CIMETIDINE

CIMETIDINE- cimetidine tablet
Liberty Pharmaceuticals, Inc.

DESCRIPTION

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

MM1
(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.

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

Each film-coated tablet, for oral administration, contains 300 mg, 400 mg or 800 mg of cimetidine. In addition, each tablet contains the following inactive ingredients: corn starch, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.

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

An 800 mg oral dose of cimetidine 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. A 1600 mg oral dose of cimetidine at bedtime 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 given as 400 mg twice daily and 300 mg four times daily decreases 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, a 300 mg oral dose of cimetidine 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, a 300 mg dose of cimetidine 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 dosed at 800 mg at bedtime, 400 mg twice daily, and 300 mg four times daily, all provide a similar, moderate (less than 60%) level of 24-hour acid suppression. However, the 800 mg bedtime dose regimen exerts its entire effect on nocturnal acid, and does not affect daytime gastric physiology.

Chemically Stimulated

Cimetidine administered orally significantly inhibited gastric acid secretion stimulated by betazole (an isomer of histamine), pentagastrin, caffeine and insulin as follows:

Cimetidine Inhibition of Stimulated Gastric Acid Secretion
Stimulant Stimulant Dose Cimetidine % Inhibition
Betazole 1.5 mg/kg (sc) 300 mg (po) 85% at 2 ½ hours
Pentagastrin 6 mcg/kg/hr (iv) 100 mg/hr (iv) 60% at 1 hour
Caffeine 5 mg/kg/hr (iv) 300 mg (po) 100% at 1 hour
Insulin 0.03 units/kg/hr (iv) 100 mg/hr (iv) 82% at 1 hour

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

300 mg of cimetidine taken orally 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. Cimetidine dosed at 300 mg orally 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. 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 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.

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 in U.S. and foreign controlled trials with cimetidine are summarized below, beginning with the regimen providing the lowest nocturnal dose.

Duodenal Ulcer Healing Rates with Various Dosage Regimens of Cimetidine*

* Averages from controlled clinical trials.

Regimen 300 mg 4 times daily 400 mg t wice daily 800 mg at bedtime 1600 mg at bedtime
week 4 68% 73% 80% 86%
week 6 80% 80% 89%
week 8 92% 94%

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

In the U.S. dose-ranging trial, over 80% of patients receiving 800 mg of cimetidine at bedtime 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 dose at bedtime was superior to 400 mg at bedtime and not different from 1600 mg at bedtime.

In foreign, double-blind studies with 800 mg of cimetidine at bedtime, 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 patients treated with cimetidine 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 one year’s therapy with 400 mg of cimetidine at bedtime 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 one year with 400 mg of cimetidine at bedtime.

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.

Active Benign Gastric Ulcer

Cimetidine has been shown to be effective in the short-term treatment of active benign gastric ulcer.

In a multicenter, double-blind U.S. study, patients with endoscopically confirmed benign gastric ulcer were treated with 300 mg of cimetidine four times a day or with placebo for six weeks. Patients were limited to those with ulcers ranging from 0.5 to 2.5 cm in size. Endoscopically confirmed healing at six weeks was seen in significantly.

Rate of Endoscopically Confirmed Gastric Ulcer Healing

* p greater then 0.05

Cimetidine (300 mg, 4 times daily) Placebo
Week 2 14/63 (22%) 7/63 (11%)
Total at week 6 43/65 (66%)* 30/67 (45%)

In a similar multicenter U.S. study of the 800 mg bedtime oral regimen, the endoscopically confirmed healing rates were:

Rate of Endoscopically Confirmed Gastric Ulcer Healing

* p = 0.005

Cimetidine (800 mg at bedtime) Placebo
Total at week 6 63/83(76%)* 44/80 (55%)

Similarly, in worldwide double-blind clinical studies, endoscopically evaluated benign gastric ulcer healing rates were consistently higher with cimetidine than with placebo.

Gastroesophageal Reflux Disease

In two multicenter, double-blind, placebo-controlled studies in patients with gastroesophageal reflux disease (GERD) and endoscopically proven erosions and/or ulcers, cimetidine was significantly more effective than placebo in healing lesions. The endoscopically confirmed healing rates.

In these trials cimetidine was superior to placebo by most measures in improving symptoms of day- and night-time heartburn, with many of the differences statistically significant. The 4 times daily regimen was generally somewhat better than the twice daily regimen where these were compared.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome)

Cimetidine significantly inhibited gastric acid secretion and reduced occurrence of diarrhea, anorexia and pain in patients with pathological hypersecretion associated with Zollinger-Ellison Syndrome, systemic mastocytosis and multiple endocrine adenomas. Use of cimetidine was also followed by healing of intractable ulcers.

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