Cimetidine and cimetidine hydrochloride are used for the short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer. Antacids may be used concomitantly as needed for relief of pain; however, simultaneous administration of cimetidine and antacids is not recommended since some antacids have been reported to interfere with absorption of cimetidine.
(See Drug Interactions.)
In controlled studies in patients with endoscopically confirmed duodenal ulcer receiving supplemental antacids, reported rates of ulcer healing for cimetidine were consistently higher than those for placebo. Ulcer healing rates from controlled studies employing various dosage regimens have averaged 68, 73, and 80% at 4 weeks and 80, 80, and 89% at 6 weeks for cimetidine 300 mg 4 times daily, 400 mg twice daily, and 800 mg at bedtime daily, respectively. At 8 weeks, healing rates have averaged 92 and 94% for 400 mg twice daily and 800 mg at bedtime daily, respectively. In a controlled study comparing various bedtime cimetidine dosages and placebo in patients with endoscopically proven duodenal ulcer who received supplemental antacids (up to 72 mEq neutralizing capacity daily) during the first week of therapy, 800 mg at bedtime daily was more effective than 400 mg at bedtime daily, with corresponding 4-week healing rates of 75 and 66%; 1600 mg at bedtime daily was not significantly more effective (81% healing rate) than the 800-mg regimen. Nocturnal pain relief occurred in more than 80% of patients after 1 day of the 800-mg regimen and daytime pain relief occurred in approximately 70% of patients after 2 days of therapy with this regimen; the 800-mg regimen was more effective than the 400-mg regimen in providing daytime and nocturnal pain relief at 4 weeks but was similar to the 1600-mg regimen. In this study, ulcer healing was less likely in patients who were smokers and in those with larger ulcers than in other patients. In one well-controlled study comparing 4 weeks of oral therapy with 1.2 g of cimetidine daily to that with 1- and 3-hour postprandial and bedtime administration of magnesium and aluminum hydroxides antacid tablets, 64% of cimetidine-treated and 52% of antacid-treated duodenal ulcer craters and erosions were healed. In another well-controlled 4-week trial comparing placebo to 1- and 3-hour postprandial and bedtime administration of an antacid suspension containing magnesium and aluminum hydroxides with simethicone, 78% of antacid-treated and 45% of placebo-treated duodenal ulcer craters disappeared. The rate of ulcer healing reported with antacid in this study is similar to that reported for cimetidine in other studies, but diarrhea occurred in 30-60% of antacid-treated patients.
Ulcer healing may occur within the first 2 weeks of cimetidine therapy and occurs in most patients within 4 weeks of therapy, but short-term therapy (i.e., up to 8 weeks) for the treatment of active duodenal ulcer will not prevent ulcer recurrence following acute healing and discontinuance of the drug. Current epidemiologic and clinical evidence supports a strong association between gastric infection with Helicobacter pylori and the pathogenesis of duodenal and gastric ulcers; long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. For additional information on the association of this infection with these and other GI conditions, .
Conventional antiulcer therapy with H2-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori, and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year). Follow-up of cimetidine-treated patients has revealed no differences in frequency or time to onset of ulcer recurrence between treated patients and controls. A limited number of uncontrolled studies have shown recurrence of ulcer 1 month after cimetidine withdrawal in 41% of patients and as early as 1 week in some patients. In some studies, rate of recurrence was slightly higher after acute cimetidine therapy than after some other forms of acute therapy, but cimetidine-treated patients generally had more serious disease initially.
The American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. Although 3-drug regimens consisting of a bismuth salt (e.g., bismuth subsalicylate) and 2 anti-infective agents (e.g., tetracycline or amoxicillin plus metronidazole) administered for 10-14 days have been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori-associated peptic ulcer disease, current evidence principally from studies in Europe suggests that 1 week of such therapy provides comparable H. pylori eradication rates. Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, H2-receptor antagonist) also have been used successfully for H. pylori eradication, and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.
Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti-H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance. Therefore, the ACG and many clinicians currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection. For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, .
Cimetidine is used in reduced dosage as maintenance therapy following healing of active duodenal ulcer to reduce ulcer recurrence. In placebo-controlled studies, duodenal ulcer recurrence rates after 1 year were 10-45% in patients receiving 400 mg of cimetidine daily at bedtime vs 44-70% in those receiving placebo. Other antiulcer therapies, with the exception of H. pylori eradication regimens
(see Uses: Duodenal Ulcer), have been associated with ulcer recurrence rates similar to those with cimetidine. Interindividual variation in these rates may depend in part on smoking, duration and severity of peptic ulcer disease, gender, and genetic factors. Because the efficacy of cimetidine in preventing duodenal ulcer recurrence appears to be substantially reduced in patients who are cigarette smokers compared with nonsmokers, patients who are cigarette smokers should be advised of the importance of discontinuing smoking in the prevention of ulcer recurrence. Maintenance therapy with cimetidine has been continued for up to 5 years in some patients.
Pathologic GI Hypersecretory Conditions
Cimetidine and cimetidine hydrochloride are used for the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, systemic mastocytosis, and multiple endocrine adenomas). The drug reduces diarrhea, anorexia and pain, and promotes healing of intractable ulcers in patients with these conditions. Although total gastrectomy has been considered the treatment of choice for Zollinger-Ellison syndrome, treatment with an H2-receptor antagonist is now generally preferred in most patients because of lesser risks.
Cimetidine is used in the short-term treatment of active, benign, gastric ulcer.
In studies in patients with gastric ulcers receiving supplemental antacids, cimetidine promoted healing of ulcers in up to 70% of patients after 4 weeks and in 66-100% of patients after 6 weeks; in controlled studies, healing rates were consistently higher with cimetidine than placebo, with ulcers healing in up to 55% of patients receiving placebo and supplemental antacids. The usefulness of cimetidine therapy for longer than 8 weeks in the treatment of active benign gastric ulcer remains to be clearly determined. When cimetidine is used in the treatment of gastric ulcer, it should be kept in mind that symptomatic response does not preclude the presence of a gastric malignancy; there have been rare cases of transient healing of gastric ulcers despite subsequently documented malignancy.
Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of gastric ulcers, and the ACG, NIH, and most clinicians currently recommend that all patients with initial or recurrent gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. The choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.
(See Duodenal Ulcer: Acute Therapy, in Uses.)For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, .
Cimetidine is used for the short-term (12 weeks) treatment and symptomatic relief of endoscopically diagnosed erosive esophagitis in patients with gastroesophageal reflux disease (GERD). By increasing gastric pH, H2-antagonists have relieved heartburn and other symptoms of reflux and have been associated with somewhat higher healing rates of endoscopically proven esophagitis when compared with placebo and have reduced antacid consumption.
Suppression of gastric acid secretion is considered by the ACG to be the mainstay of treatment for GERD, and a proton-pump inhibitor or histamine H2-receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease. The ACG states that a histamine H2-receptor antagonist administered daily in divided doses is effective in many patients with less severe GERD, and over-the-counter (OTC) antacids and histamine H2-receptor antagonists are appropriate for self-medication as initial therapy in such individuals. A histamine H2-receptor antagonist is particularly useful when taken before certain activities (e.g., heavy meal, exercise) that may result in acid reflux symptoms in some patients. The ACG states that H2-receptor antagonists generally may be used interchangeably, although the drugs may differ in potency and in their onset and duration of action. However, proton-pump inhibitors are more effective (i.e., provide more frequent and more rapid symptomatic relief and healing of esophagitis) than histamine H2-receptor antagonists in the treatment of GERD. Although higher doses and more frequent administration of histamine H2-receptor antagonists appear to increase their efficacy, such dosages are less effective and more expensive than proton-pump inhibitor therapy. Once-daily administration of a histamine H2-receptor antagonist at full dosage is not considered to be appropriate therapy for GERD.
In controlled studies in patients with GERD and endoscopically confirmed esophageal erosions and/or ulcers, cimetidine was substantially more effective than placebo in healing lesions. In one controlled study, healing rates were 45, 52, or 26% after 6 weeks and 60, 66, or 42% after 12 weeks of therapy with cimetidine 800 mg twice daily, 400 mg four times daily, or placebo, respectively. In a second controlled study, healing rates were 50 or 20% after 6 weeks and 67 or 36% after 12 weeks of therapy with cimetidine 800 mg twice daily or placebo, respectively. The manufacturer states that by most measures, cimetidine provided greater improvement of daytime and nocturnal heartburn symptoms than placebo in these studies.
Cimetidine (300 mg 4 times daily) also has been used in combination with metoclopramide (10 mg 4 times daily) in a limited number of patients who failed to respond adequately to cimetidine alone. In one study, combined therapy was more effective than cimetidine alone in providing symptomatic relief and endoscopic improvement of esophagitis. However, the ACG states that frequent adverse CNS effects of metoclopramide have appropriately decreased regular use of the drug for GERD. Although some clinicians have suggested that a histamine H2-receptor antagonist also may be used in combination with bethanechol in patients who fail to respond to a histamine H2-receptor antagonist alone, the ACG states that bethanechol has limited efficacy in the treatment of GERD.
Short-term therapy (i.e., up to 12 weeks) with H2-receptor antagonists for the treatment of GERD will not prevent recurrence following ulcer healing and discontinuance of such therapy. Esophagitis has recurred within 6 months in up to 80% of patients following discontinuance of H2-receptor antagonist therapy. Because GERD is considered a chronic disease, many patients with GERD require long-term, even lifelong, treatment. The ACG states that proton-pump inhibitors are effective and appropriate as maintenance therapy in many patients with the disease. Maintenance therapy with an H2-receptor antagonist also has been used to reduce recurrence of GERD. However, many patients initially responding to proton-pump inhibitors experience symptomatic relapse and failure of esophageal healing with subsequent use of a histamine H2-receptor antagonist.
For further information on the treatment of GERD, .
Upper GI Bleeding
Cimetidine is used for the prevention of upper GI bleeding in critically ill patients that results principally from stress-related mucosal damage (erosive gastritis, stress ulcers). While current evidence suggests that prophylactic therapy with cimetidine, particularly via continuous IV infusion, is more effective than placebo and in appropriate regimens probably at least as effective as antacids in reducing the incidence of occult and/or overt GI bleeding in critically ill patients (e.g., those with major traumatic injury, hypotension/ shock, sepsis, extensive burns, respiratory, renal, and/or hepatic insufficiency, coagulopathy), the cost-benefit of such therapy, particularly when employed extensively in the intensive care setting, remains controversial. Most studies on the efficacy of preventive therapy mainly have measured occult (a questionable end point) and/or overt GI bleeding as therapeutic end points while few have attempted to document erosions and/or clinically important ulceration per se. In addition, few studies have measured and/or distinguished effects of preventive therapy on clinically important end points (e.g., serious upper GI bleeding, transfusion requirements, hemoglobin/hematocrit, hypovolemia, death, need for surgical and or other intervention to arrest GI bleeding) or determined objective benefit (e.g., short-term survival, morbidity, duration of hospital stay).
Some evidence indicates that the development of clinically important bleeding and progression to ulceration from stress-related GI erosions occur only rarely under current standards of care (e.g., those aimed at preventing hypovolemia, sepsis, hypoalbuminemia, anemia, and malnutrition and those resulting in reduced use of vasopressors and corticosteroids and in improved ventilatory support) in intensive care settings, even in the absence of preventive therapy. Generally absent from current evidence of efficacy is a clear indication of substantial morbidity and/or mortality reduction associated with prophylactic therapy for upper GI bleeding. These and other factors currently complicate interpretation of available data. Thus, while some clinicians recommend routine prophylactic therapy for upper GI bleeding in a large proportion of critically ill hospitalized patients, other clinicians state that such therapy should be employed more selectively in those clearly at appreciable risk of clinically important bleeding. Unfortunately, establishment of clear patient selection criteria based on appropriate cost-benefit analyses requires further study and elucidation. Factored into such consideration, however, is recognition that currently available therapies appear to be more effective in preventing than in treating upper GI bleeding once it becomes clinically important. It is for this reason and because of the often unpredictable clinical outcome of patients requiring intensive care that some clinicians recommend routine prophylaxis, at least initially; however, consensus currently does not exist on the precise role of prophylactic therapy for upper GI bleeding.
Analysis of pooled data from several studies (most of them controlled and randomized) indicates that prophylactic therapy with H2-receptor antagonists, including cimetidine, in critically ill patients appears to be more effective than no therapy or placebo in preventing occult and overt upper GI bleeding. While at least one such analysis suggests that the drugs also appear to be more effective than no therapy or placebo in reducing clinically important upper GI bleeding (e.g., overt bleeding accompanied by reduced blood pressure and/or a decreased hemoglobin or requiring red blood cell transfusion), some clinicians have questioned this conclusion. In addition, a clear benefit of prophylactic therapy on survival has not been established to date. While some studies indicate that cimetidine may be less effective than antacids in preventing upper GI bleeding in critically ill patients, other data indicate that H2-antagonists, including cimetidine, when administered in appropriate regimens (e.g., IV infusions that adequately increase and maintain gastric pH) probably are at least as effective as antacids when prevention of only overt rather than occult (microscopic) and/or overt bleeding is considered the minimum therapeutic end point.
Some studies indicate that cimetidine may be effective for the treatment of upper GI bleeding (e.g., secondary to hepatic failure, esophagitis, or gastric or duodenal ulcers) when hemorrhage is not caused by the erosion of major blood vessels. However, the effect of the drug on upper GI bleeding appears to be a moderate one, and additional study to further evaluate the effect of cimetidine therapy on morbidity and mortality in such bleeding is necessary.
Cimetidine may be used for self-medication for relief of symptoms of occasional heartburn (pyrosis), acid indigestion (hyperchlorhydria), or sour stomach.
Some studies indicate that cimetidine also may be effective for the treatment of stress ulcers and peptic esophagitis.
Cimetidine has been used concomitantly with an antihistamine (H1-receptor antagonist) for the prevention and management of various allergic conditions and of various urticarias including dermatographism, thermal (heat- and cold-induced) urticarias, and chronic idiopathic urticaria. Use of an H2-receptor antagonist such as cimetidine concomitantly with an antihistamine for the management of urticarias has generally been reserved for patients who did not experience adequate relief with an antihistamine alone; the addition of an H2-receptor antagonist occasionally may provide some additional benefit.