Ranitidine Immediate Release (Page 2 of 5)

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 on Gastric Acid Secretion

Basal	Time After Dose (hours)	% Inhibition of Gastric Acid Output by Dose
		75 to 80 mg	100 mg	150 mg	200 mg
	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:

1. Gastric bacterial flora—increase in nitrate-reducing organisms, significance not known.
2. 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.
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 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 trial 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

Outpatients	Ranitidine a		Placebo a
	Number Entered	Healed/ Evaluable	Number Entered	Healed/ Evaluable
	195	69/182 (38%) b	188	31/164 (19%)
				Week 2
		Week 4	137/187 (73%) b	76/168 (45%)

^a All patients were permitted antacids as needed for relief of pain.
^b P<0.0001.
In these trials, 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 trials 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 with 300 mg at bedtime (92% versus 87%, respectively).
Trials 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 Ulcer: Ranitidine has been found to be effective as maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with ranitidine (150 mg at bedtime) than in patients treated with placebo over a 12-month period.

Table 5. Duodenal Ulcer Prevalence

Double-Blind, Multicenter, Placebo-Controlled Trials
Multicenter Trial	Drug	Duodenal Ulcer Prevalence			No. of Patients
		0 to 4 Months	0 to 8 Months	0 to 12 Months
USA	RAN	20% a	24%	35% a	138
	PLC	44%	54%	59%	139
Foreign	RAN	12% a	21% a	28% a	174
	PLC	56%	64%	68%	165

% = Life table estimate.
^a = P<0.05 (ranitidine tablets, USP versus comparator).
RAN = ranitidine.
PLC = placebo.
As with other H ₂ -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 trial of endoscopically diagnosed gastric ulcers, earlier healing was seen in the patients treated with ranitidine as shown in Table 6.

Table 6. Gastric Ulcer Patient Healing Rates

Outpatients	Ranitidine a		Placebo a
	Number Entered	Healed/ Evaluable	Number Entered	Healed/ Evaluable
Week 2	92	16/83 (19%)	94	10/83 (12%)
Week 6		50/73 (68%) b		35/69 (51%)

^a All patients were permitted antacids as needed for relief of pain.
^b P = 0.009.
In this multicenter trial, significantly more patients treated with ranitidine became pain free during therapy.
Maintenance of Healing of Gastric Ulcers: In 2 multicenter, double-blind, randomized, placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been previously healed, ranitidine 150 mg at bedtime 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 2 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 placebo-treated 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 of 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:

Table 7. Erosive Esophagitis Patient Healing Rates

	Healed/Evaluable
	Placebo a n = 229	Ranitidine 150 mg 4 times daily a n = 215
Week 4	43/198 (22%)	96/206 (47%) b
Week 8	63/176 (36%)	142/200 (71%) b
Week 12	92/159 (58%)	162/192 (84%) b

^a All patients were permitted antacids as needed for relief of pain.
^b P<0.001 versus placebo.
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 2 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.