Bismuth Subsalicylate

Children and teenagers who have or who are recovering from chicken pox or flu should NOT use this medicine to treat nausea or vomiting. If nausea or vomiting is present, patients are advised to consult a doctor because this could be an early sign of Reye's syndrome, a rare but serious illness.

There have been rare reports of neurotoxicity associated with excessive doses of bismuth subsalicylate. Effects have been reversible with discontinuation of therapy.

Metronidazole

Central Nervous System Effects: Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with metronidazole. The prevalence and severity of the neuropathy are directly related to the cumulative dose and duration of therapy, being most prevalent in patients taking high doses for prolonged treatment periods. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronida-zole therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.

Pregnancy: Teratogenic Effects. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 20 mg/kg/day approximately one and a half times the most frequently recommended human dose (750 mg/day) based on mg/kg body weight; however, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown.

Tetracycline

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY, AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypopla-sia has also been reported. TETRACYCLINE HYDROCHLORIDE IS A COMPONENT OF THE HELIDAC THERAPY, THEREFORE, HELIDAC THERAPY SHOULD NOT BE USED IN THESE PATIENT POPULATIONS. (See CONTRAINDICATIONS.)

Tetracycline hydrochloride, as a component of the HELIDAC Therapy, should not be used during pregnancy. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. Treatment should be discontinued at the first evidence of skin erythema.

The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). While this is not a problem in those with normal renal function, in patients with significantly impaired renal function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis.

General

Prescribing HELIDAC Therapy in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Bismuth Subsalicylate

Bismuth subsalicylate may cause a temporary and harmless darkening of the tongue and/or black stool. Stool darkening should not be confused with melena.

Metronidazole

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. (See CONTRAINDICATIONS.) Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of, or history of, blood dyscrasia. A mild leukopenia has been observed; however, no persistent hematologic abnormalities attributable to metronidazole have been observed.

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candicidal agent.

Tetracycline

As with other antibiotics, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, tetracycline should be discontinued and appropriate therapy should be instituted.

Pseudotumor cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. While this condition and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility for permanent sequelae exists.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats. Prominent among the effects in the mouse was an increased incidence of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels, (approximately 500 mg/kg/day, which is approximately 33 times the most frequently recommended human dose for a 50 kg adult based on mg/kg body weight), there was a statistically significant increase in the incidence of malignant liver tumors in male mice. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Long-term, oral-dosing studies in the rat showed statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

There has been no evidence of carcinogenicity for tetracycline hydrochloride in studies conducted with rats and mice. Some related antibiotics (oxytetracycline, minocycline) have shown evidence of oncogenic activity in rats.

No long-term toxicity studies have been conducted with bismuth subsalicylate.

No long-term studies have been performed to evaluate the effect of the combined use of bismuth subsalicylate, metronidazole, and tetracycline on carcinogenesis, mutagen-esis, or impairment of fertility.

Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage.

In two in vitro mammalian cell assay systems (L51784y mouse lymphoma and Chinese hamster lung cells), there was evidence of mutagenicity by tetracycline hydrochloride at concentrations of 60 and 10 µg/mL, respectively.

Bismuth did not show mutagenic potential in the NTP salmonella plate assay.

No reproductive toxicity studies have been conducted with bismuth subsalicylate.

Tetracycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 25 times the human dose.

Metronidazole, at doses up to 400 mg/kg/day (approximately 3.5 times the recommended maximum human dose based on mg/m²) for 28 days, failed to produce any adverse effects on fertility and testicular function in male rats. Fertility studies have been performed in mice at doses up to six times the maximum recommended human dose based on mg/m² and have revealed no evidence of impaired fertility.

Pregnancy: Teratogenic Effects. Pregnancy Category D: Category D is based on the pregnancy category for tetracycline hydrochloride. (See CONTRAINDICATIONS and WARNINGS, Tetracycline and Metronidazole subsections.)

Non-teratogenic Effects: (See WARNINGS.)

Pregnant women with renal disease may be more prone to develop tetracycline-associ-ated liver failure.

Labor and Delivery: The effect of this therapy on labor and delivery is unknown.

Nursing Mothers: Metronidazole and tetracycline are both secreted into human milk. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, and because of the potential for serious adverse reactions in nursing infants from tetracyclines, a decision should be made whether to discontinue nursing or to discontinue therapy, taking into account the importance of the therapy to the mother. Metronidazole is secreted in human milk in concentrations similar to those found in plasma. (See CONTRAINDICATIONS.)

Pediatric Use: Safety and effectiveness in pediatric patients infected with H. pylori have not been established. (See CONTRAINDICATIONS and WARNINGS.)

Geriatric Use: Clinical studies of HELIDAC Therapy did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing HELIDAC Therapy. As stated in the CONTRAINDICATIONS section, this therapy is contraindicated in patients with renal or hepatic impairment.

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