Cimetidine (Page 3 of 5)

Gastroesophageal Reflux Disease

In 2 multicenter, double-blind, placebo-controlled studies in patients with gastroesophageal reflux disease (GERD) and endoscopically proven erosions and/or ulcers, cimetidine tablets were significantly more effective than placebo in healing lesions. The endoscopically confirmed healing rates were:

Table 6. Rate of Endoscopically Confirmed Healing of Erosions and/or Ulcers

Trial

Cimetidine Tablets

(800 mg

twice daily)

Cimetidine Tablets

(400 mg

4 times daily)

Placebo

p-Value

(800 mg

twice daily 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 cimetidine tablets were 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 tablets 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 tablets were also followed by healing of intractable ulcers.

INDICATIONS AND USAGE

Cimetidine tablets are indicated in:

1. Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks and there is rarely reason to use cimetidine tablets at full dosage for longer than 6 to 8 weeks (see DOSAGE AND ADMINISTRATION: Duodenal Ulcer). Concomitant antacids should be given as needed for relief of pain. However, simultaneous administration of cimetidine tablets and antacids is not recommended, since antacids have been reported to interfere with the absorption of cimetidine.

2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of active ulcer. Patients have been maintained on continued treatment with cimetidine tablets 400 mg at bedtime for periods of up to 5 years.

3. Short-term treatment of active benign gastric ulcer. There is no information concerning usefulness of treatment periods of longer than 8 weeks.

4. Erosive gastroesophageal reflux (GERD). Erosive esophagitis diagnosed by endoscopy. Treatment is indicated for 12 weeks for healing of lesions and control of symptoms. The use of cimetidine tablets beyond 12 weeks has not been established (see DOSAGE AND ADMINISTRATION: GERD).

5. The treatment of pathological hypersecretory conditions (i.e., Zollinger-Ellison Syndrome, systemic mastocytosis, multiple endocrine adenomas).

CONTRAINDICATIONS

Cimetidine tablets are contraindicated for patients known to have hypersensitivity to the product.

PRECAUTIONS

General

Rare instances of cardiac arrhythmias and hypotension have been reported following the rapid administration of cimetidine hydrochloride injection by intravenous bolus.

Symptomatic response to treatment with cimetidine tablets do not preclude the presence of a gastric malignancy. There have been rare reports of transient healing of gastric ulcers despite subsequently documented malignancy.

Reversible confusional states (see ADVERSE REACTIONS) have been observed on occasion, predominantly, but not exclusively, in severely ill patients. Advancing age (50 or more years) and preexisting liver and/or renal disease appear to be contributing factors. In some patients these confusional states have been mild and have not required discontinuation of cimetidine tablets. In cases where discontinuation was judged necessary, the condition usually cleared within 3 to 4 days of drug withdrawal.

Drug Interactions

Cimetidine tablets, apparently through an effect on certain microsomal enzyme systems, has been reported to reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline, and metronidazole, thereby delaying elimination and increasing blood levels of these drugs.

Clinically significant effects have been reported with the warfarin anticoagulants; therefore, close monitoring of prothrombin time is recommended, and adjustment of the anticoagulant dose may be necessary when cimetidine tablets are administered concomitantly. Interaction with phenytoin, lidocaine, and theophylline has also been reported to produce adverse clinical effects.

However, a crossover study in healthy subjects receiving either 300 mg 4 times daily or 800 mg at bedtime of cimetidine tablets concomitantly with a 300 mg twice-daily dose of theophylline extended-release tablets demonstrated less alteration in steady-state theophylline peak serum levels with the 800 mg at bedtime regimen, particularly in subjects aged 54 years and older. Data beyond 10 days are not available. (Note: All patients receiving theophylline should be monitored appropriately, regardless of concomitant drug therapy.)

Dosage of the drugs mentioned above and other similarly metabolized drugs, particularly those of low therapeutic ratio or in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping the concomitant administration of cimetidine tablets to maintain optimum therapeutic blood levels.

Alteration of pH may affect absorption of certain drugs (e.g., ketoconazole). If these products are needed, they should be given at least 2 hours before cimetidine administration.

Additional clinical experience may reveal other drugs affected by the concomitant administration of cimetidine tablets.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month toxicity study conducted in rats, at dose levels of 150, 378 and 950 mg/kg/day (approximately 8 to 48 times the recommended human dose), there was a small increase in the incidence of benign Leydig cell tumors in each dose group; when the combined drug-treated groups and control groups were compared, this increase reached statistical significance. In a subsequent 24-month study, there were no differences between the rats receiving 150 mg/kg/day and the untreated controls. However, a statistically significant increase in benign Leydig cell tumor incidence was seen in the rats that received 378 and 950 mg/kg/day. These tumors were common in control groups as well as treated groups and the difference became apparent only in aged rats.

Cimetidine has demonstrated a weak antiandrogenic effect. In animal studies this was manifested as reduced prostate and seminal vesicle weights. However, there was no impairment of mating performance or fertility, nor any harm to the fetus in these animals at doses 8 to 48 times the full therapeutic dose of cimetidine tablets, as compared with controls. The cases of gynecomastia seen in patients treated for 1 month or longer may be related to this effect.

In human studies, cimetidine tablets have been shown to have no effect on spermatogenesis, sperm count, motility, morphology or in vitro fertilizing capacity.

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