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There are no adequate and well-controlled studies of PYLERA in pregnant women. However, tetracycline can cause fetal harm when administered to a pregnant woman. The use of drugs of the tetracycline class during the second and third trimester 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 Use In Specific Populations].
Tetracycline administered during pregnancy at high doses ( > 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 Use In Specific Populations].
Tooth Enamel Discoloration and Hypoplasia
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 drug, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. PYLERA, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated [See Use in Specific Populations].
Central and Peripheral Nervous System Effects
Metronidazole: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole: Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible; Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity.
Convulsive seizures have been reported in patients treated with metronidazole.
Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.
Tetracycline: Cases of pseudotumor cerebri in adults have 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.
Bismuth-containing products: Cases of neurotoxicity associated with excessive doses of various bismuth-containing products have been reported. Effects have been reversible with discontinuation of bismuth therapy.
The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of PYLERA therapy [See ADVERSE REACTIONS].
Development of Superinfections
As with other antibiotics, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue PYLERA and institute appropriate therapy.
Photosensitivity, manifested by an exaggerated sunburn reaction, has been observed in patients taking tetracycline [See ADVERSE REACTIONS]. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. Instruct patients taking PYLERA to avoid exposure to the sun or sun lamps. Discontinue treatment at the first evidence of skin erythema.
Darkening of the Tongue and/or Black Stool
Bismuth subcitrate potassium may cause temporary and harmless darkening of the tongue and/or black stools, generally reversible within several days after treatment is stopped [See ADVERSE REACTIONS]. Stool darkening should not be confused with melena.
Use in Patients with Blood Dyscrasias
Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy [See ADVERSE REACTIONS].
Laboratory Test Interactions
Bismuth absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract.
Bismuth subcitrate potassium may cause a temporary and harmless darkening of the stool. However, this change does not interfere with standard tests for occult blood.
Metronizadole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide (NAD+ < = > NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.
Development of Drug Resistant Bacteria
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies have been performed to evaluate the effect of PYLERA on carcinogenesis, mutagenesis, or impairment of fertility.
Bismuth Subcitrate Potassium
No carcinogenicity or reproductive toxicity studies have been conducted with bismuth subcitrate potassium. Bismuth subsalicylate did not show mutagenic potential in the NTP Salmonella plate assay.
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 1.6 times the indicated human dose for a 60 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.
Fertility studies have been conducted with male rats and mice with divergent results. Metronidazole, at doses up to 400 mg/kg/day (approximately 3 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. In another study where rats were treated with up to 400 mg/kg/day for 8 weeks, there was severe degeneration of the seminiferous epithelium in the testes which was associated with a marked decrease in testicular spermatid counts and epididymal sperm counts and a marked decrease in fecundity. These effects were partially reversible.
Fertility studies have been performed in male mice at doses up to six times the maximum recommended human dose based upon mg/m² and have revealed no evidence of impaired fertility. Another fertility study was performed in male mice at oral doses of 500 mg/kg/day (approximately 2 times the indicated human dose based on mg/mē) for 14 days. Metronidazole significantly decreased testes and epididymides weight, decreased sperm viability, and increased the incidence of abnormal sperm. The viability of sperm was normal by 2 months after the start of the treatment.
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.
Use In Specific Populations
Pregnancy Category D
[See WARNING AND PRECAUTIONS]
PYLERA contains bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride. There are no adequate and well-controlled studies of Pylera 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 pregnancy can cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development. Administration of oral tetracycline to pregnant animals at various doses resulted in yellow fluorescence in teeth and bones. If PYLERA is used during pregnancy, or if the patient becomes pregnant while taking PYLERA, the patient should be apprised of the potential hazard to the fetus.
The available human and animal data are summarized below for each of PYLERA's active ingredients:
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 ( > 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 AND PRECAUTIONS].
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.
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 subcitrate potassium
Animal reproductive studies have not been conducted with bismuth subcitrate potassium. It is also not known whether bismuth subcitrate potassium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
PYLERA contains bismuth subcitrate potassium, 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 PYLERA therapy, 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 subcitrate potassium is excreted in human milk.
Safety and effectiveness of PYLERA in pediatric patients infected with Helicobacter pylori have not been established.
Tetracycline use in children may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. PYLERA should not be used in children up to 8 years of age [See WARNINGS AND PRECAUTIONS].
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 patients aged 65 and over to determine whether they respond differently than younger patients. 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 subcitrate potassium, a component of PYLERA, 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].
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 severe renal impairment, higher serum concentrations of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis [See CONTRAINDICATIONS].
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. Use PYLERA with caution in patients with hepatic impairment.
Last reviewed on RxList: 2/6/2013
This monograph has been modified to include the generic and brand name in many instances.
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