Ranitidine: Package Insert and Label Information

RANITIDINE- ranitidine syrup
Pharmaceutical Associates, Inc.

Rx ONLY

DESCRIPTION

The active ingredient in Ranitidine Syrup (Ranitidine Oral Solution USP) is ranitidine hydrochloride (HCl) USP, a histamine H ₂ -receptor antagonist. Chemically, it is N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N’ -methyl-2-nitro-1,1-ethenediamine, HCl. It has the following structure:

The empirical formula is C ₁₃ H ₂₂ N ₄ O ₃ S•HCl, representing a molecular weight of 350.87.

Ranitidine HCl is a white to pale yellow, granular substance that is soluble in water. It has a slightly bitter taste and sulfurlike odor.

Each 1 mL of Ranitidine Syrup (Ranitidine Oral Solution USP) contains 16.8 mg of ranitidine HCl equivalent to 15 mg of ranitidine. Ranitidine Syrup (Ranitidine Oral Solution USP) also contains the inactive ingredients dibasic sodium phosphate, hydroxyethylcellulose, methylparaben, purified water, sodium chloride, sodium saccharin, spearmint flavor, sucrose and may contain monobasic sodium phosphate.

CLINICAL PHARMACOLOGY

Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H ₂ -receptors, including receptors on the gastric cells. Ranitidine does not lower serum Ca++ in hypercalcemic states. Ranitidine is not an anticholinergic agent.

Pharmacokinetics

Absorption

Ranitidine is 50% absorbed after oral administration, compared to an intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours after a 150-mg dose. The oral solution is bioequivalent to the tablets. Absorption is not significantly impaired by the administration of food or antacids. Propantheline slightly delays and increases peak blood levels of ranitidine, probably by delaying gastric emptying and transit time. In one study, simultaneous administration of high-potency antacid (150 mmol) in fasting subjects has been reported to decrease the absorption of ranitidine.

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

The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 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 to 4 hours. Peak levels average 526 ng/mL following a 150-mg twice daily dose and occur in about 3 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 average bioavailability of ranitidine given orally to pediatric patients is 48% which is comparable to the bioavailability of ranitidine in the adult population. All other pharmacokinetic parameter values (t _1/2 , Vd, and CL) are similar to those observed with intravenous ranitidine use in pediatric patients. Estimates of C _max and T _max are displayed in Table 1.

Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following Oral Dosing

Population (age)	n	Dosage Form (dose)	C max (ng/mL)	T max (hours)
Gastric or duodenal ulcer (3.5 to 16 years)	12	Tablets (1 to 2 mg/kg)	54 to 492	2.0
Otherwise healthy requiring Ranitidine (0.7 to 14 years, Single dose)	10	Oral Solution (2 mg/kg)	244	1.61
Otherwise healthy requiring Ranitidine (0.7 to 14 years, Multiple dose)	10	Oral Solution (2 mg/kg)	320	1.66

Plasma clearance measured in 2 neonatal patients (less than 1 month of age) was considerably lower (3 mL/min/kg) than children or adults and is likely due to reduced renal function observed in this population (see PRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION: Pediatric Use).

Pharmacodynamics

Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum concentrations of ranitidine are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition.

Antisecretory Activity

1. Effects on Acid Secretion

Ranitidine inhibits both daytime and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food, betazole, and pentagastrin, as shown in Table 2.

Table 2. Effect of Oral Ranitidine Syrup (Ranitidine Oral Solution USP) on Gastric Acid Secretion

	Time After Dose, hours	% Inhibition of Gastric Acid Output by Dose, mg
		75-80	100	150	200
Basal	Up to 4		99	95
Nocturnal	Up to 13	95	96	92
Betazole	Up to 3		97	99
Pentagastrin	Up to 5	58	72	72	80
Meal	Up to 3		73	79	95

It appears that basal-, nocturnal-, and betazole-stimulated secretions are most sensitive to inhibition by ranitidine, responding almost completely to doses of 100 mg or less, while pentagastrin- and food-stimulated secretions are more difficult to suppress.

2. Effects on Other Gastrointestinal Secretions

Pepsin

Oral ranitidine does not affect pepsin secretion. Total pepsin output is reduced in proportion to the decrease in volume of gastric juice.

Intrinsic Factor

Oral 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.

Other Pharmacologic Actions

• Gastric bacterial flora—increase in nitrate-reducing organisms, significance not known.
• Prolactin levels—no effect in recommended oral or 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.

Pediatrics

Oral doses of 6 to 10 mg/kg/day in 2 or 3 divided doses maintain gastric pH>4 throughout most of the dosing interval.

Clinical Trials

Active Duodenal Ulcer

In a multicenter, double-blind, controlled, US study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients treated with ranitidine as shown in Table 3.

Table 3. Duodenal Ulcer Patient Healing Rates

	Ranitidine *		Placebo *
	Number Entered	Healed/ Evaluable	Number Entered	Healed/ Evaluable
* All patients were permitted antacids as needed for relief of pain. † P<0.0001.
Outpatients
Week 2		69/182		31/164
	195	(38%) †	188	(19%)
Week 4		137/187		76/168
		(73%) †		(45%)

In these studies, patients treated with ranitidine reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.

Table 4. Mean Daily Doses of Antacid

	Ulcer Healed	Ulcer Not Healed
Ranitidine	0.06	0.71
Placebo	0.71	1.43

Foreign studies have shown that patients heal equally well with 150 mg twice daily and 300 mg at bedtime (85% versus 84%, respectively) during a usual 4-week course of therapy. If patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg twice daily as compared to 300 mg at bedtime (92% versus 87%, respectively).

Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose ulcers healed during therapy had recurrences of ulcers at the usual rates.