Cimetidine Hydrochloride Oral Solution

CIMETIDINE HYDROCHLORIDE ORAL SOLUTION- cimetidine hydrochloride solution
Hi-Tech Pharmacal Co., Inc.

Rx Only

Rev. 050:03 07/16

DESCRIPTION

Cimetidine is a histamine H2 -receptor antagonist. Chemically it is N”- cyano-N-methyl-N’ -[2-[[(5- methyl-1 H -imidazol-4-yl) methyl]thio]-ethyl], guanidine.

The molecular formula for cimetidine hydrochloride is C10 H16 N6 S•HCI and the molecular weight is 288.80 the structural formula of cimetidine hydrochloride is:

chemical structure
(click image for full-size original)

Cimetidine contains an imidazole ring, and is chemically related to histamine.

Cimetidine has a bitter taste and characteristic odor.

Solubility Characteristics

Cimetidine hydrochloride is freely soluble in water, soluble in alcohol, very slightly soluble in chloroform and practically insoluble in ether.

Each 5 mL (1 teaspoonful), for oral administration, contains cimetidine hydrochloride equivalent to cimetidine, 300 mg; alcohol, 2.8%. In addition, the oral solution contains the following inactive ingredients: FD&C Yellow No. 6, hydrochloric acid, methylparaben, natural orange flavor, polyoxyethylene, polyoxypropylene glycol, propylene glycol, propylparaben, purified water, saccharin sodium, sodium chloride, dibasic sodium phosphate anhydrous, and sorbitol. The pH range is 5.1 to 5.7.

CLINICAL PHARMACOLOGY

Cimetidine competitively inhibits the action of histamine at the histamine H2 receptors of the parietal cells and thus is a histamine H2 receptor antagonist.

Cimetidine is not an anticholinergic agent. Studies have shown that cimetidine inhibits both daytime and nocturnal basal gastric acid secretion. Cimetidine also inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine and insulin.

Antisecretory Activity

1) Acid Secretion: Nocturnal: Cimetidine 800 mg orally at bedtime reduces mean hourly H+ activity by greater than 85% over an eight-hour period in duodenal ulcer patients, with no effect on daytime acid secretion. Cimetidine 1600 mg orally h.s. produces 100% inhibition of mean hourly H+ activity over an eight-hour period in duodenal ulcer patients, but also reduces H+ activity by 35% for an additional five hours into the following morning. Cimetidine 400 mg b.i.d. and 300 mg q.i.d. decrease nocturnal acid secretion in a dose-related manner, i.e., 47% to 83% over a six-to eight-hour period and 54% over a nine-hour period, respectively.

Food Stimulated: During the first hour after a standard experimental meal, oral cimetidine 300 mg inhibited gastric acid secretion in duodenal ulcer patients by at least 50%. During the subsequent two hours cimetidine inhibited gastric acid secretion by at least 75%.

The effect of a 300 mg breakfast dose of cimetidine continued for at least four hours and there was partial suppression of the rise in gastric acid secretion following the luncheon meal in duodenal ulcer patients. This suppression of gastric acid output was enhanced and could be maintained by another 300 mg dose of cimetidine given with lunch.

In another study, cimetidine 300 mg was given with the meal increased gastric pH as compared with placebo.

Mean Gastric pH

Cimetidine

Placebo

1 hour

3.5

2.6

2 hours

3.1

1.6

3 hours

3.8

1.9

4 hours

6.1

2.2

24-Hour Mean H+ Activity: Cimetidine 800 mg h.s., 400 mg b.i.d. and 300 mg q.i.d. all provide a similar, moderate (less than 60%) level of 24-hour acid suppression. However, the 800 mg h.s. regimen exerts its entire effect on nocturnal acid, and does not affect daytime gastric physiology.

Chemically Stimulated: Oral cimetidine significantly inhibited gastric acid secretion stimulated by betazole (an isomer of histamine), pentagastrin, caffeine and insulin as follows:

Table1
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When food and betazole were used to stimulate secretion, inhibition of hydrogen ion concentration usually ranged from 45 to 75% and the inhibition of volume ranged from 30 to 65%.

2) Pepsin: Oral cimetidine 300 mg reduced total pepsin output as a result of the decrease in volume of gastric juice.

3) Intrinsic Factor: Intrinsic factor secretion was studied with betazole as a stimulant. Oral cimetidine 300 mg inhibited the rise in intrinsic factor concentration produced by betazole, but some intrinsic factor was secreted at all times.

Other

Lower Esophageal Sphincter Pressure and Gastric Emptying

Cimetidine has no effect on lower esophageal sphincter (LES) pressure or the rate of gastric emptying.

Pharmacokinetics

Cimetidine is rapidly absorbed after oral administration and peak levels occur in 45 to 90 minutes. The half-life of cimetidine is approximately 2 hours. Both oral and parenteral (I.V. or I.M.) administration provide comparable periods of therapeutically effective blood levels; blood concentrations remain above that required to provide 80% inhibition of basal gastric acid secretion for 4 to 5 hours following a dose of 300 mg.

The principal route of excretion of cimetidine is the urine. Following parenteral administration, most of the drug is excreted as the parent compound; following oral administration, the drug is more extensively metabolized, the sulfoxide being the major metabolite. Following a single oral dose, 48% of the drug is recovered from the urine after 24 hours as the parent compound. Following I.V. or I.M. administration, approximately 75% of the drug is recovered from the urine after 24 hours as the parent compound.

Clinical Trials

Duodenal Ulcer

Cimetidine has been shown to be effective in the treatment of active duodenal ulcer and, at reduced dosage, in maintenance therapy following healing of active ulcers.

Active Duodenal Ulcer: Cimetidine accelerates the rate of duodenal ulcer healing. Healing rates reported foreign controlled trials with oral cimetidine are summarized below, beginning with the regimen providing the lowest nocturnal dose.

Table 2
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A U.S., double-blind, placebo-controlled, dose-ranging study demonstrated that all once-daily at bedtime (h.s.) cimetidine regimens were superior to placebo in ulcer healing and that cimetidine 800 mg h.s. healed 75% of patients at four weeks. The healing rate with 800 mg h.s. was significantly superior to 400 mg h.s. (66%) and not significantly different from 1600 mg h.s. (81%).

In the U.S. dose-ranging trial, over 80% of patients receiving cimetidine 800 mg h.s. experienced nocturnal pain relief after one day. Relief from daytime pain was reported in approximately 70% of patients after two days. As with ulcer healing, the 800 mg h.s. dose was superior to 400 mg h.s. and not different from 1600 mg h.s.

In foreign, double-blind studies with cimetidine 800 mg h.s. 79 to 85% of patients were healed at four weeks. While short-term treatment with cimetidine can result in complete healing of the duodenal ulcer, acute therapy will not prevent ulcer recurrence after cimetidine has been discontinued. Some follow-up studies have reported that the rate of recurrence once therapy was discontinued was slightly higher for patients healed on cimetidine than for patients healed on other forms of therapy; however, the cimetidine-treated patients generally had more severe disease.

Maintenance Therapy in Duodenal Ulcer: Treatment with a reduced dose of cimetidine has been proven effective as maintenance therapy following healing of active duodenal ulcers.

In numerous placebo-controlled studies conducted worldwide, the percent of patients with observed ulcers at the end of 1 year’s therapy with cimetidine 400 mg h.s. was significantly lower (10% to 45%) than in patients receiving placebo (44% to 70%). Thus, from 55% to 90% of patients were maintained free of observed ulcers at the end of 1 year with cimetidine 400 mg h.s.

Factors such as smoking, duration and severity of disease, gender, and genetic traits may contribute to variations in actual percentages.

Trials of other anti-ulcer therapy, whether placebo-controlled, positive-controlled or open, have demonstrated a range of results similar to that seen with cimetidine.

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