This binding is not influenced by other drugs such as warfarin, diazepam, acetaminophen, propranolol, or phenobarbital. Approximately 90% of an oral dose of nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose and 77% of an I.V. dose of nizatidine is excreted as unchanged drug.

The elimination half-life is 1 to 2 hours and the systemic plasma clearance is about 50 L/hour. The volume of distribution is 0.8 to 1.5 L/kg.

Since nizatidine is primarily excreted in the urine, renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine. In anephric individuals with creatinine clearance less than 10 mL/min the half-life is 3.5 to 11 hours, and the plasma clearance is 7 to 14 L/hour. The pharmacokinetic profile for nizatidine in the elderly was not significantly different from the profile in younger normal subjects.

Gastric acid suppression correlates directly with nizatidine doses from 75 to 350 mg. Oral doses of 100 mg or 1.3 mg/kg suppressed gastric acid secretion in sham fed volunteers for 3 hours after the dose. The duration of acid suppression directly correlates with the nizatidine dose. 300 mg nizatidine suppressed acid secretion almost entirely early in the day, and the suppression persisted about 10 hours. Nocturnal acid was suppressed for 10 to 12 hours after 300 mg nizatidine.

Treatment for up to 2 weeks with nizatidine 600 mg daily did not influence the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodothyronine, thyroxin, testosterone, 5a-dihydrotestosterone, androstenedione or estradiol.

Indications And Clinical Uses: In the treatment of conditions where a controlled reduction of gastric acid secretion is required such as, ulcer healing and/or pain relief: acute duodenal ulcer, acute benign gastric ulcer, gastroesophageal reflux disease, and prophylactic use in duodenal ulcer.

Contra-Indications: Patients with known hypersensitivity to the drug. Because cross-sensitivity in this class of compounds has been observed, H2-receptor antagonists, including nizatidine, should not be administered to individuals with a history of previous hypersensitivity to other agents.

Precautions: Gastric ulcer: Where gastric ulcer is suspected the possibility of malignancy should be excluded before therapy with nizatidine is instituted.

Pregnancy: Safety during pregnancy has not been established. Reproduction studies performed in rats and rabbits at doses up to 300 times the human dose have revealed no evidence of impaired fertility or teratogenicity. If the administration of nizatidine is considered to be necessary, its use requires that the potential benefits be weighed against possible hazards to the patient and to the fetus.

Impaired Renal Function: As nizatidine is excreted via the kidney, dosage should be adjusted in patients with moderately or severely impaired renal function (see Dosage).

Hepatic Dysfunction: Nizatidine is partially metabolized in the liver; however, in patients with mild to moderate hepatic dysfunction, disposition of nizatidine is similar to that of normal subjects.

Geriatrics: Ulcer healing rates in elderly patients are similar to those in younger age groups. The incidence rates of adverse events and laboratory test abnormalities are also similar to those seen in other age groups. Age alone is not an important factor in the disposition of nizatidine. However, elderly patients may have reduced renal function (see Dosage).

Children: Safety and effectiveness in children has not been established.

Laboratory Tests: False positive tests for urobilinogen with Multistix may occur during therapy with nizatidine.

Drug Interactions: No interactions have been observed between nizatidine and theophylline, chlordiazepoxide, lorazepam, lidocaine, phenytoin, warfarin, aminophylline, diazepam, metoprolol. Nizatidine does not inhibit the cytochrome P450-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 ASA daily, increases in serum salicylate levels were seen when nizatidine, 150 mg twice daily, was administered concurrently.

Adverse Reactions: Clinical trials of nizatidine included almost 5 000 patients given nizatidine in studies of varying durations. North American placebo-controlled trials included over 1 900 patients given nizatidine and over 1 300 given placebo. Among the more common adverse events in these placebo-controlled trials, sweating (1% vs 0.2%), urticaria (0.5% vs
Hepatic: Hepatocellular injury, evidenced by elevated liver enzyme tests (AST, ALT, or alkaline phosphatase), occurred in some patients possibly or probably related to nizatidine. In some cases there was marked elevation of AST, ALT enzymes (greater than 500 IU/L) and in a single instance ALT 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. Hepatitis and jaundice have been reported. All abnormalities were reversible 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 antiandrogenic activity due to nizatidine. Impotence and decreased libido were reported with equal frequency by patients who received nizatidine and by those given placebo. Rare reports of gynecomastia occurred.

Hematologic: 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 patients. Rash and exfoliative dermatitis were also reported.

Hypersensitivity: As with other H2-receptor antagonists, rare cases of anaphylaxis following administration of nizatidine have been reported. Because cross-sensitivity in this class of compounds has been observed, H2-receptor antagonists should not be administered to individuals with a history of previous hypersensitivity to these agents. Rare episodes of hypersensitivity reactions (e.g., bronchospasm, laryngeal edema, rash, and eosinophilia) have been reported.

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

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is little clinical experience with deliberate 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. Should overdosage occur, use of activated charcoal, emesis, or lavage should be considered along with clinical monitoring and supportive therapy. Renal dialysis does not substantially increase clearance of nizatidine due to its large volume of distribution.

Dosage And Administration: Duodenal or Gastric Ulcer: One 300 mg capsule or two 150 mg capsules once daily at bedtime. Alternatively, 150 mg twice daily may be used. Healing occurs within 4 weeks in most cases of duodenal ulcer; but if healing is not documented or has not occurred, therapy should be given for 8 weeks.

Maintenance Dosage in Duodenal Ulcer: One 150 mg capsule once daily at bedtime for 6 to 12 months depending on the severity of the condition.

Gastroesophageal Reflux Disease: One 150 mg capsule twice daily for the treatment of erosions, ulcerations, and associated heartburn.

Antacids may be given concomitantly if needed.

Dosage Adjustment in Renal Impairment.

SuppliedSupplied: 150 mg: Each pale yellow and dark yellow Pulvule 3144 contains: nizatidine 150 mg. Nonmedicinal ingredients: magnesium stearate, silicone and starch; capsule shell may contain: gelatin, iron oxide yellow and titanium dioxide. Bottles of 100.

300 mg: Each pale yellow and brown Pulvule 3145 contains: nizatidine 300 mg. Nonmedicinal ingredients: carboxymethylcellulose sodium, povidone, silicone, starch and talc; capsule shell may contain: gelatin, iron oxide red, iron oxide yellow and titanium dioxide. Bottles of 100.

AXID® Lilly Nizatidine Histamine H2 Receptor Antagonist

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