CIMETIDINE HYDROCHLORIDE

INDICATIONS AND USAGE Cimetidine Hydrochloride Oral Solution is indicated in: (1) Short-term treatment of active duodenal ulcer. 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. (2) Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of active ulcer. Patients have been maintained on continued treatment with cimetidine 400 mg h.s. 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 disease (GERD). 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 ). (5) The treatment of pathological hypersecretory conditions (i.e., Zollinger-Ellison Syndrome, systemic mastocytosis, multiple endocrine adenomas).

DOSAGE AND ADMINISTRATION Duodenal Ulcer Active Duodenal Ulcer: Clinical studies have indicated that suppression of nocturnal acid is the most important factor in duodenal ulcer healing (see Clinical Pharmacology-Antisecretory Activity-Acid Secretion ). This is supported by recent clinical trials (see Clinical Pharmacology-Clinical Trials Duodenal Ulcer-Active Duodenal Ulcer ). Therefore, there is no apparent rationale, except for familiarity with use, for treating with anything other than a once-daily at bedtime dosage regimen (h.s.). In a U.S. oral dose-ranging study of 400 mg h.s., 800 mg h.s. and 1600 mg h.s., a continuous dose response relationship for ulcer healing was demonstrated. However, 800 mg h.s. is the dose of choice for most patients, as it provides a high healing rate (the difference between 800 mg h.s. and 1600 mg h.s. being small), maximal pain relief, a decreased potential for drug interactions (see Precautions-Drug Interactions ) and maximal patient convenience. Patients unhealed at 4 weeks, or those with persistent symptoms, have been shown to benefit from two to four weeks of continued therapy. It has been shown that patients who both have an endoscopically demonstrated ulcer larger than 1 cm and are also heavy smokers (i.e., smoke one pack of cigarettes or more per day) are more difficult to heal. There is some evidence which suggests that more rapid healing can be achieved in this subpopulation with cimetidine 1,600 mg at bedtime. While early pain relief with either 800 mg h.s. or 1,600 mg h.s. is equivalent in all patients, 1,600 mg h.s. provides an appropriate alternative when it is important to ensure healing within four weeks for this subpopulation. Alternatively, approximately 94% of all patients will also heal in eight weeks with cimetidine 800 mg h.s. Other cimetidine regimens in the U.S. which have been shown to be effective are: 300 mg four times daily, with meals and at bedtime, the original regimen with which U.S. physicians have the most experience, and 400 mg twice daily, in the morning and at bedtime (see Clinical Pharmacology Clinical Trials-Duodenal Ulcer-Duodenal Ulcer ). Concomitant antacids should be given as needed for relief of pain. However, simultaneous administration of cimetidine and antacids is not recommended, since antacids have been reported to interfere with the absorption of cimetidine. While healing with cimetidine often occurs during the first week or two, treatment should be continued for 4 to 6 weeks unless healing has been demonstrated by endoscopic examination. Maintenance Therapy for Duodenal Ulcer: In those patients requiring maintenance therapy, the recommended adult oral dose is 400 mg at bedtime. Active Benign Gastric Ulcer 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. Erosive Gastroesophageal Reflux Disease (GERD) The recommended adult oral dosage for the treatment of erosive esophagitis that has been diagnosed by endoscopy is 1,600 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. Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome) 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 clini …

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

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Chartwell Governmental & Specialty RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Gastrointestinal Diarrhea (usually mild) has been reported in approximately 1 in 100 patients. CNS 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. Endocrine 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. Hematologic 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. Hepatobiliary 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 the 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 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. Hypersensitivity Rare cases of fever and allergic reactions including anaphylaxis and hypersensitivity vasculitis, which cleared on withdrawal of the drug, have been reported. Renal 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. Cardiovascular Rare cases of bradycardia, tachycardia and A-V heart block have been reported with H 2 -receptor antagonists. Musculoskeletal T …

Drug Interactions 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.

DESCRIPTION Cimetidine is a histamine H 2 -receptor antagonist. Chemically it is N"-cyano-N-methyl-N'-[2-[[(5-methyl-1Himidazol-4-yl)methyl]thio]-ethyl],guanidine. The molecular formula for Cimetidine Hydrochloride, USP is C 10 H 16 N 6 S•HCl and the molecular weight is 288.80 the structural formula of Cimetidine Hydrochloride is: Cimetidine contains an imidazole ring, and is chemically related to histamine. Cimetidine has a bitter taste and characteristic odor. Solubility Characteristics Cimetidine Hydrochloride is freely soluble in water, soluble in alcohol, very slightly soluble in chloroform and practically insoluble in ether. Each 5 mL (1 teaspoonful), for oral administration, contains Cimetidine Hydrochloride, equivalent to Cimetidine 300 mg; alcohol, 2.8%. In addition, the oral solution contains the following inactive ingredients: consist of dibasic sodium phosphate, heptahydrate; FD&C Red #40; FD&C Yellow #6; hydrochloric acid; menthol; methylparaben; natural orange Wonf; poloxamer 188; propylene glycol; propylparaben; Prosweet liquid; sodium hydroxide; sodium saccharin dihydrate; sorbitol solution; and purified water. The pH range is 5.1 to 5.7. image description

OVERDOSAGE 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 have been reported to ingest over 40 grams orally on a single occasion.

HOW SUPPLIED Cimetidine Hydrochloride Oral Solution is a clear, yellow to orange solution containing 300 mg of cimetidine per 5 mL (teaspoonful) supplied in 8 fl oz (237 mL) amber PET containers NDC 0121-1025-08. Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30 °C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container. Rx Only Distributed by: PAI Pharma Greenville, SC 29605 www.paipharma.com Rev 01/25