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Tagamet

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Tagamet

CLINICAL PHARMACOLOGY

Tagamet (cimetidine) competitively inhibits the action of histamine at the histamine H2 receptors of the parietal cells and thus is a histamine H2-receptor antagonist.

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

Antisecretory Activity

1) Acid Secretion : Nocturnal: Tagamet (cimetidine) 800 mg orally 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. Tagamet (cimetidine) 1600 mg orally h.s. 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. Tagamet (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 6- to 8-hour period and 54% over a 9-hour period, respectively.

Food Stimulated: During the first hour after a standard experimental meal, oral Tagamet (cimetidine) 300 mg inhibited gastric acid secretion in duodenal ulcer patients by at least 50%. During the subsequent 2 hours Tagamet (cimetidine) inhibited gastric acid secretion by at least 75%.

The effect of a 300 mg breakfast dose of Tagamet (cimetidine) 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 Tagamet (cimetidine) given with lunch.

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

 

Mean Gastric pH

Tagamet

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

Stimulant

Stimulant Dose

Tagamet

% Inhibition

Betazole

1.5mg/kg (sc)

300mg (po)

85% at 2½ hours

Pentagastrin

6mcg/kg/hr (iv)

100mg/hr (iv)

60% at 1 hour

Caffeine

5mg/kg/hr (iv)

300mg (po)

100% at 1 hour

Insulin

0.03 units/kg/hr (iv)

100mg/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%.

Parenteral administration also significantly inhibits gastric acid secretion. In a crossover study involving patients with active or healed duodenal or gastric ulcers, either continuous I.V. infusion of Tagamet (cimetidine) 37.5 mg/hour (900 mg/day) or intermittent injection of Tagamet (cimetidine) 300 mg q6h (1200 mg/day) maintained gastric pH above 4.0 for more than 50% of the time under steady-state conditions.

2) Pepsin: Oral Tagamet (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 Tagamet (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

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

Pharmacokinetics

Tagamet (cimetidine) is rapidly absorbed after oral administration and peak levels occur in 45 to 90 minutes. The half-life of Tagamet (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.

Steady-state blood concentrations of cimetidine with continuous infusion of Tagamet (cimetidine) are determined by the infusion rate and clearance of the drug in the individual patient. In a study of peptic ulcer patients with normal renal function, an infusion rate of 37.5 mg/hour produced average steady-state plasma cimetidine concentrations of about 0.9 mcg/mL. Blood levels with other infusion rates will vary in direct proportion to the infusion rate.

The principal route of excretion of Tagamet (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

Tagamet (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: Tagamet (cimetidine) accelerates the rate of duodenal ulcer healing. Healing rates reported in U.S. and foreign controlled trials with Tagamet (cimetidine) are summarized below, beginning with the regimen providing the lowest nocturnal dose.

Duodenal Ulcer Healing Rates with Various Tagamet Dosage Regimens*

Regimen

300 mg q.i.d.

400 mg b.i.d.

800 mg h.s.

1600 mg h.s.

week 4

68%

73%

80%

86%

week 6

80%

80%

89%

week 8

92%

94%

*Averages from controlled clinical trials.

A U.S., double-blind, placebo-controlled, dose-ranging study demonstrated that all once-daily at bedtime (h.s.) Tagamet (cimetidine) regimens were superior to placebo in ulcer healing and that Tagamet (cimetidine) 800 mg h.s. healed 75% of patients at 4 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 Tagamet (cimetidine) 800 mg h.s. experienced nocturnal pain relief after 1 day. Relief from daytime pain was reported in approximately 70% of patients after 2 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 Tagamet (cimetidine) 800 mg h.s., 79% to 85% of patients were healed at 4 weeks.

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

Maintenance Therapy in Duodenal Ulcer: Treatment with a reduced dose of Tagamet (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 Tagamet (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 Tagamet (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 Tagamet (cimetidine) .

Active Benign Gastric Ulcer

Tagamet (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 Tagamet (cimetidine) 300 mg four 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 Tagamet (cimetidine) -treated patients than in patients receiving placebo, as shown below:

 

Tagamet

Placebo

week 2

14/63 (22%)

7/63 (11%)

total at week 6

43/65 (66%)*

30/67 (45%)

*p<0.05

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

 

Tagamet

Placebo

total at week 6

63/83 (76%)*

44/80 (55%)

*p=0.005

Similarly, in worldwide double-blind clinical studies, endoscopically evaluated benign gastric ulcer healing rates were consistently higher with Tagamet (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, Tagamet (cimetidine) was significantly more effective than placebo in healing lesions. The endoscopically confirmed healing rates were:

Trial

Tagamet (800 mg b.i.d.)

Tagamet (400 mg q.i.d.)

Placebo

p-Value (800 mg b.i.d. vs. placebo)

1

Week 6

45%

52%

26%

0.02

 

Week 12

60%

66%

42%

0.02

2

Week 6

50%

 

20%

<0.01

 

Week 12

67%

 

36%

<0.01

In these trials Tagamet (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 q.i.d. regimen was generally somewhat better than the b.i.d. regimen where these were compared.

Prevention of Upper Gastrointestinal Bleeding in Critically Ill Patients

A double-blind, placebo-controlled randomized study of continuous infusion cimetidine was performed in 131 critically ill patients (mean APACHE II score = 15.99) to compare the incidence of upper gastrointestinal bleeding, manifested as hematemesis or bright red blood which did not clear after adjustment of the nasogastric tube and a 5 to 10 minute lavage, persistent Gastroccult® positive coffee grounds for 8 consecutive hours which did not clear with 100 cc lavage and/or which were accompanied by a drop in hematocrit of 5 percentage points, or melena, with an endoscopically documented upper gastrointestinal source of bleed. 14% (9/65) of patients treated with cimetidine continuous infusion developed bleeding compared to 33% (22/66) of the placebo group. Coffee grounds was the manifestation of bleeding that accounted for the difference between groups. Another randomized, double-blind placebo-controlled study confirmed these results for an end point of upper gastrointestinal bleeding with a confirmed upper gastrointestinal source noted on endoscopy, and by post hoc analyses of bleeding episodes between groups.

Pathological Hypersecretory Conditions

(such as ZollingerEllison Syndrome)

Tagamet (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 Tagamet (cimetidine) was also followed by healing of intractable ulcers.

Last reviewed on RxList: 1/12/2005
This monograph has been modified to include the generic and brand name in many instances.

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