Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride

1 INDICATIONS AND USAGE Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules 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 Capsules 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.

2 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 Capsules 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 )

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 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, 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 is 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, 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, therefore, should n…

4 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 is 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, 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. 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 [see Drug Interactions ( 7.2 )] . 4.3 Cockayne Syndrome Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is 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 and tetracycline hydrochloride is 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 is contraindicated during pregnancy [see Use in Specific Populations ( 8.1 )] . 4.6 Hypersensitivity Reactions Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is 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 )] .

7 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 and disulfiram concurrently. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride 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 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. 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 [see Contraindications ( 4.2 )] . 7.3 Oral Contraceptives Concurrent use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride 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. 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 [see Warnings and Precautions ( 5.14 )] . 7.4 Anticoagulants Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride 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 is 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 may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the …

8.1 Pregnancy Risk Summary Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is contraindicated in women who are pregnant because treatment of Helicobacter pylori infection can be delayed in pregnant women, and 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 ( 5.2 ) and Data] . Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. There are maternal risks with high intravenous doses of tetracycline [see Clinical Considerations] . Metronidazole usage in pregnancy has been associated with certain congenital anomalies [see Data] . In animals, no fetotoxicity was observed when metronidazole was orally administered to pregnant mice at approximately 5% of the indicated human dose. There are no human or animal data on the use of bismuth subcitrate potassium during pregnancy. Although there are data on the separate components, there are no available data on the use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride in pregnant women. Clinical Considerations Maternal Adverse Reactions 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 ( 5.3 )] . Data Human Data Tetracycline 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. The 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. Metronidazole 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. Bismuth subcitrate potassium There are no human data on the use of bismuth subcitrate potassium during pregnancy. Animal Data Tetracycline 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 dis…

6 ADVERSE REACTIONS Most frequently reported adverse reactions (≥5%): abnormal feces, diarrhea, nausea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1-833-520-8580 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 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 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* (n = 147) OAC** (n = 152) Gastrointestinal disorders Abnormal feces*** 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%) Glositis 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%) * OBMT = Omeprazole + bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride ** OAC = Omeprazole + Amoxicillin + Clarithromycin; *** Dark stools [see Warnings and Precautions ( 5.9 )] ​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. 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 ( C…