Histamine H2 Receptor Antagonist
Action And Clinical Pharmacology: Cimetidine competitively inhibits the action of histamine at the histamine H2 receptor and thus represents a new class of pharmacological agents, the histamine H2 receptor antagonists.
Cimetidine is not an anticholingeric 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. Its ability to inhibit gastric acid secretion via this unique mechanism of action permits a new approach to the treatment of acid-related gastrointestinal disorders. In addition to its antisecretory effects, cimetidine also has cytoprotective properties.
In therapeutic studies, patients with NSAID-induced lesions or ulcers had symptomatic relief and healing when cimetidine was coadministered with the existing NSAID therapy.
Cimetidine is absorbed rapidly after oral administration. The plasma half-life is approximately 2 hours. The principal route of excretion is the urine.
The degree and duration of inhibition of basal and stimulated gastric acid secretion are dose related; the data suggest that 80% or higher inhibition throughout a 24 hour period can be achieved by a dosage regimen of 1.2 g daily given in divided doses. Cimetidine 300 mg reduced total pepsin output as a result of the decrease in volume of gastric juice. The drug had no effect on the rate of gastric emptying or lower esophageal sphincter (LES) pressure.
Indications And Clinical Uses: Primary therapy for conditions where the inhibition of gastric acid secretion is likely to be beneficial such as: Duodenal ulcer therapy. Non-malignant gastric ulcer therapy. Prophylaxis of recurrent duodenal or gastric ulcer. Gastroesophageal reflux disease. Management of upper gastrointestinal hemorrhage. Pathological hypersecretion associated with Zollinger-Ellison Syndrome, systemic mastocytosis and multiple endocrine adenomas. Prophylaxis of stress ulceration. Prophylaxis of acid aspiration pneumonitis. Adjunctive therapy in the management of cystic fibrosis in children. Treatment of NSAID-induced lesions (ulcers, erosions) and gastrointestinal symptoms and prevention of their recurrence.
Contra-Indications: In any patients who are known to have hypersensitivity to the drug.
Precautions: Pregnancy and Lactation: Experience to date with use of cimetidine in pregnant patients is limited. No significant adversities have been reported. Reproduction studies performed in rats, mice and rabbits have revealed no evidence of impaired fertility or harm to the fetus due to cimetidine. Studies have demonstrated that cimetidine crosses the placental barrier. It is also secreted in human milk. Cimetidine should be used in pregnant or lactating patients or women of child-bearing potential only when, in the judgement of the physician, the anticipated benefits outweigh the potential risks.
Cimetidine has been used in clinical trials for the prevention of acid aspiration pneumonitis in women undergoing cesarean section or vaginal delivery without harm to the fetus.
Impaired Renal Function: Because cimetidine is excreted by the kidney, a reduced dosage should normally be administered to patients with impaired renal function (see Dosage).
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, chlordiazepoxide, lidocaine, diazepam, theophylline, and nifedipine; thereby delaying elimination and increasing blood levels of these drugs. Benzodiazepines that are metabolized other than via the hepatic system do not exhibit this effect. Since clinically significant effects have been reported with the warfarin anticoagulants, close monitoring of prothrombin time is recommended, and adjustment of the anticoagulant dose may be necessary when cimetidine is administered concomitantly. Interaction with phenytoin has also been reported to produce adverse clinical effects.
Dosage of the drugs mentioned above and other similarly metabolized drugs, may require adjustment when starting or stopping concomitantly administered cimetidine, to maintain safe, optimum therapeutic blood levels.
The concomitant administration of cimetidine and NSAIDs does not result in any impairment of the efficacy of a number of NSAIDs; however, not all currently marketed NSAIDS were tested.
Gastric Ulcer: Symptomatic response to cimetidine does not preclude the presence of a gastric malignancy. Cimetidine treatment can mask the symptoms and allow transient healing of gastric cancer. The potential delay in diagnosis should be borne in mind in patients of middle age or older with new or recently changed dyspeptic symptoms.
Rapid I.V. Injection: Should be avoided as there have been rare cases of cardiac arrhythmias and hypotension reported (see Dosage).
Adverse Reactions: Mild and transient diarrhea, tiredness, and dizziness have been reported in a small number of patients during treatment with cimetidine. Skin rashes, sometimes severe, including Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis and generalized exfoliative erythroderma have been reported with H2 receptor antagonists. Reversible alopecia has also been reported.
There have been reports that a few patients have developed reversible nonprogressive gynecomastia during prolonged treatment. No evidence of induced endocrine dysfunction was found, and the condition remained unchanged or returned toward normal with continuing cimetidine treatment. No effect of cimetidine (in recommended doses) on spermatogenesis, sperm count, motility or morphology has been found in double blind controlled studies. Fertilizing capacity has not been affected in vitro. Blood levels of androgen and gonadotropin were unchanged. Reversible impotence has been reported in rare instances.
H2 antagonist administration has been associated with the occurrence of leukopenia (including agranulocytosis), thrombocytopenia, pancytopenia, and aplastic anemia, as well as extremely rare reports of immune hemolytic anemia.
A few cases of reversible confusional states have been reported, usually in elderly and/or severely ill patients, such as those with renal insufficiency or organic brain syndrome. These confusional states generally cleared within a few days of drug withdrawal.
Small increases of plasma creatinine have been reported. These did not progress with continued therapy and disappeared at the end of therapy. Some increases in serum transaminase and rare cases of hepatitis, fever, hypersensitivity vasculitis, interstitial nephritis, urinary retention and pancreatitis, which cleared on withdrawal of the drug, have been reported. Rare occurrences of sinus bradycardia, tachycardia, heart block and anaphylaxis have been reported in patients treated with H2 antagonists.
Concomitant NSAID administration does not alter the incidence of adverse reactions resulting from therapy with cimetidine for those NSAIDs that have been tested.
Reported adverse reactions in children include neurotoxicity, and inhibition of hepatic microsomal metabolism. No change in adenohypophyseal secretion has been noted in studies in children receiving cimetidine. Cimetidine may produce transient cholestasis.
There have been rare reports of reversible arthralgia and myalgia; exacerbation of joint symptoms in patients with pre-existing 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.
Symptoms And Treatment Of Overdose: Symptoms: In cases reported to date, involving oral ingestion of up to 20 g of cimetidine, no untoward effects have been noted and recovery has been uneventful.
Treatment: The usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring and supportive therapy should be employed. Studies in animals indicate that assisted respiration may be of value.
Dosage And Administration: Adults: (for cimetidine administration in children see Pediatric Dosage): In clinical studies Tagament has been used in divided doses of up to 2 400 mg/day.
Duodenal Ulcer and Nonmalignant Gastric Ulcer: Active Ulcer: The recommended adult oral dose is 800 to 1 200 mg/day. This may be given as follows: 2 Tagamet 400 once daily at bedtime or 1 Tagamet 600 twice daily, at breakfast and bedtime or 1 Tagamet 300 4 times a day, with meals and at bedtime.
In some patients 400 mg twice daily has been shown to be effective.
While healing with cimetidine may occur during the first week or two, treatment should be continued for at least 4 weeks for duodenal ulcer and at least 6 weeks for nonmalignant gastric ulcer unless healing has been demonstrated by endoscopic examination.
While some patients may require concomitant antacids initially, cimetidine alone has been shown to promote rapid relief of symptoms.
Prophylaxis of Recurrent Duodenal or Gastric Ulcer: For most patients the following regimens have been shown to be effective: 1 Tagamet 400 at bedtime or 1 Tagamet 300 twice daily, at breakfast and bedtime.
Daily maintenance therapy may be used for those patients who would benefit from a reduction of gastric acid secretion, as well as those patients who are known to suffer frequent recurrence of duodenal or gastric ulcers, and should be continued for at least 6 to 12 months. Re-evaluation of the gastric ulcer patient should be undertaken at regular time intervals.
NSAID-induced Lesions and Symptoms: The recommended adult dose of Tagamet is 800 mg/day, either as 800 mg at bedtime or 400 mg twice daily, for 8 weeks. In patients with NSAID-induced lesions who have responded to an initial course of treatment and who require ongoing NSAID therapy, recurrence of lesions may be prevented by continual concomitant maintenance treatment with cimetidine. The recommended dosage for maintenance treatment is 400 mg of cimetidine at bedtime.
Gastroesophageal Reflux Disease: The recommended adult oral dose for gastroesophageal reflux disease is 1.2 g/day which may be given as follows: 2 Tagamet 400 once daily at bedtime or 1 Tagamet 600 twice daily at breakfast and bedtime or 1 Tagamet 300 four times daily with meals and at bedtime for 8 to 12 weeks.
While some patients may require concomitant antacids initially, cimetidine alone has been shown to promote rapid relief of symptoms.
Management of Upper Gastrointestinal Hemorrhage: In patients with upper gastrointestinal bleeding of sufficient magnitude as to require blood transfusions, cimetidine should be administered parenterally, preferably by i.v. injection or intermittent infusion until 48 hours after active bleeding has stopped. At this time an oral dosage regimen may be instituted.
Recommended Dosage for Oral Administration: 1 Tagamet 600 twice daily, at breakfast and bedtime or 1 Tagamet 300 every 6 hours.
Recommended Dosage for I.M. Injection Administration: 300 mg every 6 hours.
Recommended Dosage for I.V. Injection Administration: 300 mg every 6 hours. Dilute 300 mg cimetidine in Sodium Chloride Injection 0.9%, or other compatible i.v. solution to a total volume of 20 mL and inject slowly over a period of not less than 2 minutes. This method of administration should be avoided in patients with cardiovascular disease.
Recommended Dosage for Intermittent I.V. Infusion Administration: Vial: 300 mg every 6 hours. Dilute Tagamet 300 mg in 50 or 100 mL of Dextrose Injection 5%, Sodium Chloride Injection 0.9% or other compatible i.v. solution and infuse over 15 to 20 minutes.
Viaflex Plus Single Dose Container: 300 mg every 6 hours. Infuse over 15 to 20 minutes. Contains 300 mg cimetidine in 50 mL Sodium Chloride Injection 0.9%. Do not add supplementary medication or diluent (see detailed instructions at the end of this section).
In some patients it may be necessary to increase dosage. When this is necessary, the increases should be made by more frequent administration of a 300 mg dose, but total daily dosage should not exceed 2 400 mg.
Prophylaxis of Stress Ulceration: Recommended Adult Dosage: 300 mg i.v. every 6 hours, or more frequently to maintain a gastric pH above 4 (see recommendation for i.v. administration under Management of Upper Gastrointestinal Hemorrhage).
Pathological Hypersecretory Conditions: (e.g., Zollinger-Ellison Syndrome): Recommended Adult Oral Dosage: 300 mg 4 times a day, with meals and at bedtime. In some patients, it may be necessary to administer higher and/or more frequent doses to control symptoms. Dosage should be adjusted to individual patient’s needs, but usually should not exceed 2 400 mg/day. If i.v. administration is required, the dosage schedule should be the same as that recommended for control of upper gastrointestinal bleeding.
Prophylaxis of Acid Aspiration Pneumonitis: Recommended Adult Dosage: In emergency surgery, including emergency cesarean section, 300 mg i.m. 1 hour before induction of anesthesia and 300 mg i.v. or i.m. every 4 hours until patient responds to verbal commands.
In elective surgery, including elective cesarean section, same dosage as in emergency surgery, but oral cimetidine 300 mg may be started the night before the operation. For i.v. administration, see recommendation under Management of Upper Gastrointestinal Hemorrhage.
Dosage Adjustment for Patients With Impaired Renal Function: 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 i.v. 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: Hemodialysis reduces the level of circulating cimetidine. Greater than 80% of a 300 mg i.v. dose is cleared in a single 4-hour period of hemodialysis. It is completely cleared in an 8-hour period. Ideally, the dosage schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.
Peritoneal Dialysis: Peritoneal dialysis does not appear to remove cimetidine to any appreciable extent.
Pediatric Dosage: I.V. or Oral Administration: When cimetidine is given i.v. to children, it should be injected or infused slowly over 10 to 20 minutes. 1 to 12 years: 20 to 25 mg/kg/day in divided doses every 4 to 6 hours.
Under 1 Year: Data for use of cimetidine in children under 1 year of age are limited; 20 mg/kg/day may be used in the absence of renal impairment.
In neonates under 1 week of age and in patients with moderate renal impairment the suggested dose is 10 to 15 mg/kg/day in divided doses. The dosage may need to be reduced further in the presence of additional liver impairment or with severe renal impairment.
Stability of Injectable Form: Cimetidine injection, when added to or diluted with most i.v. solutions, such as Sodium Chloride Injection 0.9%, or Dextrose Injection 5% or 10%, is stable for 48 hours at normal room temperature.
Cimetidine injection in vials should not be refrigerated.
Cimetidine infusion in Viaflex Plus containers is stable for the period indicated by the expiry date on the label.
Cimetidine infusion should be stored at room temperature.
Instructions for Administration of Tagamet Infusion in Viaflex Plus Containers: Containers should be replaced at least every 24 hours. Do not remove unit from overwrap until ready for use. Remove unit from cover using aseptic technique and check for leaks by squeezing bag firmly. Discard solution if leaks are found.
Preparation for administration: 1) Suspend container from eyelet support. 2) Remove plastic protector from outlet port at bottom of container. 3) Attach administration set. Refer to complete directions accompanying set.
Store at room temperature.
Warning: To avoid air embolism, do not use plastic containers in series connections. Do not add supplementary medication.
Availability And Storage: Infusion: Each Viaflex Plus single dose polyvinyl chloride bag contains: cimetidine 300 mg (present as the hydrochloride). Nonmedicinal ingredients: sodium chloride injection 0.9%. Sodium: 7.7 mmol (177 mg). Boxes of 24. Do not add supplementary medication or diluent.
Liquid: Each 5 mL of light orange, bittersweet melon-pineapple flavored, sugar-free liquid contains: cimetidine 300 mg (present as the hydrochloride). Nonmedicinal ingredients: alcohol, artificial casaba melon flavor, artificial pineapple flavor, dibasic sodium phosphate, FD&C yellow no. 6, glycerin, hydrochloric acid (to adjust pH), methylparaben, propylene glycol, propylparaben, sodium chloride, sodium cyclamate, sorbitol solution and water. Sodium: <1 mmol (20.885 mg). Energy: 40.03 kJ (9.53 kcal). Bottles of 250 mL.
Tablets: Tagamet 300: Each pale green, circular, biconvex, film-coated tablet, engraved Tagamet on one face and on the other, contains: cimetidine 300 mg. Nonmedicinal ingredients: carnauba wax, cornstarch, FD&C blue no. 2, iron oxide, magnesium stearate, microcrystalline cellulose, Opadry Green, povidone, sodium lauryl sulfate, sodium starch glycolate and talc. Sodium: <1 mmol (0.615 mg). Energy: 0.26 kJ (0.06 kcal). Bottles of 100 and 1 000.
Tagamet 400: Each pale green, ovoid, biconvex, film-coated tablet, engraved Tagamet on one face and on the other face, contains: cimetidine 400 mg. Nonmedicinal ingredients: carnauba wax, cornstarch, FD&C blue no. 2, iron oxide, magnesium stearate, microcrystalline cellulose, Opadry Green, povidone, sodium lauryl sulfate, sodium starch glycolate and talc. Sodium: <1 mmol (0.780 mg). Energy: 0.38 kJ (0.09 kcal). Bottles of 100.
Tagamet 600: Each pale green, ovoid, biconvex, film-coated tablet, engraved Tagamet on one face and Ã on the other face, contains: cimetidine 600 mg. Nonmedicinal ingredients: carnauba wax, cornstarch, FD&C blue no. 2, iron oxide, magnesium stearate, microcrystalline cellulose, Opadry Green, povidone, sodium lauryl sulfate, sodium starch glycolate and talc. Sodium: <1 mmol (1.17 mg). Energy: 0.57 kJ (0.14 kcal). Bottles of 100.
All tablets are gluten-, lactose-, paraben-, sucrose-, sulfite- and tartrazine-free.
TAGAMET® SmithKline Beecham Cimetidine Histamine H2 Receptor Antagonist