Bismuth subsalicylate

The components of the HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride), in combination with an H2 antagonist, are indicated for the eradication of H. pylori for treatment of patients with H. pylori infection and duodenal ulcer disease (active or a history of duodenal ulcer). Appropriate doses of H2 antagonists for the treatment of active duodenal ulcers should be prescribed in all patients. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence in patients with active duodenal ulcer disease. (See Clinical Studies and DOSAGE AND ADMINISTRATION.)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of HELIDAC Therapy and other antibacterial drugs, HELIDAC Therapy should be used only to treat or prevent 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.

The most common adverse reactions ( ≥ 1%) reported in clinical trials when all three components of this therapy were given concomitantly are listed in Table 1 below. The majority of the adverse reactions were related to the gastrointestinal tract, were reversible, and infrequently led to discontinuation of therapy.

Table 1: Incidence of Adverse Reactions Reported in Clinical Trials ( ≥ 1%)†

The additional adverse reactions ( < 1%) reported in clinical trials when all three components of this therapy were given concomitantly are listed below and divided by body system:

Gastrointestinal: dry mouth, dysphagia, eructation, GI monilia, glossitis, intestinal obstruction, rectal hemorrhage, stomatitis

Skin: acne, ecchymosis, photosensitivity reaction (see WARNINGS), pruritus, rash

Cardiovascular: cerebral ischemia, chest pain, hypertension, myocardial infarction

CNS: nervousness, somnolence

Musculoskeletal: arthritis, rheumatoid arthritis, tendonitis

Metabolic:SGOT increase, SGPT increase

Urogenital: urinary tract infection

Other: conjunctivitis, flu syndrome, infection, malaise, neoplasm, rhinitis, syncope, tooth disorder

Other Important Adverse Reactions from Labeling for the Individual Components of HELIDAC Therapy

Blood and Lymphatic system disorders: reversible neutropenia (leucopenia) in cases of prolonged treatment; rarely reversible thrombocytopenia however no persistent haematological abnormalities attributable to metronidazole have been observed. (See PRECAUTIONS)

Cardiac disorders: Flattening of the T-wave may be seen in electrocardiographic tracings.

Gastrointestinal disorders: Furry tongue, glossitis, stomatitis; these may be associated with a sudden overgrowth of candida which may occur during therapy; epigastric distress (See PRECAUTIONS)

Immune system disorders: Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva) and fever (See CONTRAINDICATIONS)

Metabolism and nutrition disorders: Cases of pancreatitis have been reported, which abated on withdrawal of the drug, have been reported.

Nervous system disorders: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. In addition, patients have reported syncope, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia. (See WARNINGS)

Renal disorders: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.

Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established.

Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia, and eosinophilia.

Gastrointestinal disorders: Anorexia, nausea, epigastric distress, glossitis, black hairy tongue, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Rare instances of esophagitis and esophageal ulceration have been reported in patients taking the tetracycline-class antibiotics in capsule and tablet form. Most of the patients who experienced esophageal irritation took the medication immediately before going to bed. Permanent discoloration of teeth may be caused when tetracycline is used during tooth development. Enamel hypoplasia has also been reported. (See WARNINGS)

Hypersensitivity: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus and serum sickness-like reactions, as fever, rash, and arthralgia.

Liver disorders: Hepatotoxicity and liver failure have been observed in patients receiving large doses of tetracycline and in tetracycline-treated patients with renal impairment. Increases in liver enzymes and hepatic toxicity have been reported rarely.

Nervous system disorders: Pseudotumor cerebri (benign intracranial hypertension) in adults and bulging fontanels in infants, Visual disturbances. Tinnitus and myasthenic syndrome have been reported rarely.

Renal and urinary disorders: Rise in BUN has been reported and is possibly dose related (See CONTRAINDICATIONS)

Skin and subcutaneous tissue disorders: Maculopapular and erythematous rashes have been reported. Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported. Onycholysis, discoloration of the nails, exfoliative dermatitis, and photosensitivity have been rarely reported. (See PRECAUTIONS)

Other: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur.

In case of an overdose, patients should contact a physician, poison control center, or emergency room. There is neither a pharmacologic basis nor data suggesting an increased toxicity of the combination compared to individual components.

Bismuth Subsalicylate

The main concern of an acute bismuth subsalicylate (BSS) overdose focuses on the salicylate burden and not on bismuth, since less than 1% of the bismuth is normally absorbed. Each 262.4-mg tablet of BSS contains an amount of salicylate comparable to approximately 130 mg aspirin. Acute ingestion of less than 150 mg/kg of aspirin (i.e., less than one tablet of bismuth subsalicylate per kilogram of body weight) is not expected to lead to toxicity. Mild to moderate toxicity may result from the ingestion of 150 to 300 mg/kg, while severe toxicity may occur from ingestions over 300 mg/kg. Salicylate intoxication is well described in the literature and presents a complex clinical picture. Multiple respiratory and metabolic effects result in fluid, electrolyte, glucose, and acid-base disturbances. Initial symptoms of salicylate toxicity include hyperpnea, nausea, vomiting, tinnitus, hyperpyrexia, lethargy, tachycardia, and confusion. In severe cases, these symptoms may progress to severe hyperpnea, convulsions, pulmonary or cerebral edema, respiratory failure, cardiovascular collapse, coma, and death.

There is no specific antidote for salicylate poisoning. If there are no contraindications, vomiting should be induced as soon as possible with syrup of ipecac, or gastric lavage should be instituted, provided that no more than one hour has elapsed since ingestion. Activated charcoal and a cathartic may be administered as primary decontamination therapy in those cases where greater than one hour has elapsed since ingestion, or to further decontaminate the gastrointestinal tract in those who have already received ipecac or gastric lavage. Plasma salicylate levels may be useful; a common nomogram can be used to help predict the severity of intoxication. Supportive and symptomatic treatment should be provided, with emphasis on correcting fluid, electrolyte, blood glucose, and acid-base disturbances. (Note: An acidotic blood pH increases the un-ionized salicylate form, allowing more to reach the central nervous system.) Elimination may be enhanced by urinary alkalinization, hemodialysis, or hemoperfusion. Since hemodialysis aids in correcting acid-base disturbances, this method may be preferred over hemoperfusion.

Metronidazole

Single oral doses of metronidazole, up to 19.5 g in adults, have been reported without resultant serious toxicity in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia.

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.

There is no specific antidote for metronidazole overdose. Management of the patient should consist of symptomatic and supportive therapy. Metronidazole is dialyzable.

Tetracycline

The acute toxicity of tetracycline in overdose is not well established in the literature. Therapeutic and overdose quantities of tetracycline can cause gastrointestinal symptoms such as nausea, vomiting, and diarrhea.

There is no specific antidote for tetracycline overdose. Management of the patient should consist of symptomatic and supportive therapy. Tetracycline is not dialyzable.

Pharmacokinetics

Pharmacokinetics for the HELIDAC Therapy components (bismuth subsalicylate chewable tablets, metronidazole tablets, and tetracycline hydrochloride capsules) when coadministered has not been studied. There is no information about the gastric mucosal concentrations of bismuth, metronidazole, and tetracycline after administration of these agents concomitantly or in combination with an acid suppressive agent. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.

Upon oral administration, bismuth subsalicylate is almost completely hydrolyzed in the gastrointestinal tract to bismuth and salicylic acid. Thus, the pharmacokinetics of bismuth subsalicylate following oral administration can be described by the individual pharmacokinetics of bismuth and salicylic acid.

Less than 1% of bismuth from oral doses of bismuth subsalicylate is absorbed from the gastrointestinal tract into the systemic circulation. Absorbed bismuth is distributed throughout the body. Bismuth is highly bound to plasma proteins ( > 90%). Bismuth has multiple disposition half-lives with an intermediate half-life of 5 to 11 days and a terminal half-life of 21 to 72 days. Elimination of bismuth is primarily through urinary and biliary routes with a renal clearance of 50 ± 18 mL/min. The mean trough blood bismuth concentration after 2 weeks oral administration of 787 mg bismuth subsalicylate (3 chewable tablets) four times daily under fasted condition was 5.1 ± 3.1 ng/mL. In another study, the mean trough blood bismuth concentration after 2 weeks oral administration of 525 mg bismuth subsalicylate (as PEPTO-BISMOL® liquid suspension) four times daily was 5 ng/mL with the highest value being 32 ng/mL.

More than 80% of the salicylic acid is absorbed from oral doses of bismuth subsalicylate chewable tablets. Salicylic acid is about 90% plasma protein bound. The volume of distribution is about 170 mL/kg of body weight. Salicylic acid is extensively metabolized and about 10% is excreted unchanged in the urine. The metabolic clearance of salicylic acid is saturable; accordingly, nonlinear pharmacokinetics is observed at bismuth subsalicylate doses above 525 mg. Salicylic acid metabolic clearance is lower in females than in males. The terminal half-life of salicylic acid upon a single oral dose of 525 mg bismuth subsalicylate is between 2 to 5 hours. After a single oral dose of 525 mg bismuth subsalicylate (2 chewable tablets), the mean peak plasma salicylic acid concentration was 13.1 ± 3.4 μg/mL under fasted condition. The mean steady-state serum total salicylate concentration after 2 weeks oral administration of 525 mg bismuth subsalicylate (as PEPTO-BISMOL liquid suspension) four times daily was 24 μg/mL with the highest value being 70 μg/mL.

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 250 mg producing a peak plasma concentration of 6 μg/mL. Studies reveal no significant bioavailability differences between males and females; however because of weight differences, the resulting plasma levels in males are generally lower.

Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole also appears in cerebrospinal fluid, saliva, and human milk in concentrations similar to those found in plasma.

The average elimination half-life 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-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m².

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 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. (See PRECAUTIONS, Nursing Mothers) Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. The relative contribution of systemic versus local antimicrobial activity against H. pylori for agents used in eradication therapy has not been established.

Microbiology

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride are antibacterial agents. Metronidazole is metabolized through reductive pathways into reactive intermediates that have cytotoxic action. Tetracycline hydrochloride interacts with the 30S subunit of the bacterial ribosome and inhibits protein synthesis. The antibacterial action of bismuth salts is not well understood.

Bismuth subsalicylate, metronidazole, and tetracycline administered individually as combination therapy have been shown to be active against most strains of Helicobacter pylori in vitro, and in clinical infections as described in the Clinical Studies and INDICATIONS AND USAGE sections.

In one study, susceptibility testing of Helicobacter pylori isolates was performed for metronidazole using agar dilution methodology1 and minimum inhibitory concentrations (MICs) were determined.

Susceptibility testing of Helicobacter pylori for metronidazole has not been standardized. No interpretive criteria have been established for testing metronidazole against H. pylori. The clinical significance of metronidazole MIC values against H. pylori is unknown.

Clinical Studies

Three clinical trials in the U.S. (Studies 1, 2 and 3) evaluated the effect of therapy on the eradication of H. pylori using bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. The patient population in these studies consisted predominantly of duodenal ulcer patients with active disease. In addition to bismuth subsalicylate, metronidazole, tetracycline hydrochloride triple therapy, most patients were also prescribed antisecretory therapy at doses recommended for ulcer healing, with the majority receiving ranitidine. The efficacy in these studies was assessed using H. pylori eradication, or cure of infection. Use of cure of infection as a surrogate for reduced ulcer recurrence is based on an extensive review of the literature. Eradication rates are derived from results of Studies 1 (randomized, controlled study) and Study 3 (uncontrolled, nonrandomized) and are shown in Table 2. H. pylori eradication was defined as no positive test (culture, histology, rapid urease, or 13C breath test) at least 4 weeks following the end of treatment. In the analysis performed, dropouts and patients with missing H. pylori tests post-treatment were excluded. HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) was effective in eradicating H. pylori.

Table 2: H. pylori Eradication Rates in Patients with Active Duodenal Ulcer Disease (Studies 1 and 3)

Study 2 evaluated the long-term outcome in patients treated for active duodenal ulcer by frequently monitoring for ulcer recurrence for up to 1 year after therapy. This study compared patients who received bismuth subsalicylate (BSS), metronidazole (MTZ), and tetracycline hydrochloride (TCN) for 2 weeks with ranitidine to those who received ranitidine alone. The ulcer recurrence rates at 6 months (Table 3) and one year (Table 4) regardless of post-treatment eradication status are summarized below for duodenal ulcer patients who were H. pylori positive at baseline.

Table 3: Duodenal Ulcer Recurrence Rates at 6 Months†

Table 4: Duodenal Ulcer Recurrence Rates at 1 Year†

Eradication of H. pylori in Patients with a History of Duodenal Ulcer Disease

A controlled, multicenter trial (Study 4) in the U.S. compared the rates of eradication of H. pylori following 14 days of treatment with HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) or control (bismuth subsalicylate, metronidazole placebo, and tetracycline placebo) in 103 patients infected with H. pylori who had a history of duodenal ulcer disease. No H2-receptor antagonist was used. H. pylori eradication was assessed by rapid urease testing, histology, and culture at least 4 weeks after the last dose. HELIDAC Therapy was effective in eradicating H. pylori. The eradication rates are noted in the table below:

Table 5: H. pylori Eradication Rates in Patients with a History of Duodenal Ulcer Disease (Study 4)

Compliance with the triple therapy regimen was also evaluated in the clinical study. In the intent-to-treat population, 93% of the HELIDAC Therapy group took at least 75% of their medication.

REFERENCES

1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial susceptibility Tests for Bacteria that Grow Aerobically—Approved Standard Seventh Edition. Clinical and Laboratory Standards Institute document M7-A8, Vol. 29, No.2, CLSI, Wayne, PA, January 2009.

Bismuth subsalicylate is an antacid and anti-diarrhea medication.

Bismuth subsalicylate is used to treat diarrhea, nausea, heartburn, indigestion, and upset stomach.

Bismuth subsalicylate may also be used for purposes not listed in this medication guide.

Bismuth subsalicylate is used to treat diarrhea, nausea, heartburn, indigestion, and upset stomach.

This medication should not be given to a child or teenager who has a fever, especially if the child also has flu symptoms or chicken pox. Salicylates can cause a serious and sometimes fatal condition called Reye's syndrome in children.

You should not use bismuth subsalicylate if you have a stomach ulcer, a recent history of stomach or intestinal bleeding, or if you are allergic to salicylates such as aspirin, Doan's Extra Strength, Salflex, Tricosal, and others.

Bismuth subsalicylate is used to treat diarrhea in adults and teenagers. It is also used to relieve the symptoms of an upset stomach, such as heartburn, indigestion, and nausea in adults and teenagers.

bismuth subsalicylate is available without a prescription.

Bismuth subsalicylate is a mild antibiotic.

Metronidazole and tetracycline are also antibiotics that fight bacteria in your body.

Bismuth subsalicylate, metronidazole, and tetracycline is a combination medicine used to treat peptic ulcer (duodenal ulcer) with H pylori infection.

This medication may also be used for purposes not listed in this medication guide.

Do not use this medicine if you are pregnant or breast-feeding.

Tetracycline can make birth control pills less effective. Ask your doctor about using non-hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking Helidac.

Do not give this medication to a child younger than 8 years old.

Do not drink alcohol while you are taking Helidac and for at least 1 day after you stop taking it.

Avoid taking Helidac with milk or other dairy products. Also avoid taking the medicine at the same time you take any multivitamins, mineral supplements, or antacids. These products can make it harder for your body to absorb Helidac.

Avoid taking Helidac with milk or other dairy products. Also avoid taking the medicine at the same time you take any multivitamins, mineral supplements, or antacids. These products can make it harder for your body to absorb the medicine.

If you also take cholestyramine or colestipol, do not take these medicines within 2 hours before or after you take Helidac.

Do not drink alcohol while you are taking Helidac and for at least 1 day after you stop taking it. Drinking alcohol while taking Helidac may cause nausea, vomiting, headache, or flushing (warmth, redness, tingly feeling).

Check the labels of any medicines or food products you use to make sure they do not contain alcohol.

Avoid exposure to sunlight or tanning beds. Helidac can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop taking Helidac and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.