Bismuth Subcitrate Potassium, Metronidazole, Tetracycline Hydrochloride

INDICATIONS AND USAGE Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule is a combination of metronidazole, a nitroimidazole antimicrobial, tetracycline, - a tetracycline class antimicrobial and bismuth subcitrate potassium, indicated for use, in combination with omeprazole, for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. ( 1.1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and other antibacterial drugs, bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.2 ) 1.1 Eradication of Helicobacter pylori in Patients with Active Duodenal Ulcer or History of Duodenal Ulcer Disease Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules in combination with omeprazole are indicated for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori . The eradication of Helicobacter pylori has been shown to reduce the risk of duodenal ulcer recurrence. 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and other antibacterial drugs, bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION Administer three bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 4 times a day (after meals and at bedtime) for 10 days. One omeprazole 20 mg capsule should be taken twice a day with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules after the morning and evening meal for 10 days ( Table 1 ). Table 1: Daily Dosing Schedule for Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules Time of dose Number of capsules of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride Number of capsules of omeprazole 20 mg After morning meal 3 1 After lunch 3 0 After evening meal 3 1 At bedtime 3 0 Instruct patients to swallow the bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules whole with a full glass of water (8 ounces). Ingestion of adequate amounts of fluid, particularly with the bedtime dose, is recommended to reduce the risk of esophageal irritation and ulceration by tetracycline hydrochloride. If a dose is missed, patients should continue the normal dosing schedule until medication is gone. Patients should not take double doses. If more than 4 doses are missed, the prescriber should be contacted. Administer three bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 4 times a day (after meals and at bedtime) for 10 days. ( 2 ) Administer bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules with omeprazole 20 mg twice daily (after the morning and evening meals). ( 2 )

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 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 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 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, 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 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are used during pregnancy, or if the patient becomes pregnant while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, 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 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, 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. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, 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 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride 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 Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 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 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 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 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 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 ) ]

CONTRAINDICATIONS Disulfiram usage within the last two weeks. ( 4.1 , 7.1 ) Alcoholic beverage consumption for at least three days during or after therapy. ( 4.2 , 7.2 ) Patients with Cockayne syndrome. ( 4.3 , 6.3 ) Severe renal impairment. ( 4.4 ) Women who are pregnant. ( 4.5 , 8.1 ) Known hypersensitivity to product components. ( 4.6 ) 4.1 Disulfiram Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are contraindicated in patients who have taken disulfiram within the last two weeks. Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, and disulfiram concurrently [see Drug Interactions ( 7.1 ) ]. 4.2 Alcohol Alcoholic beverages or other products containing propylene glycol should not be consumed during and for at least 3 days after therapy with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. A disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) may occur due to the interaction between alcohol or propylene glycol and metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [see Drug Interactions ( 7.2 ) ]. 4.3 Cockayne Syndrome Bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride capsules are contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome [see Adverse Reactions ( 6.3 )]. 4.4 Severe Renal Impairment Bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride capsules are contraindicated in patients with severe renal impairment. The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN) [see Adverse Reactions ( 6.3 ) ]. In patients with significantly impaired renal function, higher serum concentrations of tetracyclines may lead to azotemia, hyperphosphatemia, and acidosis. 4.5 Pregnancy Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are contraindicated during pregnancy [see Use in Specific Populations ( 8.1 ) ]. 4.6 Hypersensitivity Reactions Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are contraindicated in patients with known hypersensitivity (e.g. urticaria, erythematous rash, flushing, and fever) to bismuth subcitrate potassium, metronidazole or other nitroimidazole derivatives, or tetracycline [see Adverse Reactions ( 6.3 ) ].

DRUG INTERACTIONS Disulfiram: Psychotic reactions can occur; do not take concurrently or within the last 2 weeks of disulfiram. ( 4.1 , 7.1 ) Alcohol: Abdominal cramps, nausea, vomiting, headaches, and flushing can occur; do not consume during therapy and for at least 3 days afterwards. ( 4.2 , 7.2 ) Oral Contraceptives: Decreased efficacy possibly resulting in pregnancy; use a different or additional form of contraception. ( 5.14 , 7.3 ) Anticoagulants: Potentiation of the anticoagulant effect; Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored. ( 5.14 , 7.4 ) Lithium: Increased lithium serum concentrations; measure serum lithium and serum creatinine concentrations during therapy. ( 5.14 , 7.5 ) Antacids, Multivitamins or Dairy Products: Decreased absorption of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules; do not take concomitantly. ( 7.6 ) Busulfan: Increased busulfan serum concentrations; avoid concomitant use, monitor for busulfan toxicity. ( 7.7 ) CYP inducers and CYP inhibitors: Prolonged or accelerated half-life of metronidazole or concomitant medications; use with caution. ( 7.8 , 7.9 ) 7.1 Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and disulfiram concurrently. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should not be given to patients who have taken disulfiram within the last two weeks [ see Contraindications ( 4.1 ) ] . 7.2 Alcohol Consumption of alcoholic beverages or administration of other products containing propylene glycol during treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and for at least 3 days afterwards may cause a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) due to the interaction between alcohol or propylene glycol and metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. Discontinue alcoholic beverage or other products containing propylene glycol during and for at least 3 days after therapy with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [ see Contraindications ( 4.2 ) ] . 7.3 Oral Contraceptives Concurrent use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. Breakthrough bleeding has been reported. Women of child-bearing potential should use a different or additional form of contraception while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [ see Warnings and Precautions ( 5.14 ) ] . 7.4 Anticoagulants Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 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. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [ see Warnings and Precautions ( 5.14 ) ] . 7.5 Lithium In patients stabilized on relatively high doses of lithium, short-term use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Serum lithium and serum creatinine concentrations should be monitored several days after beginning treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules to detect any increase that may precede clinical symptoms of lithium toxicity [ see Warnings and Precautions ( 5.14 ) ] . 7.6 Antacids, Multivitamins, or Dairy Products The absorption of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may be reduced if administered with antacids containing aluminium, calcium, or magnesium; preparations containing iron, zinc, or sodium bicarbonate; or milk or dairy products due to the interaction between these products and tetracycline. These products should not be consumed concomitantly with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. However, the clinical significance of reduced tetracycline systemic exposure is unknown as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori has not been established. 7.7 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 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 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 Warnings and Precautions ( 5.14 ) ] . 7.8 Inhibitors of CYP450 liver enzymes The simultaneous administration of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and drugs that inhibit microsomal liver enzymes, such as cimetidine, may result in a prolonged half-life and decreased plasma clearance of metronidazole. 7.9 Inducers of CYP450 liver enzymes The simultaneous administration of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported in this situation. Monitor phenytoin concentrations during treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules.

ADVERSE REACTIONS Most frequently reported adverse reactions (≥5%): abnormal feces, diarrhea, nausea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules plus omeprazole (OBMT) to eradicate Helicobacter pylori was assessed in an open-label, randomized, active-controlled clinical trial conducted in North America. The duration of treatment was 10 days with 147 patients exposed to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules plus omeprazole (OBMT) and 152 exposed to control, consisting of omeprazole, amoxicillin, and clarithromycin (OAC). The age of the population in the study ranged from 18 to 75 years, with 59% male patients and 59% Caucasian patients. Adverse drug reactions were reported in 58% of patients in the OBMT group and 59% of patients in the OAC group. There were no adverse reactions leading to discontinuation of the study during the clinical trial. Adverse reactions with an incidence of ≥ 5% in OBMT group include abnormal feces, diarrhea, nausea, and headache. Adverse drug reactions with an incidence of ≥ 5% in OAC group include diarrhea, dysgeusia, dyspepsia, nausea and headache. Table 2 lists adverse reactions with an incidence of ≥ 1%, in either group (OBMT vs OAC) and in order of decreasing incidence for the OBMT group. Table 2: Adverse reactions with an incidence of ≥ 1% from North American trial, [n (%)] Preferred Term OBMT OBMT = Omeprazole + Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules (n = 147) OAC OAC = Omeprazole + Amoxicillin + Clarithromycin; (n = 152) Gastrointestinal disorders Abnormal feces Dark stools [ see Warnings and Precautions ( 5.9 ) ] 23 (15.6%) 7 (4.6%) Nausea 12 (8.2%) 14 (9.2%) Diarrhea 10 (6.8%) 20 (13.2%) Abdominal Pain 7 (4.8%) 2 (1.3%) Dyspepsia 4 (2.7%) 10 (6.6%) Constipation 2 (1.4%) 5 (3.3%) Dry Mouth 2 (1.4%) 1 (0.7%) Flatulence 0 4 (2.6%) Glossitis 0 2 (1.3%) General disorders and administration site conditions Asthenia 5 (3.4%) 2 (1.3%) Infections and infestations Vaginal infection 4 (2.7%) 3 (2.0%) Nervous system disorders Headache 8 (5.4%) 8 (5.3%) Dysgeusia 6 (4.1%) 18 (11.8%) Dizziness 4 (2.7%) 4 (2.6%) Investigations Laboratory test abnormal 3 (2.0%) 4 (2.6%) Alanine aminotransferase increased 2 (1.4%) 0 Aspartate aminotransferase increased 2 (1.4%) 0 Renal and urinary disorders Urine abnormality 2 (1.4%) 0 Skin and subcutaneous tissue disorders Rash Maculo-Papular 2 (1.4%) 0 Rash 1 (0.7%) 3 (2.0%) Pruritus 0 4 (2.6%) Adverse reactions with an incidence of <1% for OBMT group are: back pain, vomiting, tongue darkening [ see Warnings and Precautions ( 5.9 ) ] , anxiety, gastritis, gastroenteritis, myalgia, chest pain, increased appetite, blood creatine phosphokinase increased, malaise, somnolence, tachycardia, duodenal ulcer, visual disturbance, weight increased. 6.2 Postmarketing Experience Additionally, the following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders : abdominal distention, eructation, flatulence General disorders and administration site conditions : chest discomfort, fatigue Infections and infestations : candidiasis, pseudomembranous colitis ( Clostridium difficile colitis) Nervous Systems : peripheral neuropathy Skin and subcutaneous disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome (drug rash with eosinophilia and systemic symptoms) [see Warnings and Precautions ( 5.5 )] 6.3 Other Important Adverse Reactions from Labeling for the Individual Components of Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules Metronidazole Blood and Lymphatic system disorders: Reversible neutropenia (leucopenia) in cases of prolonged treatment; rarely reversible thrombocytopenia however no persistent hematological abnormalities attributable to metronidazole have been observed [ see Warnings and Precautions ( 5.10 ) ] . Cardiac disorders: QT prolongation has been reported with metronidazole, particularly when administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings. Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain, constipation, anorexia, metallic taste, furry tongue, glossitis, stomatitis and candida overgrowth. Hypersensitivity/Immune system disorders: Acute generalized exanthematous pustulosis (AGEP) [see Warnings and Precautions ( 5.5 )], urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever [see Contraindications ( 4.6 )] . Metabolism and nutrition disorders: Pancreatitis. Nervous system disorders: Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, headache, syncope, dizziness, vertigo, incoordination, ataxia, tinnitus, hearing impairment, hearing loss, confusion, dysarthria, irritability, depression, weakness, and insomnia [ see Warnings and Precautions ( 5.6 ) ] . Dermatologic disorders: Erythematous rash and pruritus. Renal and urinary disorders: Dysuria, cystitis, polyuria, incontinence, darkened urine, and a sense of pelvic pressure. Hepatic : Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome (latency from drug start to signs of liver failure as short as 2 days) [see Contraindications ( 4.3 ) ] . Other: Dyspareunia, decrease of libido, proctitis, joint pains. Tetracycline Hydrochloride Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia, and eosinophilia. Gastrointestinal disorders: Nausea, vomiting, diarrhea, anorexia, glossitis, black hairy tongue, dysphagia, enterocolitis, inflammatory lesions (with Candida overgrowth) in the anogenital region, esophagitis and esophageal ulceration. Nervous system disorders: Intracranial hypertension including pseudotumor cerebri, tinnitus, and myasthenic syndrome. Renal and urinary disorders: Increased BUN. Skin and subcutaneous tissue disorders: Maculopapular and erythematous rashes, onycholysis, fixed drug eruption, discoloration of the nails, exfoliative dermatitis and photosensitivity have been rarely reported [ see Warnings and Precautions ( 5.8 ) ] . Liver : Hepatotoxicity and liver failure. Hypersensitivity reactions : Urticaria, angioedema, anaphylaxis, Henoch-Schonlein purpura, pericarditis, exacerbation of systemic lupus erythematosus, and serum sickness-like reactions.

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are a combination of antibacterial agents (metronidazole and tetracycline hydrochloride) and bismuth subcitrate potassium [ see Microbiology ( 12.4 ) ] . 12.3 Pharmacokinetics The pharmacokinetics of the individual components of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride are summarized below. In addition, two studies on bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules were conducted to determine the effect of co-administration on the pharmacokinetics of the components. Bismuth Subcitrate Potassium (Bismuth) Absorption and Distribution Orally absorbed bismuth is distributed throughout the entire body. Bismuth is highly bound to plasma proteins (>90%). Metabolism and Excretion The elimination half-life of bismuth is approximately 5 days in both blood and urine. Elimination of bismuth is primarily through urinary and biliary routes. The rate of renal elimination appears to reach steady state 2 weeks after treatment discontinuation with similar rates of elimination at 6 weeks after discontinuation. The average urinary elimination of bismuth is 2.6% per day in the first two weeks after discontinuation (urine drug concentrations 24 to 250 mcg/mL) suggesting tissue accumulation and slow elimination. Metronidazole Absorption and Distribution Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between 1 and 2 hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose, with oral administration of 500 mg producing a peak plasma concentration of 12 mcg/mL. Metronidazole appears in the plasma mainly as unchanged compound with lesser quantities of the 2-hydroxymethyl metabolite also present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole also appears in cerebrospinal fluid, saliva, and breast milk in concentration similar to those found in plasma. Metabolism and Excretion The average elimination half-life of metronidazole in normal volunteers is 8 hours. The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(β-hydroxyethyl) 2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73m 2 . Decreased renal function does not alter the single dose pharmacokinetics of metronidazole. In patients with decreased liver function, plasma clearance of metronidazole is decreased. Tetracycline Hydrochloride Absorption, Distribution, Metabolism and Excretion Tetracycline hydrochloride is absorbed (60%-90%) in the stomach and upper small intestine. The presence of food, milk or cations may significantly decrease the extent of absorption. In the plasma, tetracycline is bound to plasma proteins in varying degrees. It is concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in biologically active form. Tetracycline hydrochloride is distributed into most body tissues and fluids. It is distributed into the bile and undergoes varying degrees of enterohepatic recirculation. Tetracycline hydrochloride tends to localize in tumors, necrotic or ischemic tissue, liver and spleen and form tetracycline-calcium orthophosphate complexes at sites of new bone formation or tooth development. Tetracycline readily crosses the placenta and is excreted in high amounts in breast milk. Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules A comparative bioavailability study of metronidazole (375 mg), tetracycline hydrochloride (375 mg) and bismuth subcitrate potassium (420 mg, equivalent to 120 mg Bi 2 O 3 ) administered as bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules or as 3 separate capsule formulations administered simultaneously was conducted in healthy male volunteers. The pharmacokinetic parameters for the individual drugs, when administered as separate capsule formulations or as bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, are similar as shown in Table 3 . Table 3: Mean (%CV) Pharmacokinetic Parameters for Metronidazole, Tetracycline hydrochloride, and Bismuth Subcitrate Potassium in Healthy Volunteers (N=18) C max (ng/mL) (%C.V. C.V. Coefficient Variation ) AUC T (ng · h/mL) (%C.V. * ) AUC ∞ (ng · h/mL) (%C.V. * ) Metronidazole Metronidazole Capsule 9044 (20) 80289 (15) 81849 (16) Bismuth Subcitrate, Metronidazole and Tetracycline Hydrochloride Capsules Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules given as a single dose of 3 capsules 8666.3 (22) 83018 (17) 84413 (17) Tetracycline Tetracycline Capsules 748.0 (40) 9544 (55) 9864 (53) Bismuth Subcitrate, Metronidazole and Tetracycline Hydrochloride Capsules † 774 (47) 9674 (50) 9987 (49) Bismuth Bismuth Capsule 22 (123) 47 (129) 65.4 (113) Bismuth Subcitrate, Metronidazole and Tetracycline Hydrochloride Capsules † 17 (202) 43 (191) 57 (178) Effect of Bismuth on the Bioavailability of Tetracycline Hydrochloride There is an anticipated reduction in tetracycline hydrochloride systemic absorption due to an interaction with bismuth. The effect of a reduced tetracycline hydrochloride systemic exposure, due to an interaction with bismuth, on the clinical efficacy of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules is not thought to be clinically meaningful as the contribution of systemic, as compared to local, antimicrobial activity against Helicobacter pylori has not been established. Effect of Food on the Bioavailability of Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules The pharmacokinetic parameters for metronidazole, tetracycline hydrochloride and bismuth were also determined when bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules were administered under fasting and fed conditions, as shown in Table 4 . Food reduced the systemic absorption of all three bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule components, with AUC values for metronidazole, tetracycline hydrochloride and bismuth being reduced by 6%, 34% and 60%, respectively. Reduction in the absorption of all three bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule components in the presence of food is not considered to be clinically significant. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should be given after meals and at bedtime, in combination with omeprazole twice a day. Table 4: Mean Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules Pharmacokinetic Parameters in Fasted and Fed States (N=18) Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules given as a single dose of 3 capsules FED FASTED Metronidazole Tetracycline Bismuth Metronidazole Tetracycline Bismuth C max (ng/mL) (%C.V.) 6835.0 (13) 515.8 (36) 1.7 (61) 8666.3 (22) 773.8 (47) 16.7 (202) T max (hours) T max is expressed as median (range) (range) 3.0 (1.3 - 4.0) 4.0 (2.5 - 5.0) 3.5 (0.8 - 6.0) 0.75 (0.5 - 3.5) 3.3 (1.3 - 5.0) 0.6 (0.5 - 1.7) AUC ∞ (ng · h/mL) (%C.V.) 79225.6 (18) 5840.1 (312) 18.4 (116) 84413.6 (17) 9986.7 (49) 56.5 (178) Effect of Omeprazole on the Bioavailability of Bismuth The effect of omeprazole on bismuth absorption was assessed in 34 healthy vo