CIMETIDINE HYDROCHLORIDE ORAL SOLUTION
0506

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. The structural formula is:

C₁₀H₁₆N₆S•HCl M.W. 288.80

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

(The liquid dosage form contains cimetidine as the hydrochloride.)

Cimetidine hydrochloride has a bitter taste and characteristic odor.

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

Each 5 mL (one teaspoonful), for oral administration contains, cimetidine hydrochloride equivalent to 300 mg of cimetidine; alcohol, 2.8%. Inactive ingredients consist of FD&C Yellow No. 6, artificial peach mint flavor, hydrochloric acid, methylparaben, poloxamer 407, propylene glycol, propylparaben, purified water, saccharin sodium, sodium chloride, dibasic sodium phosphate heptahydrate and sorbitol solution.

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

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

The principal route of excretion of 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.

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.

Cimetidine hydrochloride oral solution is indicated in:

Most patients heal within 4 weeks and there is rarely reason to use cimetidine 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 oral cimetidine and antacids is not recommended, since antacids have been reported to interfere with the absorption of oral cimetidine.

Patients have been maintained on continued treatment with cimetidine 400 mg h.s. for periods of up to five years.

There is no information concerning usefulness of treatment periods of longer than 8 weeks.

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

(i.e., Zollinger-Ellison Syndrome, systemic mastocytosis, multiple endocrine adenomas).

Cimetidine is contraindicated for patients known to have hypersensitivity to the product.

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 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, 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 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 q.i.d. or 800 mg h.s. concomitantly with a 300 mg b.i.d. dosage of theophylline extended-release tablets demonstrated less alteration in steady-state theophylline peak serum levels with the 800 mg h.s. 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 gynecomastia 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 a 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 per 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.

Adverse effects reported in patients taking cimetidine are described below by body system. Incidence figures of 1 in 100 and greater are generally derived from controlled clinical studies.

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 H₂-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 H₂-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 H₂-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 H₂-receptor antagonists. Reversible alopecia has been reported very rarely.

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

Studies in animals indicate that toxic doses are associated with respiratory failure and tachycardia that may be controlled by assisted respiration and the administration of a beta-blocker.

Reported acute ingestions orally of up to 20 grams have been associated with transient adverse effects similar to those encountered in normal clinical experience. The usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.

There have been reports of severe CNS symptoms, including unresponsiveness, following ingestion of between 20 and 40 grams of cimetidine, and extremely rare reports following concomitant use of multiple CNS-active medications and ingestion of cimetidine at doses less than 20 grams. An elderly, terminally ill dehydrated patient with organic brain syndrome receiving concomitant antipsychotic agents and cimetidine 4800 mg intravenously over a 24 hour period experienced mental deterioration with reversal on cimetidine discontinuation.

There have been two deaths in adults who were reported to have ingested over 40 grams orally on a single occasion.

In those patients requiring maintenance therapy, the recommended adult oral dose is 400 mg at bedtime.

The recommended adult oral dosage for short-term treatment of active benign gastric ulcer is 800 mg h.s., or 300 mg four times a day with meals and at bedtime. Controlled clinical studies were limited to six weeks of treatment (see CLINICAL PHARMACOLOGY - Clinical Trials). 800 mg h.s. is the preferred regimen for most patients based upon convenience and reduced potential for drug interactions. Symptomatic response to cimetidine does 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 b.i.d. or 400 mg q.i.d.) 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 and 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 indicated.

Patients with severely impaired renal function have been treated with cimetidine. However, such usage has been very limited. On the basis of this experience the recommended dosage is 300 mg every 12 hours orally or by intravenous injection. 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 lowest frequency of dosing compatible 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.

Cimetidine hydrochloride oral solution 300 mg/5 mL is a clear, light orange, peach-mint flavored liquid available in 8 fl. oz. amber bottles.

Store at controlled room temperature, between 20° and 25°C (68° and 77°F) (see USP).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Rev. E 7/2003

Manufactured By:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960