Cimetidine: Package Insert and Label Information

CIMETIDINE- cimetidine tablet, film coated
Mylan 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:

Structural Formula

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

Cimetidine has a bitter taste and characteristic odor.

Solubility Characteristics

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

Each tablet, for oral administration, contains 200 mg, 300 mg, 400 mg or 800 mg cimetidine, USP. Inactive ingredients are: croscarmellose sodium, crospovidone, hypromellose, lecithin, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, pregelatinized starch (corn), sodium alginate, sodium lauryl sulfate, titanium dioxide, triacetin, vanillin, FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake and D&C Yellow No. 10 Aluminum Lake.

CLINICAL PHARMACOLOGY

Cimetidine tablets 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 tablets inhibit both daytime and nocturnal basal gastric acid secretion. Cimetidine tablets also inhibit gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine and insulin.

Antisecretory Activity

1) Acid Secretion

Nocturnal

An 800 mg oral dose of cimetidine tablets at bedtime reduces mean hourly H+ activity by greater than 85% over an 8-hour period in duodenal ulcer patients, with no effect on daytime acid secretion. A 1,600 mg oral dose of cimetidine tablets at bedtime produces 100% inhibition of mean hourly H+ activity over an 8-hour period in duodenal ulcer patients, but also reduces H+ activity by 35% for an additional 5 hours into the following morning. Cimetidine tablets given as 400 mg twice daily and 300 mg 4 times daily decreases nocturnal acid secretion in a dose-related manner, i.e., 47% to 83% over a 6- to 8-hour period and 54% over a 9-hour period, respectively.

Food Stimulated

During the first hour after a standard experimental meal, a 300 mg oral dose of cimetidine tablets inhibited gastric acid secretion in duodenal ulcer patients by at least 50%. During the subsequent 2 hours cimetidine tablets inhibited gastric acid secretion by at least 75%.

The effect of a 300 mg breakfast dose of cimetidine tablets continued for at least 4 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 tablets given with lunch.

In another study, a 300 mg dose of cimetidine tablets given with the meal increased gastric pH as compared with placebo.

Table 1. 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 tablets dosed at 800 mg at bedtime, 400 mg twice daily, and 300 mg 4 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 tablets administered orally significantly inhibited gastric acid secretion stimulated by betazole (an isomer of histamine), pentagastrin, caffeine and insulin as follows:

Table 2. Cimetidine Tablets Inhibition of Stimulated Gastric Acid Secretion

Stimulant

Stimulant Dose

Cimetidine Tablets

% Inhibition

Betazole

1.5 mg/kg (sc)

300 mg (po)

85% at 2 1/2 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 tablets 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 tablets 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 tablets has no effect on lower esophageal sphincter (LES) pressure or the rate of gastric emptying.

Pharmacokinetics

Cimetidine tablets are rapidly absorbed after oral administration and peak levels occur in 45 to 90 minutes. The half-life of cimetidine tablets 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.

Following parenteral administration, most of the drug is excreted as the parent compound in the urine, the principle route of excretion of cimetidine tablets. After oral administration, the drug is extensively metabolized in which the sulfoxide is 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 tablets have 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 tablets accelerate the rate of duodenal ulcer healing. Healing rates reported in U.S. and foreign controlled trials with cimetidine tablets are summarized below, beginning with the regimen providing the lowest nocturnal dose.

Table 3. Duodenal Ulcer Healing Rates with Various Dosage Regimens of Cimetidine Tablets *
*
Averages from controlled clinical trials.

Regimen

300 mg

4 times daily

400 mg

twice 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 tablets were superior to placebo in ulcer healing and that 800 mg of cimetidine tablets at bedtime healed 75% of patients at 4 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 tablets at bedtime experienced nocturnal pain relief after one day. Relief from daytime pain was reported in approximately 70% of patients after 2 days. As with ulcer healing, the 800 mg dose at bedtime was superior to 400 mg at bedtime and not different from 1,600 mg at bedtime.

In foreign, double-blind studies with 800 mg of cimetidine tablets at bedtime, 79% to 85% of patients were healed at 4 weeks.

While short-term treatment with cimetidine tablets can result in complete healing of the duodenal ulcer, acute therapy will not prevent ulcer recurrence after cimetidine tablets have 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 tablets than for patients healed on other forms of therapy; however, the patients treated with cimetidine tablets generally had more severe disease.

Maintenance Therapy in Duodenal Ulcer

Treatment with a reduced dose of cimetidine tablets have 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 400 mg of cimetidine tablets 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 1 year with 400 mg of cimetidine tablets 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 tablets.

Active Benign Gastric Ulcer

Cimetidine tablets have 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 tablets 4 times a day or with placebo for 6 weeks. Patients were limited to those with ulcers ranging from 0.5 to 2.5 cm in size. Endoscopically confirmed healing at 6 weeks was seen in significantly* more patients treated with cimetidine tablets than in patients receiving placebo, as shown below:

Table 4. Rate of Endoscopically Confirmed Gastric Ulcer Healing
*
p < 0.05

Cimetidine Tablets

(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:

Table 5. Rate of Endoscopically Confirmed Gastric Ulcer Healing
*
p = 0.005

Cimetidine Tablets

(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 tablets than with placebo.

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