BISMUTH SUBCITRATE POTASSIUM, METRONIDAZOLE, TETRACYCLINE HYDROCHLORIDE

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are a combination antimicrobial product containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride for oral administration. Each size 0 elongated capsule contains: bismuth subcitrate potassium, 140 mg metronidazole, 125 mg smaller capsule (size 3) containing tetracycline hydrochloride, 125 mg Tetracycline hydrochloride is encapsulated within a smaller capsule to create a barrier to avoid contact with bismuth subcitrate potassium. Each bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule contains the following inactive ingredients: magnesium stearate NF, lactose monohydrate NF, talc USP, gelatin NF and titanium dioxide USP. The imprinting black ink contains ammonium hydroxide NF, ferrosoferric oxide NF, propylene glycol USP and shellac USP. Bismuth subcitrate potassium is a white to off-white powder. It is soluble, and a double salt of bismuth citrate and potassium citrate, containing an additional part of potassium hydroxide. The schematized empirical molecular formula of bismuth subcitrate potassium is BiK 5 (OH) 2 (C 6 H 5 O 7 ) 2. H 2 O. The equivalent theoretical molecular formula is BiC 12 H 14 K 5 O 1 7 . The molecular mass of the theoretical molecular formula of a single unit of bismuth subcitrate potassium is 834.7. Metronidazole is a white to pale yellow, odorless crystals or crystalline powder. Metronidazole is 2-methyl-5-nitroimidazole-1-ethanol, with a molecular formula of C 6 H 9 N 3 O 3 and the following structural formula: Molecular weight: 171.15 Tetracycline hydrochloride is a yellow, odorless, crystalline powder. Tetracycline hydrochloride is (4S,4aS,5aS,6S,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-penta-hydroxy-6-methyl-1, 11-dioxo-2-napthacenecarboxamide monohydrochloride with a molecular formula of C 22 H 24 N 2 O 8 •HCl and the following structural formula: Molecular weight: 480.90 structure metronidazole structure tetracycline

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.

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 )

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 ) ].

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.

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.