General: Rare instances of cardiac arrhythmias and hypotension have been reported following the rapid administration of Tagamet (cimetidine hydrochloride) Injection by intravenous bolus.
Symptomatic response to Tagamet 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 Tagamet therapy. In cases where discontinuation was judged necessary, the condition usually cleared within 3 to 4 days of drug withdrawal.
Drug Interactions: Tagamet, 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 Tagamet 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 Tagamet 300 mg q.i.d. or 800 mg h.s. concomitantly with a 300 mg b.i.d. dosage of theophylline (Theo-Dur®, Key Pharmaceuticals, Inc.) 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 10 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 Tagamet 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 Tagamet.
Carcinogenesis, Mutagenesis, Impairment of Fertility: 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.
Tagamet (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 Tagamet, as compared with controls. The cases of gynecomastia seen in patients treated for 1 month or longer may be related to this effect.
In human studies, Tagamet has been shown to have no effect on spermatogenesis, sperm count, motility, morphology or in vitro fertilizing capacity.
Pregnancy: Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats, rabbits and mice at doses up to 40 times the normal human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Tagamet. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers: Cimetidine is secreted in human milk and, as a general rule, nursing should not be undertaken while a patient is on a drug.
Pediatric Use: Clinical experience in children is limited. Therefore, Tagamet therapy cannot be recommended for children 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.
Immunocompromised Patients: 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.