warnings and cautions
5 WARNINGS AND PRECAUTIONS Fetal Toxicity: Advise pregnant women of the risk for permanent discoloration of teeth with tetracycline if used during the second or third trimester (5.1, 8.1) Maternal Toxicity: Risk of hepatotoxicity in pregnant women with high doses of intravenous tetracycline also resulting in stillborn or premature birth (5.2, 8.1) Central and Peripheral Nervous System Effects: encephalopathy and peripheral neuropathy with metronidazole, pseudotumor cerebri with tetracycline and neurotoxicity with bismuth-containing products; Monitor patients with CNS conditions closely and discontinue promptly if abnormal neurologic signs develop. (5.4) Development of Superinfection: If superinfection occurs, discontinue PYLERA and institute appropriate therapy. (5.5) Photosensitivity: avoid exposure to sun and sun lamps. (5.6) 5.1 Fetal Toxicity There are no adequate and well-controlled studies of PYLERA in pregnant women. However, tetracycline can cause fetal harm when administered to a pregnant women. 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 [See Warnings and Precautions (5.3) ] . Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in 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 (8.1) ] 5.2 Maternal Toxicity 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 (8.3) ]. 5.3 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 commom during long-term use of the drug, but has been observed following repeated short-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 (8.4) ] . 5.4 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 adiminstration 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 (6.3) ] 5.5 Development of Superinfections Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with an antifungal agent. 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 5.6 Photosensitivity Photosensitivity, manifested by an exaggerated sunburn reaction, has been observed in patients taking tetracycline [See Adverse Reactions (6.3) ] . 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. 5.7 Darkening of the Tongue and/or Black Stool Bismuth subcitrate potassium may cause temporary and harmless darkening of the tongue and/or black stool, generally reversible within several days after treatment is stopped [See Adverse Reactions (6.1) ] . Stool darkening should not be confused with melena. 5.8 Use in Patients with Blood Dyscrasias Metronidazole is a nitroimidazole, and should be used with care in patients with evidence 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 (6.3) ] . 5.9 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 5.10 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.