RANITIDINE INJECTION USP

This Pharmacy Bulk Package is intended for preparing IV admixtures only.

Not for Direct Infusion.

Rx ONLY

The active ingredient in Ranitidine Injection USP, 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 structural formula:

The molecular formula is C₁₃H₂₂N₄O₃S • HCl, representing a molecular weight of 350.87.

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

Ranitidine Injection USP is a clear, colorless to yellow, sterile, 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 a preservative; 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 spans are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous (IV) infusion (see DOSAGE AND ADMINISTRATION and DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE).

Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H₂- receptors, including receptors on the gastric cells. Ranitidine does not lower serum Ca++ in hypercalcemic states. Ranitidine is not an anticholinergic agent.

Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/mL. Following single IV or IM 50-mg doses, serum concentrations of ranitidine are in this range for 6 to 8 hours.

1. Effects on Acid Secretion: Ranitidine injection inhibits basal gastric acid secretion as well as gastric acid secretion stimulated by betazole and pentagastrin, as shown in Table 2.

In a group of 10 known hypersecretors, ranitidine plasma levels of 71, 180, and 376 ng/mL inhibited basal acid secretion by 76%, 90%, and 99.5%, respectively.

It appears that basal- and betazole-stimulated secretions are most sensitive to inhibition by ranitidine, while pentagastrin-stimulated secretion is more difficult to suppress.

2. Effects on Other Gastrointestinal Secretions:

•  Pepsin: Ranitidine does not affect pepsin secretion. Total pepsin output is reduced in proportion to the decrease in volume of gastric juice.
•  Intrinsic Factor: Ranitidine has no significant effect on pentagastrin-stimulated intrinsic factor secretion.
•  Serum Gastrin: Ranitidine has little or no effect on fasting or postprandial serum gastrin.

• Gastric bacterial flora — increase in nitrate-reducing organisms, significance not known.
• Prolactin levels — no effect in recommended oral or intravenous (IV) dosage, but small, transient, dose-related increases in serum prolactin have been reported after IV bolus injections of 100 mg or more.
• Other pituitary hormones — no effect on serum gonadotropins, TSH, or GH. Possible impairment of vasopressin release.
• No change in cortisol, aldosterone, androgen, or estrogen levels.
• No antiandrogenic action.
• No effect on count, motility, or morphology of sperm.

The ranitidine concentration necessary to suppress basal acid secretion by at least 90% has been reported to be 40 to 60 ng/mL in pediatric patients with duodenal or gastric ulcers.

In a study of 20 critically ill pediatric patients receiving ranitidine IV at 1 mg/kg every 6 hours, 10 patients with a baseline pH≥4 maintained this baseline throughout the study. Eight of the remaining 10 patients with a baseline of pH≤2 achieved pH≥4 throughout varying periods after dosing. It should be noted, however, that because these pharmacodynamic parameters were assessed in critically ill pediatric patients, the data should be interpreted with caution when dosing recommendations are made for a less seriously ill pediatric population.

In another small study of neonatal patients (n=5) receiving ECMO, gastric pH<4 pretreatment increased to >4 after a 2 mg/kg dose and remained above 4 for at least 15 hours.

Ranitidine 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.

Ranitidine injection is contraindicated for patients known to have hypersensitivity to the drug.

• Symptomatic response to therapy with ranitidine does not preclude the presence of gastric malignancy.
• Since ranitidine 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 ranitidine 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 ranitidine 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 ranitidine may precipitate acute porphyric attacks in patients with acute porphyria. Ranitidine should therefore be avoided in patients with a history of acute porphyria.

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

Although ranitidine 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 ranitidine 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 α-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.

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.

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

The safety and effectiveness of ranitidine injection have been established in the age-group of 1 month to 16 years for the treatment of duodenal ulcer. Use of ranitidine 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 ranitidine may be useful and safe for increasing gastric pH for patients at risk of gastrointestinal hemorrhage.

Clinical studies of ranitidine 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 ranitidine, 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: Geriatrics and DOSAGE AND ADMINISTRATION:Dosage Adjustment for Patients with Impaired Renal Function).

Transient pain at the site of IM injection has been reported. Transient local burning or itching has been reported with IV administration of ranitidine.

The following have been reported as events in clinical trials or in the routine management of patients treated with oral or parenteral ranitidine. The relationship to therapy with rantitidine has been unclear in many cases. Headache, sometimes severe, seems to be related to administration of ranitidine.

Rarely, malaise, dizziness, somnolence, insomnia, and vertigo. Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been reported, predominantly in severely ill elderly patients. Rare cases of reversible blurred vision suggestive of a change in accommodation have been reported. Rare reports of reversible involuntary motor disturbances have been received.

As with other H₂-blockers, rare reports of arrhythmias such as tachycardia, bradycardia, asystole, atrioventricular block, and premature ventricular beats.

Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and rare reports of pancreatitis.

In normal volunteers, SGPT values were increased to at least twice the pretreatment levels in 6 of 12 subjects receiving 100 mg q.i.d. intravenously for 7 days, and in 4 of 24 subjects receiving 50 mg q.i.d. intravenously for 5 days. There have been occasional reports of hepatocellular, cholestatic, or mixed hepatitis, with or without jaundice. In such circumstances, ranitidine should be immediately discontinued. These events are usually reversible, but in rare circumstances death has occurred. Rare cases of hepatic failure have also been reported.

Rare reports of arthralgias and myalgias.

Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia) have occurred in a few patients. These were usually reversible. Rare cases of agranulocytosis, pancytopenia, sometimes with marrow hypoplasia, and aplastic anemia and exceedingly rare cases of acquired immune hemolytic anemia have been reported.

Controlled studies in animals and humans have shown no stimulation of any pituitary hormone by ranitidine and no antiandrogenic activity, and cimetidine-induced gynecomastia and impotence in hypersecretory patients have resolved when ranitidine has been substituted. However, occasional cases of gynecomastia, impotence, and loss of libido have been reported in male patients receiving ranitidine, but the incidence did not differ from that in the general population.

Rash, including rare cases of erythema multiforme. Rare cases of alopecia and vasculitis.

A large epidemiological study suggested an increased risk of developing pneumonia in current users of histamine-2-receptor antagonists (H₂RAs) compared to patients who had stopped H₂RA treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07 to 2.48). However, a causal relationship between use of H₂RAs and pneumonia has not been established.

Rare cases of hypersensitivity reactions (e.g., bronchospasm, fever, rash, eosinophilia), anaphylaxis, angioneurotic edema, and small increases in serum creatinine.

There has been virtually no experience with overdosage with ranitidine 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 ranitidine 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.

In some hospitalized patients with pathological hypersecretory conditions or intractable duodenal ulcers, or in patients who are unable to take oral medication, ranitidine injection may be administered parenterally according to the following recommendations:

While limited data exist on the administration of IV ranitidine to children, the recommended dose in pediatric patients is for a total daily dose of 2 to 4 mg/kg, to be divided and administered every 6 to 8 hours, up to a maximum of 50 mg given every 6 to 8 hours. This recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric patients. Limited data in neonatal patients (less than one month of age) receiving ECMO have shown that a dose of 2 mg/kg is usually sufficient to increase gastric pH to >4 for at least 15 hours. Therefore, doses of 2 mg/kg given every 12 to 24 hours or as a continuous infusion should be considered.

The administration of ranitidine as a continuous infusion has not been evaluated in patients with impaired renal function. On the basis of experience with a group of subjects with severely impaired renal function treated with ranitidine, the recommended dosage in patients with a creatinine clearance <50 mL/min is 50 mg every 18 to 24 hours. Should the patient’s condition require, the frequency of dosing may be increased to every 12 hours or even further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.

Elderly patients are more likely to have decreased renal function, therefore caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatrics and PRECAUTIONS: Geriatric Use).

Undiluted, ranitidine injection tends to exhibit a yellow color that may intensify over time without adversely affecting potency. Ranitidine injection is stable for 48 hours at room temperature when added to or diluted with most commonly used IV solutions, e.g., 0.9% sodium chloride injection, 5% dextrose injection, 10% dextrose injection, lactated ringer’s injection, or 5% sodium bicarbonate injection.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

This Pharmacy Bulk Package is intended for use in a Pharmacy Admixture Service. Under a laminar flow hood, dispense aliquots from vial into infusion fluids using a suitable sterile dispensing device. Use of a syringe with needle is not recommended.

The withdrawal of container spans should be accomplished without delay. However, should this not be possible, a maximum of 24 hours from initial closure entry is permitted to complete fluid transfer operations.

Discard unused solution from bulk package no later than 24 hours after initial entry.

Ranitidine Injection USP, 25 mg/mL, containing phenol 0.5% as preservative, is available as 1000 mg, in a 40 mL pharmacy bulk package, individually boxed, NDC 55390-618-01.

Manufactured by                                          Manufactured for
Ben Venue Laboratories, Inc.                      Bedford Laboratories™
Bedford, OH 44146                                      Bedford, OH 44146

September 2006                                            RNP-PB-P01