Pregnancy Category D   
Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules contains bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. There are no adequate and well-controlled studies of Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules in pregnant women. However, tetracycline can cause fetal harm when administered to a pregnant woman. The use of tetracycline during the second and third trimester of pregnancy can also cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development. Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. 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 (see WARNINGS).

The available human and animal data are summarized below for each of Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules active ingredients:

Tetracycline   
Published case reports have described the yellowing of bones and teeth in human infants exposed to tetracycline during the second and third trimester of pregnancy. The yellowing is caused by the direct deposition of tetracycline during the mineralization process. This discoloration is more common during long-term use of the drug but has also been observed following repeated short-term courses. All tetracyclines form a stable calcium complex in any bone forming tissue. A decrease in fibula growth rate was observed in premature infants given oral tetracycline in doses of 25 mg/kg every six hours. This effect resolved when the drug was discontinued. One long-term follow-up study in children exposed to tetracycline in-utero showed no adverse effects on bone growth and development.

Tetracycline administered during pregnancy at high doses (greater than 2 g IV) was associated with rare but serious cases of maternal hepatotoxicity. This syndrome may result in stillborn or premature birth due to maternal pathology (see WARNINGS).

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 reversible retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Multiple studies of limited design were conducted with pregnant and lactating female rats that resulted in fetuses and neonates with yellow discoloration of bones and teeth.

Metronidazole   
There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

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 10 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.

Bismuth subsalicylate

Animal reproductive studies have not been conducted with bismuth subsalicylate. It is also not known whether bismuth subsalicylate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

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

Nursing Mothers: Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules contains bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in animal studies, a decision should be made whether to discontinue nursing or to discontinue metronidazole, taking into account the importance of the therapy to the mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

Tetracycline is present in human milk at concentrations similar to maternal serum levels; however, it binds with calcium in human milk. Data indicate that oral absorption of tetracycline in infants is low due to the calcium binding in human milk. It is not known whether bismuth subsalicyate is excreted in human milk.

Pediatric Use: Safety and effectiveness of Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules in pediatric patients infected with H. pylori have not been established.

Tetracycline use in children may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules should not be used in children up to 8 years of age (see WARNINGS).

Geriatric Use: Clinical studies of Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules 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, elderly patients may have a greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapies. Bismuth subsalicylate, a component of Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules, is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, additional monitoring may be required (see CONTRAINDICATIONS).

Renal Impairment: 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 (see CONTRAINDICATIONS).

Hepatic Impairment: Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. Use Bismuth Subsalicylate Chewable Tablets/Metronidazole Tablets/Tetracycline Hydrochloride Capsules with caution in patients with hepatic impairment (see PRECAUTIONS).