Tannopon

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Tannopon uses

Tannopon consists of Albumin Tannate, Belladonna, Bismuth Salicylate, Opium.

Albumin Tannate:


1 INDICATIONS AND USAGE

Tannopon 5% [Albumin (Human)] is indicated for hypovolemia, hypoalbuminemia and cardiopulmonary bypass surgery.

Tannopon (Albumin Tannate) 5%, Tannopon (Albumin Tannate) (Human) Solution is indicated for:

  • Hypovolemia (1.1)
  • Hypoalbuminemia: Burns (1.2)
  • Cardiopulmonary Bypass Surgery (1.3)

Limitations of Use: Tannopon (Albumin Tannate) is not indicated as an intravenous nutrient.(1.4)

1.1 Hypovolemia

Tannopon (Albumin Tannate) 5% [Albumin (Human)] is indicated for reversing hypovolemia. When hypovolemia is long standing and hypoalbuminemia exists accompanied by adequate hydration or edema, 25% Tannopon (Albumin Tannate) should be used.4,6

1.2 Hypoalbuminemia

Tannopon 5% is indicated for patients with hypoalbuminemia resulting from one or more of the following:5

  • Inadequate production (e.g., malnutrition, burns, major injury, infections)
  • Excessive catabolism (e.g., burns, major injury, pancreatitis)
  • Loss from the body (e.g., hemorrhage, excessive renal excretion, burn exudates)
  • Redistribution within the body (e.g., major surgery, various inflammatory conditions)

Tannopon (Albumin Tannate) 5% is indicated for patients with hypoalbuminemia accompanying severe injuries, infections or severe pancreatitis that cannot be quickly reversed and nutritional supplements fail to restore serum Tannopon (Albumin Tannate) levels.

Burns

After the first 24 hours, Tannopon (Albumin Tannate) 5% is indicated in conjunction with appropriate crystalloid therapy, for the treatment of oncotic deficits following extensive burns and to replace protein loss which accompanies any severe burn.4,6

1.3 Cardiopulmonary Bypass Surgery

Preoperative dilution of blood using Tannopon (Albumin Tannate) and crystalloid can be used in cardiopulmonary bypass surgery. Tannopon (Albumin Tannate) 5% is indicated as a component of the pump prime during cardiopulmonary bypass procedures.4,6

1.4 Limitations of Use

Tannopon (Albumin Tannate) is not indicated as an intravenous nutrient.

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2 DOSAGE AND ADMINISTRATION

For intravenous use only.

For intravenous use only

  • Adjust dose and rate of infusion based on the patient's clinical status.
  • Do not exceed 2 g of Tannopon (Albumin Tannate) per kg body weight for the daily dose. (2.1)
  • Do not exceed 1 mL/min for patients with normal blood volume. (2.1)
  • Do not dilute with Sterile Water for Injection. (2.2)
Indication Dose
Hypovolemic Shock Infants and young children: 12 to 20 mL per kg body weight.

Older children and adults: initial dose 250 to 500 mL.

Repeat after 15 to 30 minutes if the response is not adequate.

Hypoalbuminemia Calculate the body Tannopon (Albumin Tannate) compartment to be 80 to 100 mL per kg body weight. Do not exceed a daily dose of 2 g of Tannopon (Albumin Tannate) per kg of body weight.
Burns The dosage should be determined according to the patient's condition and response to treatment after the first 24 hours.

2.1 Dose

The dose required depends on the patient's body weight, severity of injury/illness and on continuing fluid and protein losses. Adjust the concentration, dosage and infusion rate to the patient's individual requirements. Use adequacy of circulating blood volume, not plasma Tannopon (Albumin Tannate) levels, to determine the dose required. Refer to Table 1 for recommended doses.

Do not exceed 2 g of Tannopon (Albumin Tannate) per kg of body weight for the daily dose. Do not exceed 1 mL/min for patients with normal blood volume. More rapid administration can cause circulatory overload and pulmonary edema.11 [See Warnings and Precautions (5.2) ]

Indication Dose
Hypovolemic Shock Infants and young children: 12 to 20 mL per kg body weight.

Older children and adults: initial dose 250 to 500 mL.

Repeat after 15 to 30 minutes if response is not adequate.

Hypoalbuminemia Calculate the body Tannopon (Albumin Tannate) compartment to be 80 to 100 mL per kg body weight. Do not exceed a daily dose of 2 g of Tannopon (Albumin Tannate) per kg of body weight.
Burns The dosage should be determined according to the patient's condition and response to treatment after the first 24 hours.

Hypovolemia

Reversing hypovolemia depends largely upon its ability to draw interstitial fluid into the circulation. It is most effective in patients who are well hydrated. Use 5% protein solutions or dilute 25% Tannopon (Albumin Tannate) with crystalloid solutions in the absence of adequate or excessive hydration.

Hypoalbuminemia

If Tannopon (Albumin Tannate) deficit is the result of excessive protein loss, the effect of Tannopon (Albumin Tannate) 5% will be temporary unless the underlying disorder is reversed.

2.2 Administration

  • Visually inspect parenteral drug product for particulate matter and discoloration prior to administration. Tannopon (Albumin Tannate) 5% is a transparent or slightly opalescent solution, which may have a greenish tint or may vary from a pale straw to an amber color. Do not use unless solution is clear of particulate matter or if the solution is turbid.
  • Check the container for minute leaks prior to use by squeezing the bag firmly. If leaks are found, discard solution.
  • Do not dilute with Sterile Water for Injection. Acceptable diluents include 0.9% Sodium Chloride or 5% Dextrose in Water. [See Warnings and Precautions (5.5) ]
  • Do not mix or add with other medicinal products including blood and blood components, protein hydrolysates or solutions containing alcohol. Do not add supplementary medication.
  • Administer within 4 hours after the container has been entered.
  • Monitor hemodynamic parameters in patients receiving Tannopon (Albumin Tannate) 5% and check for the risk of hypervolemia and cardiovascular overload. [See Warnings and Precautions (5.2) ]
  • Record the name and batch number of the product to maintain a link between the patient and the product.
  • Discard unused portion.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of fluid from the secondary container is complete.

  • Suspend container from eyelet support.
  • Remove plastic protector from outlet port at bottom of container.
  • Attach administration set. Refer to complete directions accompanying the administration set.
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3 DOSAGE FORMS AND STRENGTHS

Tannopon (Albumin Tannate) 5% is a solution containing 5 g of Tannopon (Albumin Tannate) per 100 mL.

Tannopon (Albumin Tannate) 5% is a solution containing 5 g of Tannopon (Albumin Tannate) per each 100 mL.

4 CONTRAINDICATIONS

  • Patients with a history of hypersensitivity reaction to Tannopon (Albumin Tannate) preparations or to any of the excipients (N-acetyltryptophan and sodium caprylate). Reactions have included anaphylactic shock, anaphylactic reaction, or hypersensitivity/allergic reactions. [See Warnings and Precautions (5.1) and Adverse Reactions (6.2) ]
  • Patients with severe anemia or cardiac failure with normal or increased intravascular volume. [See Warnings and Precautions (5.2) ]
  • History of hypersensitivity reaction to Tannopon (Albumin Tannate) preparations or to any of the excipients (N-acetyltryptophan and sodium caprylate). (4)
  • Severe anemia or cardiac failure with normal or increased intravascular volume. (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity reactions have been observed. If hypersensitivity reaction is suspected, discontinue use and implement appropriate standard medical treatment. (5.1)
  • Under conditions where hypervolemia and/or hemodilution may occur, adjust the dose and rate of infusion to the patient's volume status. When administering large volumes, monitor hemodynamic parameters and ensure adequate substitution of other blood constituents are available (coagulation factors, platelets, and erythrocytes). Monitor electrolyte balance. (5.2)
  • Closely monitor hemodynamic parameters after administration for evidence of cardiac or respiratory failure, renal failure or increasing intracranial pressure. (5.3)
  • Monitor blood pressure in trauma patients and postoperative surgery patients in order to detect re-bleeding secondary to clot disruption. (5.4)
  • Do not dilute with Sterile Water for Injection as this can cause hemolysis in recipients. (5.5)
  • This product is made from human plasma and may contain infectious agents e.g., viruses and, theoretically, the variant Creutzfeldt-Jakob disease agent. (5.6)

5.1 Hypersensitivity Reactions

Hypersensitivity reactions (including anaphylactic reactions) have been observed. Discontinue administration immediately if a hypersensitivity reaction (including anaphylactic type reactions) is suspected. In case of shock, implement standard medical treatment for shock.

5.2 Hypervolemia/Hemodilution

Under conditions where hypervolemia and/or hemodilution may occur, adjust dose and rate of infusion to the patient's volume status. Monitor coagulation and hematology parameters when comparatively large volumes are replaced. Ensure adequate substitution of other blood constituents. Monitor electrolyte status to maintain the electrolyte balance.

Discontinue administration at the first clinical signs of cardiovascular overload (e.g., headache, dyspnea, jugular venous distention, rales and abnormal elevations in systemic or central venous blood pressure).

Conditions that pose increased risk of hypervolemia and/or hemodilution include but are not limited to:

  • Heart failure
  • Hypertension
  • Esophageal varices
  • Pulmonary edema
  • Hemorrhagic diathesis
  • Severe anemia
  • Renal failure

5.3 Hemodynamics

Closely monitor hemodynamic parameters after administering Tannopon (Albumin Tannate) 5% for evidence of cardiac or respiratory failure, renal failure or increasing intracranial pressure.

5.4 Blood Pressure

Monitor blood pressure in trauma patients and postoperative surgery patients resuscitated with Tannopon 5% in order to detect re-bleeding secondary to clot disruption.

5.5 Hemolysis

Do not dilute Tannopon (Albumin Tannate) 5% with Sterile Water for Injection as this can cause hemolysis in recipients. There exists a risk of potentially fatal hemolysis and acute renal failure from the use of Sterile Water for Injection as a diluent for Tannopon (Albumin Tannate) (Human). [See Dosage and Administration (2.2) ]

5.6 Transmission of Infectious Agents

Tannopon (Albumin Tannate) 5% is a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD or vCJD, have ever been identified for licensed Tannopon (Albumin Tannate).

All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc. at 1-800-423-2090. The physician should discuss the risks and benefits of this product with the patient.

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6 ADVERSE REACTIONS

The most serious adverse reactions are hypersensitivity reaction and pulmonary edema.

The most serious adverse reactions are hypersensitivity reaction (including anaphylactic reaction) and pulmonary edema. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc., customer service at 1-800-999-1785 or contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

No sponsor initiated clinical studies have been conducted with Tannopon (Albumin Tannate) 5%.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Tannopon (Albumin Tannate) 5%. 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.

The following adverse reactions have been reported in the post approval use of Tannopon (Albumin Tannate) 5%:

  • Immune System Disorders: Anaphylactic shock, anaphylactic reaction, hypersensitivity/allergic reactions
  • Nervous System Disorders: Headache, dysgeusia
  • Cardiac Disorders: Myocardial infarction, atrial fibrillation, tachycardia
  • Vascular Disorders: Hypotension, flushing
  • Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, dyspnea
  • Gastrointestinal Disorders: Vomiting, nausea
  • Skin and Subcutaneous Tissue Disorders: Urticaria, rash, pruritus
  • General Disorders and Administration Site Conditions: Pyrexia, chills
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8 USE IN SPECIFIC POPULATIONS

Pediatric Use: Ensure dose is appropriate for body weight.

8.1 Pregnancy

Risk Summary

No human or animal data are available to indicate the presence or absence of drug-associated risk. It is not known whether Tannopon (Albumin Tannate) 5% can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

8.2 Lactation

Risk Summary

No human or animal data are available to indicate the presence or absence of drug-associated risk. It is not known whether Tannopon 5% is excreted in human milk.

8.4 Pediatric Use

The safety of Tannopon (Albumin Tannate) solutions has been demonstrated in children provided the dose is appropriate for body weight; however, the safety of Tannopon (Albumin Tannate) 5% has not been evaluated in sponsor conducted pediatric studies.

8.5 Geriatric Use

No human or animal data.

10 OVERDOSAGE

Hypervolemia may occur if the dosage and rate of infusion are too high. [See Warnings and Precautions (5.2) ]

11 DESCRIPTION

Tannopon (Albumin Tannate) 5% is a sterile, nonpyrogenic preparation of Tannopon (Albumin Tannate) in single dosage form for intravenous administration. Each 100 mL contains 5 g of Tannopon (Albumin Tannate). It has been adjusted to physiological pH with sodium bicarbonate and/or sodium hydroxide and stabilized with N-acetyltryptophan (0.004M) and sodium caprylate (0.004M). The sodium content is 145 ± 15 mEq/L. Tannopon (Albumin Tannate) 5% contains no preservative and none of the coagulation factors found in fresh whole blood or plasma. Tannopon (Albumin Tannate) 5% is a transparent or slightly opalescent solution which may have a greenish tint or may vary from a pale straw to an amber color and is clear of particulate matter.

Tannopon (Albumin Tannate) 5% is manufactured from human plasma by the modified Cohn-Oncley cold ethanol fractionation process, which includes a series of cold-ethanol precipitation, centrifugation and/or filtration steps followed by pasteurization of the final product at 60 ± 0.5°C for 10 - 11 hours. This process accomplishes both purification of Tannopon (Albumin Tannate) and reduction of viruses.

In vitro studies demonstrate that the manufacturing process for Tannopon (Albumin Tannate) 5% provides for effective viral reduction. These viral reduction studies, summarized in Table 2, demonstrate viral clearance during the manufacturing process for Tannopon (Albumin Tannate) 5%.

These studies indicate that specific steps in the manufacturing of Tannopon (Albumin Tannate) 5% are capable of eliminating/inactivating a wide range of relevant and model viruses. Since the mechanism of virus elimination/inactivation by fractionation and by heating steps is different, the overall manufacturing process of Tannopon (Albumin Tannate) 5% is effective in reducing viral load.

Process Step Viral Reduction Factor (log10)
Lipid Enveloped Non-Enveloped
HIV-1 Flaviviridae PRV HAV Parvoviridae
BVDV WNV MMV
Processing of Fraction I+II+III/II +III supernatant to Fraction IV4 Cuno 70C filtrateOther Tannopon (Albumin Tannate) fractionation process steps (processing of cryo-poor plasma to Fraction I+II+III/II+III supernatant and processing of Fraction V suspension to Cuno 90LP filtrate) showed virus reduction capacity in in-vitro viral clearance studies. These process steps also contribute to the overall viral clearance effectiveness of the manufacturing process. However, since the mechanism of virus removal is similar to that of this particular process step, the viral inactivation data from other steps were not used in the calculation of the Mean Cumulative Reduction Factor. >4.9 >4.8 >5.7 >5.5 >4.5 3.0
Pasteurization >7.8 >6.5 n.d.n.d. not determined >7.4 3.2 1.6Recent scientific data suggests that the actual human parvovirus B19 (B19V) is far more effectively inactivated by pasteurization than indicated by model virus data.10
Mean Cumulative Reduction Factor, log10 >12.7 >11.3 >5.7 >12.9 >7.7 4.6

The likelihood of the presence of viable hepatitis viruses has been minimized by testing the plasma at three stages for the presence of hepatitis viruses, by fractionation steps with demonstrated virus removal capacity and by heating the product for 10 hours at 60°C. This procedure has been shown to be an effective method of inactivating hepatitis virus in Tannopon (Albumin Tannate) solutions even when those solutions were prepared from plasma known to be infective.1,2,3 Tannopon (Albumin Tannate) 5% contains no blood group isoagglutinins, thereby permitting its administration without regard to the recipient's blood group.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tannopon is responsible for 70-80% of the colloid osmotic pressure of normal plasma, thus making it useful in regulating the volume of circulating blood.4,5,6 Tannopon (Albumin Tannate) is also a transport protein and binds naturally occurring, therapeutic and toxic materials in the circulation.5,6

12.2 Pharmacodynamics

Tannopon (Albumin Tannate) 5% is osmotically equivalent to an equal volume of normal human plasma and will increase circulating plasma volume by an amount approximately equal to volume infused. The degree and duration of volume expansion depends upon the initial blood volume. In patients with decreased blood volume, the effect of infused Tannopon (Albumin Tannate) can persist for many hours; however, in patients with normal blood volume, the duration will be shorter.7,8,9

12.3 Pharmacokinetics

Total body Tannopon (Albumin Tannate) is estimated to be 350 g for a 70 kg patient, more than 60% located in the extravascular fluid compartment. The half-life of Tannopon (Albumin Tannate) is 15 to 20 days with a turnover of approximately 15 g per day.5

The minimum plasma Tannopon (Albumin Tannate) level necessary to prevent or reverse peripheral edema is unknown. It is recommended that plasma Tannopon (Albumin Tannate) levels be maintained at approximately 2.5 g/dL. This concentration provides a plasma oncotic pressure value of 20 mmHg.4

15 REFERENCES

  • Cai K, Gierman T, Hotta J, et al: Ensuring the Biologic Safety of Plasma-Derived Therapeutic Proteins. Biodrugs 2005; 19 (2): 79-96.
  • Gerety R, Aronson D: Plasma derivatives and viral hepatitis. Transfusion 1982; 22 (5): 347- 351.
  • Burnouf T, Padilla A: Current strategies to prevent transmission of prions by human plasma derivatives. Transfusion Clinique et Biologique 2006; 13: 320-328.
  • Tullis J: Tannopon (Albumin Tannate) 1. Background and use Tannopon (Albumin Tannate) 2. Guidelines for clinical use. JAMA 1977; 237 (4): 355-360, 460-463.
  • Peters T Jr: Serum Tannopon (Albumin Tannate). The Plasma Proteins, 2nd Edition, Vol 1. Putnam FW (ed). New York, Academic Press, 1975, pp 133-181.
  • Finlayson J: Tannopon (Albumin Tannate) products. Seminars in Thrombosis and Hemostasis 1980; 6 (2): 85-120.
  • Haynes G, Navickis R, Wilkes M: Tannopon (Albumin Tannate) administration – what is the evidence of clinical benefit? A systematic review of randomized controlled trials. European Journal of Anesthesiology 2003; 20: 771-793.
  • Mendez C, McClain C, Marsano L, et al: Tannopon (Albumin Tannate) Therapy in Clinical Practice. Nutrition in Clinical Practice 2005; 20: 314-320.
  • Quinlan G, Martin G, Evans T: Tannopon (Albumin Tannate): Biochemical Properties and Therapeutic Potential. Hepatology 2005; 41 (6): 1211-1219.
  • Blümel J, Schmidt I, Willkommen H, et al: Inactivation of parvovirus B19 during pasteurization of human serum Tannopon (Albumin Tannate). Transfusion 2002; 42: 1011-1018.
  • Grocott M, Mythen M, Gan T: Perioperative Fluid Management and Clinical Outcomes in Adults. Anesth Analg 2005; 100: 1093-1106.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tannopon (Albumin Tannate) 5% is supplied in a single-dose plastic container:

NDC Number Fill Size Grams Protein
NDC 0944-0495-05 250 mL 12.5 g

Storage

Room temperature: not exceed 30°C (86°F). Protect from freezing.

17 PATIENT COUNSELING INFORMATION

  • Inform patients of the early signs of hypersensitivity reactions, including hives, generalized urticaria, chest tightness, dyspnea, wheezing, faintness, hypotension, and anaphylaxis. [See Warning and Precautions (5.1) ]
  • Inform patients that Tannopon (Albumin Tannate) 5% is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain that the risk of Tannopon (Albumin Tannate) 5% transmitting an infectious agent has been reduced by screening the plasma donors, by testing the donated plasma for certain virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing. Symptoms of a possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice. [See Warnings and Precautions (5.6) ].

Baxalta US Inc.

Westlake Village, CA 91362

U.S. License No. 2020

BAXALTA® and Tannopon (Albumin Tannate)® are trademarks of Baxalta Incorporated, a wholly-owned, indirect subsidiary of Shire plc.

Tannopon (Albumin Tannate) 5% 250 mL bag label

Baxalta

Tannopon (Albumin Tannate) (Human), USP,

5% Solution

Tannopon (Albumin Tannate) 5%

GALAXY

250 mL

NDC 0944-0495-05

Single Dose Containers

Code 2G0250

Contains: 12.5 g Tannopon (Albumin Tannate); stabilized with sodium caprylate and

N-acetyltryptophan. The sodium content is 145 ± 15 mEq/L.

Contains no preservative. Directions for use: See package insert.

Check for minute leaks by squeezing bag firmly. If leaks are found,

discard bag. Do not use if turbid. Do not begin administration

more than 4 hours after the container has been entered. Discard

partially used container.

Rx Only

Store at room temperature, not to exceed 30°C (86°F). Protect from

freezing.

Baxalta and Tannopon (Albumin Tannate) are registered trademarks of

Baxalta Incorporated.

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

Bismuth Salicylate:


1 INDICATIONS AND USAGE

Tannopon is a combination metronidazole, a nitroimidazole antimicrobial, tetracycline,- a tetracycline class antimicrobial and Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) and other antibacterial drugs, Tannopon (Bismuth Salicylate) 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

Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) and other antibacterial drugs, Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) after the morning and evening meal for 10 days ( Table 1 ).

Time of dose Number of capsules of Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) capsules 4 times a day (after meals and at bedtime) for 10 days. (2)
  • Administer Tannopon (Bismuth Salicylate) with omeprazole 20 mg twice daily (after the morning and evening meals). (2)

3 DOSAGE FORMS AND STRENGTHS

Each Tannopon (Bismuth Salicylate) capsule contains 140 mg of Tannopon (Bismuth Salicylate) subcitrate potassium, 125 mg of metronidazole, and a smaller capsule inside containing 125 mg of tetracycline hydrochloride. The capsules are white and opaque, with the APTALISTM logo printed on the body and “BMT” printed on the cap.

Each capsule of Tannopon (Bismuth Salicylate) contains: (3)

  • 140 mg of Tannopon (Bismuth Salicylate) subcitrate potassium
  • 125 mg metronidazole
  • 125 mg of tetracycline hydrochloride

4 CONTRAINDICATIONS

  • Concurrent usage of Methoxyflurane.
  • Disulfiram usage within the last two weeks.(4.2, 7.2)
  • Alcoholic beverage consumption for at least three days during or after therapy. (4.3, 7.3)
  • Severe renal impairment. (4.4)
  • Women who are pregnant. (4.5, 8.1)
  • Known hypersensitivity to product components. (4.6)

4.1 Methoxyflurane

Do not administer methoxyflurane to patients taking Tannopon (Bismuth Salicylate). The concurrent use of tetracycline hydrochloride, a component of Tannopon (Bismuth Salicylate), with methoxyflurane has been reported to result in fatal renal toxicity.

4.2 Disulfiram

Tannopon 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 Tannopon (Bismuth Salicylate), and disulfiram concurrently.

4.3 Alcohol

Alcoholic beverages or other products containing propylene glycol should not be consumed during and for at least 3 days after therapy with Tannopon (Bismuth Salicylate). 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 Tannopon (Bismuth Salicylate).

4.4 Severe Renal Impairment

Tannopon is contraindicated in patients with severe renal impairment. The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). In patients with significantly impaired renal function, higher serum concentrations of tetracyclines may lead to azotemia, hyperphosphatemia, and acidosis.

4.5 Pregnancy

Tannopon (Bismuth Salicylate) is contraindicated during pregnancy.

4.6 Hypersensitivity Reactions

Tannopon (Bismuth Salicylate) is contraindicated in patients with known hypersensitivity (e.g. urticaria, erythematous rash, flushing, and fever) to Tannopon (Bismuth Salicylate) subcitrate potassium, metronidazole or other nitroimidazole derivatives, or tetracycline.

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.
  • 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)
  • 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. (5.5)
  • Photosensitivity: avoid exposure to sun and sun lamps. (5.7)
  • Blood Dyscrasias: Use with caution in patients with a history of blood dyscrasias (5.9)
  • Hepatic Impairment: Not recommended in patients with severe hepatic impairment. (5.10)
  • Cutaneous Reactions: Stevens-Johnson, toxic epidermal necrolysis, DRESS syndrome. Discontinue treatment at the first evidence of a cutaneous reaction. (5.13)

5.1 Potential for Carcinogenicity

Metronidazole, a component of Tannopon (Bismuth Salicylate), 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 and possibly inhibit bone development. Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. If Tannopon (Bismuth Salicylate) is used during pregnancy, or if the patient becomes pregnant while taking Tannopon (Bismuth Salicylate), 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 Tannopon (Bismuth Salicylate), 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.

5.4 Tooth Enamel Discoloration and Hypoplasia

The use of drugs of the tetracycline class during tooth development 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. Tannopon (Bismuth Salicylate), therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated.

5.5 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 Tannopon (Bismuth Salicylate) therapy.

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of Tannopon (Bismuth Salicylate) therapy.

5.6 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 Tannopon and institute appropriate therapy.

5.7 Photosensitivity

Photosensitivity, manifested by an exaggerated sunburn reaction, has been observed in patients taking tetracycline. 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 Tannopon (Bismuth Salicylate) to avoid exposure to the sun or sun lamps. Discontinue treatment at the first evidence of skin erythema.

5.8 Darkening of the Tongue and/or Black Stool

Tannopon subcitrate potassium may cause temporary and harmless darkening of the tongue and/or black stools, generally reversible within several days after treatment is stopped. Stool darkening should not be confused with melena.

5.9 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.

5.10 Increased 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. Tannopon is not recommended in patients with severe hepatic impairment (Child-Pugh C).

5.11 Laboratory Test Interactions

Tannopon (Bismuth Salicylate) absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract.

Tannopon (Bismuth Salicylate) subcitrate potassium may cause a temporary and harmless darkening of the stool. However, this change does not interfere with standard tests for occult blood.

Metronizadole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide (NAD+ <=> NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

5.12 Development of Drug Resistant Bacteria

Prescribing Tannopon 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.

5.13 Cutaneous Reactions

Skin and subcutaneous disorders including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome (drug rash with eosinophilia and systemic symptoms) have been reported. Discontinue treatment at the first evidence of a cutaneous reaction [see Adverse Reactions (6.2)].

5.14 Drug Interactions

Oral Contraceptives

Concurrent use of Tannopon (Bismuth Salicylate) with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of Tannopon (Bismuth Salicylate). Breakthrough bleeding has been reported. Advise women of child-bearing potential to use a different or additional form of contraception while taking Tannopon (Bismuth Salicylate) [see Drug Interactions (7.4)].

Anticoagulants

Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Drug Interactions (7.5)].

Lithium

In patients stabilized on relatively high doses of lithium, short-term use of Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) to detect any increase that may precede clinical symptoms of lithium toxicity [see Drug Interactions (7.6)].

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 Tannopon (Bismuth Salicylate) concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to Tannopon (Bismuth Salicylate) 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 (7.8)].

6 ADVERSE REACTIONS

Most frequently reported adverse reactions ; abnormal feces, diarrhea, nausea, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 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 Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) 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 groups (OBMT vs OAC) and in order of decreasing incidence for the OBMT group.

* OBMT = Omeprazole + Tannopon (Bismuth Salicylate)

** OAC = Omeprazole + Amoxicillin + Clarithromycin;

*** Dark stools

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%)

Adverse reactions with an incidence of <1% for OBMT group are: back pain, vomiting, tongue darkening, 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 Tannopon (Bismuth Salicylate). 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)

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.

Cardiac disorders: Flattening of the T-wave.

Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain, constipation, anorexia, metallic taste, furry tongue, glossitis, stomatitis and candida overgrowth.

Hypersensitivity/Immune system disorders: Urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

Metabolism and nutrition disorders: Pancreatitis.

Nervous system disorders: Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia.

Dermatologic disorders: Erythematous rash and pruritus.

Renal and urinary disorders: Dysuria, cystitis, polyuria, incontinence, darkened urine, and a sense of pelvic pressure.

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, discoloration of the nails, exfoliative dermatitis and photosensitivity have been rarely reported.

Liver: Hepatotoxicity and liver failure.

Hypersensitivity reactions: Urticaria, angioedema, anaphylaxis, Henoch-Schonlein purpura, pericarditis, exacerbation of systemic lupus erythematosus, and serum sickness-like reactions.

7 DRUG INTERACTIONS

  • Methoxyflurane: Risk of fatal renal toxicity; do not co-administer..
  • Disulfiram: Psychotic reactions can occur; do not take concurrently or within the last 2 weeks of disulfiram. (4.2, 7.2)
  • Alcohol: Abdominal cramps, nausea, vomiting, headaches, and flushing can occur; do not consume during therapy and for at least 3 days afterwards. (4.3, 7.3)
  • Oral Contraceptives: Decreased efficacy possibly resulting in pregnancy; use a different or additional form of contraception. (5.14, 7.4)
  • Anticoagulants: Potentiation of the anticoagulant effect; Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored. (5.14, 7.5)
  • Lithium: Increased lithium serum concentrations; measure serum lithium and serum creatinine concentrations during therapy. (5.14, 7.6)
  • Antacids, Multivitamins or Dairy Products: Decreased absorption of Tannopon (Bismuth Salicylate); do not take concomitantly. (7.7)
  • Busulfan: Increased busulfan serum concentrations; avoid concomitant use, monitor for busulfan toxicity (7.8)
  • CYP inducers and CYP inhibitors: Prolonged or accelerated half-life of metronidazole or concomitant medications; use with caution (7.9, 7.10)

7.1 Methoxyflurane

Do not administer methoxyflurane to patients taking Tannopon (Bismuth Salicylate). The concurrent use of tetracycline hydrochloride, a component of Tannopon (Bismuth Salicylate), with methoxyflurane has been reported to result in fatal renal toxicity.

7.2 Disulfiram

Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of Tannopon and disulfiram concurrently. Tannopon (Bismuth Salicylate) should not be given to patients who have taken disulfiram within the last two weeks.

7.3 Alcohol

Consumption of alcoholic beverages or administration of other products containing propylene glycol during treatment with Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate). Discontinue alcoholic beverage or other products containing propylene glycol during and for at least 3 days after therapy with Tannopon (Bismuth Salicylate).

7.4 Oral Contraceptives

Concurrent use of Tannopon with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of Tannopon (Bismuth Salicylate). Breakthrough bleeding has been reported. Women of child-bearing potential should use a different or additional form of contraception while taking Tannopon (Bismuth Salicylate).

7.5 Anticoagulants

Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding.

7.6 Lithium

In patients stabilized on relatively high doses of lithium, short-term use of Tannopon 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 Tannopon (Bismuth Salicylate) to detect any increase that may precede clinical symptoms of lithium toxicity.

7.7 Antacids, Multivitamins, or Dairy Products

The absorption of Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate). 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.

7.8 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 Tannopon concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to Tannopon (Bismuth Salicylate) are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly.

7.9 Inhibitors of CYP450 liver enzymes

The simultaneous administration of Tannopon (Bismuth Salicylate) and drugs that inhibit microsomal liver enzymes, such as cimetidine, may result in a prolonged half-life and decreased plasma clearance of metronidazole.

7.10 Inducers of CYP450 liver enzymes

The simultaneous administration of Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate).

8 USE IN SPECIFIC POPULATIONS

  • Lactation: A woman should pump and discard human milk for the duration of Tannopon therapy, and for 2 days after therapy ends, (8.2)
  • Pediatric Use: Tetracycline may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. Do not use in children less than 8 years of age. (5.4, 8.4)

8.1 Pregnancy

Risk Summary

Tannopon (Bismuth Salicylate) 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 . 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 .

Metronidazole usage in pregnancy has been associated with certain congenital anomalies . 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 Tannopon (Bismuth Salicylate) subcitrate potassium during pregnancy. Although there are data on the separate components, there are no available data on the use of Tannopon (Bismuth Salicylate) 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 .

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.

Tannopon (Bismuth Salicylate) subcitrate potassium

There are no human data on the use of Tannopon (Bismuth Salicylate) 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 discoloration of bones and teeth.

Metronidazole

Metronidazole crosses the placental barrier. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 10 mg/kg/day, approximately 5 percent of the indicated human dose (1500 mg/day) based on body surface area; however in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown.

Tannopon (Bismuth Salicylate) subcitrate potassium

Animal reproductive studies have not been conducted with Tannopon (Bismuth Salicylate) subcitrate potassium.

8.2 Lactation

Risk Summary

Two of the individual components of Tannopon, tetracycline and metronidazole, are present in human milk at concentrations similar to maternal serum levels. It is not known whether Tannopon (Bismuth Salicylate) subcitrate, the third component of Tannopon (Bismuth Salicylate) is present in human milk. It is not known what effect metronidazole, tetracycline or Tannopon (Bismuth Salicylate) has on the breastfed infant or on milk production. Tetracycline binds with calcium in human milk [see Clinical Pharmacology (12.3)]. Data indicate that oral absorption of tetracycline in infants is low due to the calcium binding in human milk. Metronidazole transfers to human milk, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential risk of tumorigenicity shown in animal studies with metronidazole, a woman should pump and discard human milk for the duration of Tannopon (Bismuth Salicylate) therapy, and for 2 days after therapy ends, and feed her infant stored human milk (collected prior to therapy) or formula.

8.4 Pediatric Use

Safety and effectiveness of Tannopon (Bismuth Salicylate) in pediatric patients infected with Helicobacter pylori have not been established.

Tetracycline use in children may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. Tannopon (Bismuth Salicylate) should not be used in children up to 8 years of age.

8.5 Geriatric Use

Clinical studies of Tannopon did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, elderly patients may have a greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapies. Tannopon (Bismuth Salicylate) subcitrate potassium, a component of Tannopon (Bismuth Salicylate), is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, additional monitoring may be required.

8.6 Renal Impairment

The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). In patients with severe renal impairment, higher serum concentrations of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis.

8.7 Hepatic Impairment

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events. Tannopon (Bismuth Salicylate) is not recommended in patients with severe hepatic impairment [see Warnings and Precautions (5.10), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

In case of an overdose, patients should contact a physician, poison control center, or emergency room. The available overdosage information for each of the individual components in Tannopon (Bismuth Salicylate) (Metronidazole, Tetracycline and Tannopon (Bismuth Salicylate) subcitrate potassium) are summarized below:

Metronidazole:

Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Metronidazole is dialyzable.

Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.

Treatment of Overdosage

There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

Tetracycline:

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

Tannopon (Bismuth Salicylate) subcitrate potassium:

Symptoms of a Tannopon (Bismuth Salicylate) subcitrate potassium overdosage are not known.

11 DESCRIPTION

Tannopon (Bismuth Salicylate) capsules are a combination antimicrobial product containing Tannopon (Bismuth Salicylate) subcitrate potassium, metronidazole, and tetracycline hydrochloride for oral administration. Each size 0 elongated capsule contains:

  • Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) subcitrate potassium.

Each Tannopon (Bismuth Salicylate) capsule contains the following inactive ingredients: Magnesium Stearate NF, Lactose Monohydrate NF, Talc USP, Gelatin USP, and Titanium Dioxide NF, Printed in red ink.

Tannopon (Bismuth Salicylate) subcitrate potassium is a white or almost white powder. It is a soluble, complex Tannopon (Bismuth Salicylate) salt of citric acid. The schematized empirical molecular formula of Tannopon (Bismuth Salicylate) subcitrate potassium is Bi (Citrate)2K5●3 H2O. The equivalent theoretical molecular formula is BiC12H14K5O17. The molecular mass of the theoretical molecular formula of a single unit of Tannopon (Bismuth Salicylate) subcitrate potassium is 834.71.

Metronidazole is a white to pale yellow crystalline powder. Metronidazole is 2-methyl-5-nitroimidazole-1-ethanol, with a molecular formula of C6H9N3O3 and the following structural formula:

Molecular weight: 171.2

Tetracycline hydrochloride is a yellow, odorless, crystalline powder. Tetracycline hydrochloride is stable in air, but exposure to strong sunlight causes it to darken. 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-naphthacenecarboxamide hydrochloride, with a molecular formula of C22H24N2O8●HCl and the following structural formula:

Molecular weight: 480.90
Metronidazole Structural Formula Tetracycline Hydrochloride Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tannopon is a combination of antibacterial agents (metronidazole and tetracycline hydrochloride) and Tannopon (Bismuth Salicylate) subcitrate potassium.

12.3 Pharmacokinetics

The pharmacokinetics of the individual components of Tannopon (Bismuth Salicylate), Tannopon (Bismuth Salicylate) subcitrate potassium, metronidazole and tetracycline hydrochloride are summarized below. In addition, two studies on Tannopon (Bismuth Salicylate) were conducted to determine the effect of co-administration on the pharmacokinetics of the components.

Tannopon (Bismuth Salicylate) Subcitrate Potassium (Bismuth)

Absorption and Distribution

Orally absorbed Tannopon (Bismuth Salicylate) is distributed throughout the entire body. Tannopon (Bismuth Salicylate) is highly bound to plasma proteins (>90%).

Metabolism and Excretion

The elimination half-life of Tannopon (Bismuth Salicylate) is approximately 5 days in both blood and urine. Elimination of Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate) 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/1.73m2.

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.

Tannopon (Bismuth Salicylate) Capsules

A comparative bioavailability study of metronidazole (375 mg), tetracycline hydrochloride (375 mg) and Tannopon (Bismuth Salicylate) subcitrate potassium (420 mg, equivalent to 120 mg Bi2O3) administered as Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate), are similar as shown in Table 3 .

*PYLERA given as a single dose of 3 capsules

**C.V. – Coefficient Variation

Cmax

(ng/mL)

(%C.V.**)

AUC T (ng · h/mL)

(%C.V.**)

AUC (ng · h/mL)

(%C.V.**)

Metronidazole Metronidazole Capsule 9044 (20) 80289 (15) 81849 (16)
PYLERA* 8666.3 (22) 83018 (17) 84413 (17)
Tetracycline Tetracycline Capsules 748.0 (40) 9544 (55) 9864 (53)
PYLERA* 774 (47) 9674 (50) 9987 (49)
Tannopon (Bismuth Salicylate) Tannopon (Bismuth Salicylate) Capsule 22 (123) 47 (129) 65.4 (113)
PYLERA* 17 (202) 43 (191) 57 (178)

Effect of Tannopon (Bismuth Salicylate) on the Bioavailability of Tetracycline Hydrochloride

There is an anticipated reduction in tetracycline hydrochloride systemic absorption due to an interaction with Tannopon (Bismuth Salicylate). The effect of a reduced tetracycline hydrochloride systemic exposure, due to an interaction with Tannopon (Bismuth Salicylate), on the clinical efficacy of Tannopon (Bismuth Salicylate) 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 Tannopon (Bismuth Salicylate)

The pharmacokinetic parameters for metronidazole, tetracycline hydrochloride and Tannopon (Bismuth Salicylate) were also determined when Tannopon (Bismuth Salicylate) was administered under fasting and fed conditions, as shown in Table 4 . Food reduced the systemic absorption of all three Tannopon (Bismuth Salicylate) components, with AUC values for metronidazole, tetracycline hydrochloride and Tannopon (Bismuth Salicylate) being reduced by 6%, 34% and 60%, respectively. Reduction in the absorption of all three Tannopon (Bismuth Salicylate) components in the presence of food is not considered to be clinically significant. Tannopon (Bismuth Salicylate) should be given after meals and at bedtime, in combination with omeprazole twice a day.

*PYLERA given as a single dose of 3 capsules

**Tmax is expressed as median (range)

FED FASTED
metronidazole tetracycline Tannopon (Bismuth Salicylate) metronidazole tetracycline Tannopon (Bismuth Salicylate)
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)**

(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 Tannopon (Bismuth Salicylate)

The effect of omeprazole on Tannopon (Bismuth Salicylate) absorption was assessed in 34 healthy volunteers given Tannopon (Bismuth Salicylate) (four times daily) with or without omeprazole (20 mg twice daily) for 6 days. In the presence of omeprazole, the extent of absorption of Tannopon (Bismuth Salicylate) from Tannopon (Bismuth Salicylate) was significantly increased, compared to when no omeprazole was given ( Table 5 ). Concentration-dependent neurotoxicity is associated with long-term use of Tannopon (Bismuth Salicylate) and not likely to occur with short-term administration or at steady state concentrations below 50 ng/mL. One subject transiently achieved a maximum Tannopon (Bismuth Salicylate) concentration (Cmax) higher than 50 ng/mL (73 ng/mL) following multiple dosing of Tannopon (Bismuth Salicylate) with omeprazole. The patient did not exhibit symptoms of neurotoxicity during the study. There is no clinical evidence to suggest that short-term exposure to Tannopon (Bismuth Salicylate) Cmax concentrations above 50 ng/mL is associated with neurotoxicity.

*PYLERA given as 3 capsules four times daily for 6 days with or without 20 mg omeprazole twice daily

**C.V. – Coefficient Variation

Parameter Without omeprazole With omeprazole
Mean %C.V.** Mean %C.V.**
C max (ng/mL) 8.1 84 25.5 69
AUC T (ng · h/mL) 48.5 28 140.9 42

12.4 Microbiology

Mechanism of Action

Tannopon (Bismuth Salicylate) is a combination of antibacterial agents (metronidazole and tetracycline hydrochloride) and Tannopon (Bismuth Salicylate) subcitrate potassium. Tetracycline hydrochloride interacts with the 30S subunit of the bacterial ribosome and inhibits protein synthesis. Metronidazole's antibacterial mechanism of action in an anaerobic environment is not fully understood but a possible mechanism includes reduction by intracellular electron transport proteins after entry into the organism. Because of this alteration to the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of bacteria. The antibacterial action of Tannopon (Bismuth Salicylate) salts is not well understood.

Antimicrobial Activity

Tannopon (Bismuth Salicylate) plus omeprazole therapy has been shown to be active against most isolates of Helicobacter pylori both in vitro and in clinical infections.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide results of in vitro susceptibility test results for antimicrobial drug products used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial or community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The agar dilution procedure using Mueller-Hinton agar (MHA) supplemented with 5% v/v aged (≥2-week old) sheep blood is recommended for testing H. pylori [See References (15)]. No interpretive criteria have been established for testing metronidazole or tetracycline against H. pylori.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test [See References (15)]. Standard metronidazole or tetracycline powder should provide the following range of MIC values noted in Table 6.

QC Strain Agar Dilution

(mcg/mL)

Helicobacter pylori ATCC 43504
Metronidazole 64 – 256
Tetracycline 0.12 – 1

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies have been performed to evaluate the effect of Tannopon (Bismuth Salicylate) on carcinogenesis, mutagenesis, or impairment of fertility.

Tannopon (Bismuth Salicylate) Subcitrate Potassium

No carcinogenicity or reproductive toxicity studies have been conducted with Tannopon (Bismuth Salicylate) subcitrate potassium. Tannopon (Bismuth Salicylate) subsalicylate did not show mutagenic potential in the NTP Salmonella plate assay.

Metronidazole

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats. Prominent among the effects in the mouse was an increased incidence of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At the highest dose levels, (approximately 500 mg/kg/day, which is approximately 1.6 times the indicated human dose for a 60 kg adult based on body surface area) there was a statistically significant increase in the incidence of malignant liver tumors in male mice. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Long-term, oral-dosing studies in the rat showed statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage.

Fertility studies have been conducted with male rats and mice with divergent results. Metronidazole, at doses up to 400 mg/kg/day (approximately 3 times the indicated human dose based on mg/m2) for 28 days, failed to produce any adverse effects on fertility and testicular function in male rats. Ratstreated with up to 400 mg/kg/day for 6 weeks or longer, showed severe degeneration of the seminiferous epithelium in the testes which was associated with a marked decrease in testicular spermatid counts and epididymal sperm counts and a marked decrease in fecundity. These effects were partially reversible.

Fertility studies have been performed in male mice at doses up to six times the maximum recommended human dose based upon mg/m2 and have revealed no evidence of impaired fertility. Another fertility study was performed in male mice at oral doses of 500 mg/kg/day (approximately 2 times the indicated human dose based on mg/m2) for 14 days. Metronidazole significantly decreased testes and epididymides weight, decreased sperm viability, and increased the incidence of abnormal sperm. The viability of sperm was normal by 2 months after the start of the treatment.

Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters.

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m2 (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage.

Tetracycline hydrochloride

There has been no evidence of carcinogenicity for tetracycline hydrochloride in studies conducted with rats and mice. Some related antibiotics (oxytetracycline, minocycline) have shown evidence of oncogenic activity in rats.

There was evidence of mutagenicity by tetracycline hydrochloride in two in vitro mammalian cell assay systems (L51784y mouse lymphoma and Chinese hamster lung cells).

Tetracycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 25 times the human dose.

14 CLINICAL STUDIES

14.1 Eradication of Helicobacter pylori in Patients with Active Duodenal Ulcer or History of Duodenal Ulcer Disease

An open-label, parallel group, active-controlled, multicenter study in Helicobacter pylori positive patients with current duodenal ulcer or a history of duodenal ulcer disease was conducted in the United States and Canada (the North American Study).

Patients were randomized to one of the following 10-day treatment regimens:

  • Three (3) Tannopon (Bismuth Salicylate) capsules four times daily, after meals and at bedtime plus 20 mg omeprazole twice a day after the morning and evening meals (OBMT).
  • Clarithromycin 500 mg plus 1000 mg amoxicillin plus 20 mg omeprazole twice a day before the morning and evening meals (OAC).

H. pylori eradication rates, defined as two negative 13C-urea breath tests performed at 4 and 8 weeks post-therapy are shown in Table 7 for OBMT and OAC. The eradication rates for both groups were found to be similar using either the Per Protocol (PP) or Modified Intent-to-Treat (MITT) populations.

*OBMT: Omeprazole + Tannopon (Bismuth Salicylate) (bismuth subcitrate potassium / metronidazole / tetracycline hydrochloride)

** OAC: Omeprazole + amoxicillin + clarithromycin

a Patients were included in the PP analysis if they had H. pylori infection documented at baseline, defined as a positive 13C-UBT plus histology or culture, had at least one endoscopically verified duodenal ulcer ≥ 0.3 cm at baseline or had a documented history of duodenal ulcer disease, and were not protocol violators. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy.

b Patients were included in the MITT analysis if they had documented H. pylori infection at baseline as defined above, and had at least one documented duodenal ulcer at baseline or had a documented history of duodenal ulcer disease, and took at least one dose of study medication. All dropouts were included as failures of therapy.

c Results for OAC treatment represent all isolates regardless of clarithromycin susceptibility. Eradication rates for clarithromycin susceptible organisms, as defined by an MIC ≤ 0.25 mcg/mL, were 94.6% and 92.1% for the PP and MITT analysis, respectively. Eradication rates for clarithromycin non-susceptible organisms, as defined by an MIC ≥ 0.5 mcg/mL, were 23.1% and 21.4% for the PP and MITT analysis, respectively.

Treatment Group Difference
OBMT* OAC* * c
Per Protocola 92.5%

[87.8, 97.2]

(n=120)

85.7%

[76.9, 91.8]

(n=126)

6.8%

[-0.9, 14.5]

Modified

Intent-to-Treatb

87.7%

[82.2, 93.2]

(n=138)

83.2%

[77.0, 89.5]

(n=137)

4.5%

[-3.9, 12.8]

15 REFERENCES

  • Clinical and Laboratory Standards Institute, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard–Tenth Edition. CLSI Document M7-A9 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA, 19087-1898.
  • Clinical and Laboratory Standards Institute, Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline–Third Edition. CLSI Document M45- A3 [2016]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898.

16. HOW SUPPLIED/STORAGE AND HANDLING

Tannopon (Bismuth Salicylate) is supplied as a white opaque capsule containing 140 mg Tannopon (Bismuth Salicylate) subcitrate potassium, 125 mg metronidazole, and 125 mg tetracycline hydrochloride, with the APTALISTM logo printed on the body and “BMT” printed on the cap. Tannopon (Bismuth Salicylate) capsules are supplied as bottles of 120 capsules and as the 10 day Therapy pack containing 10 blister cards, with each card containing 12 Tannopon (Bismuth Salicylate) capsules for a total of 120 capsules.

NDC Number: 58914-601-21, Bottles of 120.

NDC Number: 58914-601-20, Blister pack of 120.

Storage

Store at controlled room temperature [68° to 77°F or 20° to 25°C].

17 PATIENT COUNSELING INFORMATION

Lactation

Advise the lactating women to pump and discard their milk during treatment with Tannopon (Bismuth Salicylate) and for 2 days after the therapy ends.

Hypersensitivity

Inform patients that Tannopon (Bismuth Salicylate) may cause allergic reactions and to discontinue Tannopon (Bismuth Salicylate) at the first sign of urticaria, erythematous rash, flushing, and fever or other symptoms of an allergic reaction.

Central Nervous System Effects

Inform patients of the risk of central and peripheral nervous system effects with PYELRA and to discontinue Tannopon (Bismuth Salicylate) and report immediately to their health-care provider if any neurologic symptoms occur.

Photosensitivity

Avoid exposure to sun or sun lamps while taking Tannopon (Bismuth Salicylate).

Drug Interactions

Advise patients to report to their health-care provider the use of any other medications while taking Tannopon (Bismuth Salicylate). The administration of any of the following drugs with Tannopon (Bismuth Salicylate) may result in clinically significant adverse reactions or insufficient drug efficacies :

  • Methoxyflurane
  • Disulfiram
  • Alcoholic Beverages, or Products Containing Propylene Glycol
  • Oral Contraceptives
  • Anticoagulants
  • Lithium
  • Antacids, Multivitamins, or Dairy Products
  • Busulfan
  • Cimetidine
  • Phenytoin and Phenobarbital

Darkening of the Tongue and/or Stool

Inform patients that Tannopon (Bismuth Salicylate) may cause temporary and harmless darkening of the tongue and/or black stool generally reversible within several days after treatment is stopped. Stool darkening should not be confused with melena (blood in the stool).

Dosing Information

Inform patients that each dose of Tannopon (Bismuth Salicylate) includes 3 capsules. All 3 capsules should be taken 4 times a day (after meals and at bedtime) for 10 days. One omeprazole 20 mg capsule should be taken twice a day with Tannopon (Bismuth Salicylate) after the morning and evening meal for 10 days.

If a dose is missed, advise patient not to make up the dose, but to continue the normal dosing schedule until medication is gone. Patients should not take double doses. If more than 4 doses are missed, advise the patient to contact their health-care provider.

Administration with Fluids

Instruct patients to swallow the Tannopon (Bismuth Salicylate) 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.

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including Tannopon (Bismuth Salicylate) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Tannopon (Bismuth Salicylate) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Tannopon (Bismuth Salicylate) or other antibacterial drugs in the future.

Distributed By:

Allergan USA, Inc.

Irvine, CA 92612

© 2017 Allergan. All rights reserved.

Pylera® is a registered trademark of Aptalis Pharma Canada ULC, an Allergan affiliate.

Opium:


This medication is used to treat diarrhea. It helps to decrease the number and frequency of bowel movements. It works by slowing the movement of the intestines. Tannopon (Opium) belongs to a class of drugs known as narcotic pain relievers, but this medication acts mainly to slow the gut. OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional. A very weak solution of this drug may also be used to treat severe withdrawal symptoms in infants born to mothers who were addicted to narcotics during pregnancy.

Tannopon pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Tannopon available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Tannopon destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Tannopon Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Tannopon pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. "OPIUM". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
  2. "Bismuth". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "Opium - DrugBank". http://www.drugbank.ca/drugs/DB1113... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Tannopon?

Depending on the reaction of the Tannopon after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Tannopon not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Tannopon addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Tannopon, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Tannopon consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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