RANITIDINE

RANITIDINE- ranitidine hydrochloride tablet
Wockhardt USA LLC.

DESCRIPTION

Ranitidine hydrochloride, USP is 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. The molecular formula is C₁₃ H₂₂ N₄ O₃ S•HCl, representing a molecular weight of 350.87.

Ranitidine HCl is a white to pale yellow, crystalline substance that is very soluble in water. It has a slightly bitter taste and sulfurlike odor. The structural formula is:

Each Ranitidine Tablet, USP 150 mg for oral administration contains 168 mg of ranitidine hydrochloride equivalent to 150 mg of ranitidine. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, castor oil, titanium dioxide and talc.

Each Ranitidine Tablet, USP 300 mg for oral administration contains 336 mg of ranitidine hydrochloride equivalent to 300 mg of ranitidine. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, castor oil, titanium dioxide and talc.

CLINICAL PHARMACOLOGY

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.

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. 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 halflife of 4.8 hour, 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 (t1/2, Vd, and CL) are similar to those observed with intravenous ranitidine use in pediatric patients. Estimates of Cmax and Tmax are displayed in Table 1.

Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following Oral Dosing
Population (age)	n	Dosage Form (dose)	Cmax (ng/mL)	Tmax (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	Syrup (2 mg/kg)	244	1.61
Otherwise healthy requiring Ranitidine (0.7 to 14 years, Multiple dose)	10	Syrup (2 mg/kg)	320	1.66

Plasma clearance measured in two 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 Seretion: 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 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
Pentagastin	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 :

1. Gastric bacterial flora — increase in nitrate-reducing organisms, significance not known.
2. 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.
3. Other pituitary hormones — no effect on serum gonadotropins, TSH, or GH. Possible impairment of vasopressin release.
4. No change in cortisol, aldosterone, androgen, or estrogen levels.
5. No antiandrogenic action.
6. No effect on count, motility, or morphology of sperm.

Pediatrics: Oral doses of 6 to 10 mg/kg/day in two or three 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.

*All patients were permitted antacids as needed for relief of pain.
†p <0.0001.
Table 3. Duodenal Ulcer Patient Healing Rates
	Ranitidine*		Placebo*
	Number Entered	Healed / Evaluable	Number Entered	Healed / Evaluable
Outpatients		69/182 (38%) †		31/164 (19%)
Week 2	195		188
Week 4		137/187 (73%) †		76/168 (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 bed time (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 bed time (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.

Maintenance Therapy in Duodenal Uicer: Ranitidine has been found to be effective as maintenance therapy for patients following healing of acute duodenal ulcers. In two independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with ranitidine (150 mg at bed time) than in patients treated with placebo over a 12-month period.

% = Life table estimate.
* = p <0.05 (ranitidine versus comparator).
RAN = ranitidine.
PLC = placebo.
Table 5. Duodenal Ulcer Prevalence
Double-Blind, Multicenter, Placebo-Controlled Trials
Multicenter Trial	Drug	Duodenal Ulcer Prevalence			No. Of Patients
		0-4 Months	0-8 Months	0-12 Months
USA	RAN	20%*	24%*	35%*	138
	PLC	44%	54%	59%	139
Foreign	RAN	12%*	21%*	28%*	174
	PLC	56%	64%	68%	165

As with other H2-antagonists, the factors responsible for the significant reduction in the prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of ulcers that may occur during maintenance therapy, or both.

Gastric Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically diagnosed gastric ulcers, earlier healing was seen in the patients treated with ranitidine as shown in Table 6.

*All patients were permitted antacids as needed for relief of pain.
†p =0.009.
Table 6. Gastric Ulcer Patient Healing Rates
	Ranitidine*		Placebo*
	Number Entered	Healed / Evaluable	Number Entered	Healed / Evaluable
Outpatients		16/83 (19%)		10/83 (12%)
Week 2	92		94
Week 6		50/73 (68%) †		35/69 (51%)

In this multicenter trial, significantly more patients treated with ranitidine became pain-free during therapy.

Maintenance of Helaing of Gastric Ulcers: In two multicenter, double-blind, randomized, placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been previously healed, ranitidine 150 mg at bed time was significantly more effective than placebo in maintaining healing of gastric ulcers.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome): Ranitidine inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome, systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative, “short-gut” syndrome, idiopathic). Use of ranitidine was followed by healing of ulcers in 8 of 19 (42%) patients who were intractable to previous therapy.

Gastroesophageal Reflux Disease (GERD): In two multicenter, double-blind, placebo-controlled, 6-week trials performed in the United States and Europe, ranitidine 150 mg twice daily was more effective than placebo for the relief of heartburn and other symptoms associated with GERD. Ranitidine-treated patients consumed significantly less antacid than did placebotreated patients.

The US trial indicated that ranitidine 150 mg twice daily significantly reduced the frequency of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The improvement was maintained throughout the 6-week trial period. Moreover, patient response rates demonstrated that the effect on heartburn extends through both the day and night time periods.

In 2 additional US multicenter, double-blind, placebo-controlled, 2-week trials, ranitidine 150 mg twice daily was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency and severity of heartburn.

Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, ranitidine 150 mg 4 times daily was significantly more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving associated heartburn. The erosive esophagitis healing rates were as follows:

*All patients were permitted antacids as needed for relief of pain.
†p <0.001 versus placebo.
Table 7. Erosive Esophagitis Patient Healing Rates
	Healed / Evaluable
	Placebo* n=229	Ranitidine HCl 150 mg 4 times daily* n=215
Week 4	43/198 (22%)	96/206 (47%) †
Week 8	63/176 (36%)	142/200 (71%) †
Week 12	92/159 (58%)	162/192 (84%) †

No additional benefit in healing of esophagitis or in relief of heartburn was seen with a ranitidine dose of 300 mg 4 times daily.

Maintenance of Healing of Erosive Esophagitis: In two multicenter, double-blind, randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis had been previously healed, ranitidine 150 mg twice daily was significantly more effective than placebo in maintaining healing of erosive esophagitis.