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Bismuth-containing Products

There have been rare reports of neurotoxicity associated with excessive doses of various bismuth-containing products. 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 metronidazole therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.

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 hypoplasia has also been reported. TETRACYCLINE HYDROCHLORIDE IS A COMPONENT OF PYLERA™ CAPSULES (bismuth subcitrate potassium) . THEREFORE, PYLERA™ CAPSULES (bismuth subcitrate potassium) SHOULD NOT BE USED IN THESE PATIENT POPULATIONS. (See CONTRAINDICATIONS)

Tetracycline hydrochloride should not be used during pregnancy (see WARNINGS above about use during tooth development). Results of animal studies indicate that tetracycline crosses the placenta, is 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 tetracycline. 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 PYLERA™ 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-containing Products

Bismuth subcitrate potassium and other bismuth-containing products may cause a temporary and harmless darkening of the tongue and/or black stool. Stool darkening must 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 an antifungal 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 tetracycline. 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

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

Bismuth Subcitrate Potassium

No carcinogenicity or reproductive toxicity studies have been conducted with bismuth subcitrate potassium. Bismuth subcitrate potassium did not show mutagenic potential in the NTP Salmonella plate assay.

Metronidazole

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 the highest dose levels, (approximately 500 mg/kg/day, which is approximately 1.4 times the indicated human dose for a 50 kg adult based on body surface area), 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.

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.

Metronidazole, at doses up to 400 mg/kg/day (approximately 2 times the indicated 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.

Tetracycline hydrochloride

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.

There was evidence of mutagenicity by tetracycline hydrochloride in two in vitro mammalian cell assay systems (L51784y mouse lymphoma and Chinese hamster lung cells).

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.

Pregnancy

Teratogenic Effects. Pregnancy Category D

Category D is based on the pregnancy category for tetracycline hydrochloride. (See CONTRAINDICATIONS and WARNINGS/Tetracycline subsections)

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 5 percent of the indicated human dose (1500 mg/day) based on body surface area; 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. There are no adequate and well-controlled studies in pregnant women.

Non-teratogenic Effects

Pregnant women with renal disease may be more prone to develop tetracycline-associated liver failure. (See WARNINGS)

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. Metronidazole is secreted in human milk in concentrations similar to those found in plasma. 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. (See CONTRAINDICATIONS)

Pediatric Use

Tetracycline use in children may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. PYLERA™ should not be used in children less than 8 years of age. Safety and effectiveness of PYLERA™ in pediatric patients infected with Helicobacter pylori have not been established. (See CONTRAINDICATIONS and WARNINGS)

Geriatric Use

Of the 324 patients who received PYLERA™ in clinical studies, 40 were ≥ 65 years old. Clinical studies of PYLERA™ 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 PYLERA™. As stated in the CONTRAINDICATIONS section, PYLERA™ is contraindicated in patients with renal or hepatic impairment.

Last reviewed on RxList: 6/13/2007
This monograph has been modified to include the generic and brand name in many instances.