Ranitidine Hydrochloride

RANITIDINE HYDROCHLORIDE — ranitidine hydrochloride injection, solution
Zydus Pharmaceuticals (USA) Inc.

DESCRIPTION

The active ingredient in ranitidine 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:

formula
(click image for full-size original)

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

Ranitidine hydrochloride USP is a white to pale yellow, crystalline powder that is very soluble in water.

Ranitidine injection USP 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.

CLINICAL PHARMACOLOGY

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

Pharmacokinetics

Absorption

Ranitidine hydrochloride is absorbed very rapidly after intramuscular (IM) injection. Mean peak levels of 576 ng/mL occur within 15 minutes or less following a 50 mg intramuscular dose. Absorption from intramuscular sites is virtually complete, with a bioavailability of 90% to 100% compared with intravenous (IV) administration. Following oral administration, the bioavailability of ranitidine tablets is 50%.

Distribution

The volume of distribution is about 1.4 L/kg. Serum protein binding averages 15%.

Metabolism

In humans, the N-oxide is the principal metabolite in the urine; however, this amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl ranitidine (1%). The remainder of the administered dose is found in the stool. Studies in patients with hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically insignificant, alterations in ranitidine half-life, distribution, clearance, and bioavailability.

Excretion

Following intravenous injection, approximately 70% of the dose is recovered in the urine as unchanged drug. Renal clearance averages 530 mL/min, with a total clearance of 760 mL/min. The elimination half-life is 2.0 to 2.5 hours.

Four patients with clinically significant renal function impairment (creatinine clearance 25 to 35 mL/min) administered 50 mg of ranitidine intravenously had an average plasma half-life of 4.8 hours, a ranitidine clearance of 29 mL/min, and a volume of distribution of 1.76 L/kg. In general, these parameters appear to be altered in proportion to creatinine clearance (see DOSAGE AND ADMINISTRATION).

Geriatrics

The plasma half-life is prolonged and total clearance is reduced in the elderly population due to a decrease in renal function. The elimination half-life is 3.1 hours (see PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients With Impaired Renal Function).

Pediatrics

There are no significant differences in the pharmacokinetic parameter values for ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when correction is made for body weight. The pharmacokinetics of ranitidine hydrochloride in pediatric patients are summarized in Table 1.

Table 1 Ranitidine Pharmacokinetics in Pediatric Patients Following Intravenous Dosing

T½ = Terminal half-life; CLp = Plasma clearance of ranitidine.

ECMO = extracorporeal membrane oxygenation.

Population (age) n Dose (mg/kg) t½ (hours) Vd (L/kg) CLp (mL/min/kg)
Peptic ulcer disease (<6 years) (6 to 11.9 years) (>12 years) Adults 6 11 6 6 1.25 or 2.5 1.25 or 2.5 1.25 or 2.5 2.5 2.2 2.1 1.7 1.9 1.29 1.14 0.98 1.04 11.41 8.96 9.89 8.77
Peptic ulcer disease (3.5–16 years) 12 0.13 to 0.80 1.8 2.3 795 mL/min/1.73/m2
Children in intensive care (1 day–12.6 years) 17 1.0 2.4 2 11.7
Neonates receiving ECMO 12 2 6.6 1.8 4.3

Plasma clearance in neonatal patients (less than 1 month of age) receiving ECMO was considerably lower (3 to 4 mL/min/kg) than observed in children or adults. The elimination half-life in neonates averaged 6.6 hours as compared to approximately 2 hours in adults and pediatric patients.

Pharmacodynamics

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

Antisecretory Activity

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.

Table 2 Effect of Intravenous Ranitidine Hydrochloride on Gastric Acid Secretion
Time After Dose, hours % Inhibition of Gastric Acid Output by Intravenous Dose, mg
20 mg 60 mg 100 mg
Betazole Up to 2 93 99 99
Pentagastrin Up to 3 47 66 77

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 hydrochloride, while pentagastrin-stimulated secretion is more difficult to suppress.

2. Effects on Other Gastrointestinal Secretions

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