Zantac Description

The active ingredient in ZANTAC Injection is ranitidine hydrochloride (HCl), a histamine H2 -receptor antagonist. Chemically it is N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N?-methyl-2-nitro-1,1-ethenediamine, hydrochloride. It has the following structure:

The empirical formula is C13 H22 N4 O3 S?HCl, representing a molecular weight of 350.87.

Ranitidine HCl is a white to pale yellow, granular substance that is soluble in water.

ZANTAC Injection is a clear, colorless to yellow, nonpyrogenic liquid. The yellow color of the liquid tends to intensify without adversely affecting potency. The pH of the injection solution is 6.7 to 7.3.

Each 1 mL of aqueous solution contains ranitidine 25 mg (as the hydrochloride); phenol 5 mg as preservative; and 0.96 mg of monobasic potassium phosphate and 2.4 mg of dibasic sodium phosphate as buffers.

A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous (IV) infusion.

Zantac Indications And Usage

ZANTAC Injection is indicated in some hospitalized patients with pathological hypersecretory conditions or intractable duodenal ulcers, or as an alternative to the oral dosage form for short-term use in patients who are unable to take oral medication.

Zantac Contraindications

ZANTAC Injection is contraindicated for patients known to have hypersensitivity to the drug.

Zantac Precautions

General

• Symptomatic response to therapy with ZANTAC does not preclude the presence of gastric malignancy.
• Since ZANTAC is excreted primarily by the kidney, dosage should be adjusted in patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution should be observed in patients with hepatic dysfunction since ZANTAC is metabolized in the liver.
• In controlled studies in normal volunteers, elevations in SGPT have been observed when H2 -antagonists have been administered intravenously at greater than recommended dosages for 5 days or longer. Therefore, it seems prudent in patients receiving IV ranitidine at dosages ?100 mg q.i.d. for periods of 5 days or longer to monitor SGPT daily (from day 5) for the remainder of IV therapy.
• Bradycardia in association with rapid administration of ZANTAC Injection has been reported rarely, usually in patients with factors predisposing to cardiac rhythm disturbances. Recommended rates of administration should not be exceeded (see DOSAGE AND ADMINISTRATION).
• Rare reports suggest that ZANTAC may precipitate acute porphyric attacks in patients with acute porphyria. ZANTAC should therefore be avoided in patients with a history of acute porphyria.

Laboratory Tests

False-positive tests for urine protein with MULTISTIX® may occur during therapy with ZANTAC, and therefore testing with sulfosalicylic acid is recommended.

Drug Interactions

Although ZANTAC has been reported to bind weakly to cytochrome P-450 in vitro, recommended doses of the drug do not inhibit the action of the cytochrome P-450?linked oxygenase enzymes in the liver. However, there have been isolated reports of drug interactions that suggest that ZANTAC may affect the bioavailability of certain drugs by some mechanism as yet unidentified (e.g., a pH-dependent effect on absorption or a change in volume of distribution).

Increased or decreased prothrombin times have been reported during concurrent use of ranitidine and warfarin. However, in human pharmacokinetic studies with dosages of ranitidine up to 400 mg/day, no interaction occurred; ranitidine had no effect on warfarin clearance or prothrombin time. The possibility of an interaction with warfarin at dosages of ranitidine higher than 400 mg/day has not been investigated.

In a ranitidine-triazolam drug-drug interaction study, triazolam plasma concentrations were higher during b.i.d. dosing of ranitidine than triazolam given alone. The mean area under the triazolam concentration-time curve (AUC) values in 18- to 60-year-old subjects were 10% and 28% higher following administration of 75-mg and 150-mg ranitidine tablets, respectively, than triazolam given alone. In subjects older than 60 years of age, the mean AUC values were approximately 30% higher following administration of 75-mg and 150-mg ranitidine tablets. It appears that there were no changes in pharmacokinetics of triazolam and ?-hydroxytriazolam, a major metabolite, and in their elimination. Reduced gastric acidity due to ranitidine may have resulted in an increase in the availability of triazolam. The clinical significance of this triazolam and ranitidine pharmacokinetic interaction is unknown.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

There was no indication of tumorigenic or carcinogenic effects in life-span studies in mice and rats at oral dosages up to 2,000 mg/kg per day.

Ranitidine was not mutagenic in standard bacterial tests ( Salmonella , Escherichia coli ) for mutagenicity at concentrations up to the maximum recommended for these assays.

In a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats was without effect on the outcome of two matings per week for the next 9 weeks.

Pregnancy

Teratogenic Effects

Pregnancy Category B . Reproduction studies have been performed in rats and rabbits at oral doses up to 160 times the human oral dose and have revealed no evidence of impaired fertility or harm to the fetus due to ZANTAC. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

ZANTAC is secreted in human milk. Caution should be exercised when ZANTAC is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of ZANTAC Injection have been established in the age-group of 1 month to 16 years for the treatment of duodenal ulcer. Use of ZANTAC in this age-group is supported by adequate and well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients, and an analysis of the published literature.

Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory conditions have not been established.

Limited data in neonatal patients (less than one month of age) receiving ECMO suggest that ZANTAC may be useful and safe for increasing gastric pH for patients at risk of gastrointestinal hemorrhage.

Geriatric Use

Clinical studies of ZANTAC Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. However, in clinical studies of oral formulations of ZANTAC, of the total number of subjects enrolled in US and foreign controlled clinical trials, for which there were subgroup analyses, 4,197 were 65 and over, while 899 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients with Impaired Renal Function).

Zantac Overdosage

There has been virtually no experience with overdosage with ZANTAC Injection and limited experience with oral doses of ranitidine. Reported acute ingestions of up to 18 g orally have been associated with transient adverse effects similar to those encountered in normal clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and hypotension have been reported.

When overdosage occurs, clinical monitoring and supportive therapy should be employed.

Studies in dogs receiving dosages of ZANTAC in excess of 225 mg/kg per day have shown muscular tremors, vomiting, and rapid respiration. Single oral doses of 1,000 mg/kg in mice and rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg, respectively.