Bismuth Subcitrate Potassium, Metronidazole, And Tetracycline Hydrochloride

5 WARNINGS AND PRECAUTIONS Fetal Toxicity: Advise pregnant women of the risk throughout pregnancy for retardation of skeletal development seen in animal studies and permanent discoloration of teeth with tetracycline if used during the second or third trimester. ( 5.2 , 8.1 ) Maternal Toxicity: Risk of hepatotoxicity in pregnant women with high doses of intravenous tetracycline also resulting in stillborn or premature birth. ( 5.3 , 8.1 ) Tooth Enamel discoloration and hypoplasia: permanent discoloration may develop with use during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years). ( 5.4 ) Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with metronidazole. If symptoms or signs of SCARs develop, discontinue PYLERA immediately and institute appropriate therapy. ( 5.5 ) Central and Peripheral Nervous System Effects: encephalopathy, convulsive seizures, aseptic meningitis and peripheral neuropathy with metronidazole, intracranial hypertension with tetracycline and neurotoxicity with bismuth-containing products. Monitor patients with CNS conditions closely and discontinue promptly if abnormal neurologic signs develop. ( 5.6 ) Photosensitivity: avoid exposure to sun and sun lamps. ( 5.8 ) Blood Dyscrasias: Use with caution in patients with a history of blood dyscrasias. ( 5.10 ) Hepatic Impairment: Not recommended in patients with severe hepatic impairment. ( 5.11 ) 5.1 Potential for Carcinogenicity Metronidazole, a component of PYLERA, has been shown to be carcinogenic in mice and rats. Tumors affecting the liver, lungs, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters [see Nonclinical Toxicology (13) ] . It is unknown whether metronidazole is associated with carcinogenicity in humans. 5.2 Fetal Toxicity Tetracycline can cause fetal harm when administered to a pregnant woman. Based on animal data, use of drugs of the tetracycline class during the second and third trimester of pregnancy can cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development [see Warnings and Precautions (5.4) ] . Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. If PYLERA is used during pregnancy, or if the patient becomes pregnant while taking PYLERA, advise the patient of the potential risk to the fetus [see Contraindications (4.5) and Use in Specific Populations (8.1) ] . 5.3 Maternal Toxicity Tetracycline, a component of PYLERA, 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 Contraindications (4.5) and Use in Specific Populations (8.1) ] . 5.4 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 (8.4) ] . 5.5 Severe Cutaneous Adverse Reactions Metronidazole : Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue PYLERA capsules immediately and institute appropriate therapy. Tetracycline : Fixed drug eruptions have occurred with tetracycline and have been associated with worsening severity upon subsequent administrations, including generalize bullous fixed drug eruption [see Adverse Reactions (6.3) ] . If severe skin reactions occur, discontinue PYLERA immediately, and institute appropriate therapy. 5.6 Central and Peripheral Nervous System Effects Metronidazole : Convulsive seizures, encephalopathy, aseptic meningitis and peripheral neuropathy (including optic neuropathy) have been reported. 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. Aseptic meningitis symptoms may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. Tetracycline : Intracranial hypertension (IH), including pseudotumor cerebri, has been associated with the use of tetracyclines. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin should be avoided because isotretinoin is also known to cause IH. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation, patients should be monitored until they stabilize. 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) ] . 5.7 Development of Potential for Microbial Overgrowth Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with an antifungal agent. As with other antibacterial drugs, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue PYLERA and institute appropriate therapy. 5.8 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. 5.9 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 (6.1) ] . Stool darkening should not be confused with melena. 5.10 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 (6.3) ] . 5.11 Increased Drug Plasma Concentrations in Patients with Hepatic Impairment Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events. PYLERA is not recommended in patients with severe hepatic impairment (Child-Pugh C) [see Clinical Pharmacology (12.3) ] . 5.12 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. Metronidazole 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. 5.13 Development of Drug Resistant Bacteria Prescribing PYLERA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.14 Drug Interactions Oral Contraceptives Concurrent use of PYLERA with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of PYLERA. Breakthrough bleeding has been reported. Advise women of child-bearing potential to use a different or additional form of contraception while taking PYLERA [see Drug Interactions (7.3) ] . Anticoagulants PYLERA may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if PYLERA is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Drug Interactions (7.4) ] . Lithium In patients stabilized on relatively high doses of lithium, short-term use of PYLERA may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations daily for several days after beginning treatment with PYLERA to detect any increase that may precede clinical symptoms of lithium toxicity [see Drug Interactions (7.5) ] . Busulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer PYLERA concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to PYLERA are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly [see Drug Interactions (7.7) ] . Drugs that Prolong the QT interval QT prolongation has been reported with metronidazole, a component of PYLERA, particularly when administered with drugs with the potential for prolonging the QT interval.