Cimetidine Tablets USP Rx only

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

Each tablet, for oral administration, contains 300 mg, 400 mg, or 800 mg cimetidine. In addition, each tablet contains the following inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate and sodium starch glycolate. The coating for the tablets contains: carnauba wax, hypromellose, polyethylene glycol, polysorbate 80, talc, titanium dioxide, and triethyl citrate. The coating for the 300 mg and 400 mg tablets also contains D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, and FD&C Yellow No. 6 Aluminum Lake.

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 were:

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 four times daily regimen was generally somewhat better than the twice daily regimen where these were compared.

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.

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

Symptomatic response to cimetidine therapy does 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 therapy. In cases where discontinuation was judged necessary the condition was usually cleared within 3 to 4 days of drug withdrawal.

Cimetidine, apparently through an effect on certain microsomal enzyme systems, has been reported to reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propanolol, 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 is 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 cimetidine 300 mg four times daily or 800 mg at bedtime concomitantly with a 300 mg twice daily dosage of theophylline extended-release tablets (Theo-Dur ^®*) 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 ten 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 concomitantly administered cimetidine 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.

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, as compared with controls. The cases of gynecomoastia seen in patients treated for one month or longer may be related to this effect.

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

Cimetidine is secreted in human milk and, as a general rule, nursing should not be undertaken while a patient is on this drug.

Clinical experience in pediatric patients is limited. Therefore, cimetidine therapy cannot be recommended for pediatric patients under 16, unless, in the judgment of the physician, anticipated benefits outweigh the potential risks. In very limited experience, doses of 20 to 40 mg/kg/day have been used.

In immunocompromised patients, decreased gastric acidity, including that produced by acid-suppressing agents such as cimetidine, may increase the possibility of a hyperinfection of strongyloidiasis.

Diarrhea (usually mild) has been reported in approximately 1 in 100 patients.

Headaches, ranging from mild to severe, have been reported in 3.5% of 924 patients taking 1600 mg/day, 2.1% of 2,225 patients taking 800 mg/day and 2.3% of 1,897 patients taking placebo. Dizziness and somnolence (usually mild) have been reported in approximately 1 in 100 patients on either 1600 mg/day or 800 mg/day.

Reversible confusional states, e.g., mental confusion, agitation, psychosis, depression, anxiety, hallucinations, disorientation, have been reported predominantly, but not exclusively, in severely ill patients. They have usually developed within 2 to 3 days of initiation of cimetidine therapy and have cleared within 3 to 4 days of discontinuation of the drug.

Gynecomastia has been reported in patients treated for one month or longer. In patients being treated for pathological hypersecretory states, this occurred in about 4% of cases while in all others the incidence was 0.3% to 1% in various studies. No evidence of induced endocrine dysfunction was found, and the condition remained unchanged or returned toward normal with continuing cimetidine treatment.

Reversible impotence has been reported in patients with pathological hypersecretory disorders, e.g., Zollinger-Ellison Syndrome, receiving cimetidine, particularly in high doses for at least 12 months (range 12 to 79 months, mean 38 months). However, in large-scale surveillance studies at regular dosage, the incidence has not exceeded that commonly reported in the general population.

Decreased white blood cell counts in cimetidine-treated patients (approximately 1 per 100,000 patients), including agranulocytosis (approximately 3 per million patients, have been reported, including a few reports of recurrence on rechallenge. Most of these reports were in patients who had serious concomitant illnesses and received drugs and/or treatment known to produce neutropenia. Thrombocytopenia (approximately 3 per million patients) and, very rarely, cases of pancytopenia or aplastic anemia have also been reported. As with some other H ₂-receptor antagonists, there have been extremely rare reports of immune hemolytic anemia.

Dose-related increases in serum transaminase have been reported. In most cases they did not progress with continued therapy and returned to normal at the end of therapy. There have been rare reports of cholestatic or mixed cholestatic-hepatocellular effects. These were usually reversible. Because of the predominance of cholestatic features, severe parenchymal injury is considered highly unlikely. However, as in the occasional liver injury with other H ₂-receptor antagonists, in exceedingly rare circumstances fatal outcomes have been reported.

There has been reported a single case of biopsy-proven periportal hepatic fibrosis in a patient receiving cimetidine.

Rare cases of pancreatitis, which cleared on withdrawal of the drug, have been reported.

Rare cases of fever and allergic reactions including anaphylaxis and hypersensitivity vasculitis, which cleared on withdrawal of the drug, have been reported.

Small, possibly dose-related increases in plasma creatinine, presumably due to competition for renal tubular secretion, are not uncommon and do not signify deteriorating renal function. Rare cases of interstitial nephritis and urinary retention, which cleared on withdrawal of the drug, have been reported.

Rare cases of bradycardia, tachycardia and A-V heart block have been reported with H ₂-receptor antagonists.

There have been rare reports of reversible arthralgia and myalgia; exacerbation of joint symptoms in patients with preexisting arthritis has also been reported. Such symptoms have usually been alleviated by a reduction in cimetidine dosage. Rare cases of polymyositis have been reported, but no causal relationship has been established.

Mild rash and, very rarely, cases of severe generalized skin reactions including Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis and generalized exfoliative erythroderma have been reported with H ₂-receptor antagonists. Reversible alopecia has been reported very rarely.

There have been extremely rare reports of strongyloidiasis hyperinfection in immunocompromised patients.

A large epidemiological study suggested an increased risk of developing pneumonia in current users of histamine-2-receptor antagonists (H ₂RAs) compared to patients who had stopped H ₂RA treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07 to 2.48). However, a causal relationship between use of H ₂RAs and pneumonia has not been established.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The recommended adult oral dosage for short-term treatment of active benign gastric ulcer is 800 mg at bedtime, or 300 mg four times a day with meals and at bedtime. Controlled clinical studies were limited to six weeks of treatment (see Clinical Trials). 800 mg at bedtime is the preferred regimen for most patients based upon convenience and reduced potential for drug interactions. Symptomatic response to cimetidine dose not preclude the presence of a gastric malignancy. It is important to follow gastric ulcer patients to assure rapid progress to complete healing.

The recommended adult oral dosage for the treatment of erosive esophagitis that has been diagnosed by endoscopy is 1600 mg daily in divided doses (800 mg twice daily or 400 mg four times daily) for 12 weeks. The use of cimetidine beyond 12 weeks has not been established.

Recommended adult oral dosage: 300 mg four times a day with meals at bedtime. In some patients it may be necessary to administer higher doses more frequently. Doses should be adjusted to individual patient needs, but should not usually exceed 2400 mg per day and should continue as long as clinically needed.

Patients with severely impaired renal function have been treated with cimetidine. However, such dosage has been very limited. On the basis of this experience the recommended dosage is 300 mg every 12 hours orally. Should the patient’s condition require, the frequency of dosing may be increased to every 8 hours or even further with caution. In severe renal failure, accumulation may occur and the lower frequency of dosing comparable with an adequate patient response should be used. When liver impairment is also present, further reductions in dosage may be necessary. Hemodialysis reduces the level of circulating cimetidine. Ideally, the dosage schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.