Bismuth Salts (Monograph)

Brand names: Bismatrol, Devrom, Diotame, Kaopectate, Kao-Tin, ... show all 8 brands Peptic Relief, Pepto-Bismol, Pylera
Drug class: Antidiarrhea Agents
VA class: GA208
Chemical name: Bismuth pentapotassium dihydroxide bis(2-hydroxypropane-1,2,3-tricarboxylate hydrate
Molecular formula: C₁₂H₁₄BiK₅O₁₇C₇H₅BiO₆C₇H₅BiO₄
CAS number: 880149-29-1

Introduction

Antidiarrhea agent; antidyspepsia agent; internal deodorant.

Antiulcer agent (as part of multiple-drug regimens for Helicobacter pylori infection).

Uses for Bismuth Salts

Diarrhea

Bismuth subsalicylate used as self-medication in children and adults for symptomatic control of acute nonspecific diarrhea and travelers’ diarrhea.

Bismuth subsalicylate has been used in adults for prevention of travelers’ diarrhea^{† [off-label]}; however, less effective than anti-infective agents.

Helicobacter pylori Infection and Duodenal Ulcer Disease

Bismuth subsalicylate used for treatment of Helicobacter pylori infection and duodenal ulcer disease (active disease or history of duodenal ulcer); eradication of H. pylori shown to reduce the risk of duodenal ulcer recurrence.

Bismuth subsalicylate used in multiple-drug regimens that also include metronidazole, tetracycline hydrochloride, and a histamine H₂-receptor antagonist or proton-pump inhibitor (quadruple therapy); such drug combinations recommended by the American College of Gastroenterology (ACG) as first-line treatment option for eradication of H. pylori infection. ACG recommends consideration of such quadruple-drug regimens in penicillin-allergic patients and those who have previously received a macrolide antibiotic. If the initial 14-day regimen does not eradicate H. pylori, retreat with multiple-drug regimen that does not include metronidazole to avoid possible development of metronidazole resistance.

Multiple-drug regimens including bismuth subsalicylate, metronidazole, tetracycline hydrochloride, and a proton-pump inhibitor (instead of a histamine H₂-receptor antagonist) may be more effective against metronidazole-resistant strains of H. pylori; such regimens recommended by ACG as acceptable treatment option for persistent H. pylori infection (“salvage” treatment).

Fixed combination containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride (Pylera) used in conjunction with omeprazole for the treatment of H. pylori infection and duodenal ulcer (active ulcer or history of duodenal ulcer within past 5 years).

Flatulence or Stool Odor

Bismuth subgallate used as self-medication in children and adults for the reduction of flatulence or stool odor from a colostomy or ileostomy.

Bismuth subgallate has been used as self-medication for reduction of odor from fecal incontinence^{† [off-label]}, irritable bowel syndrome^{† [off-label]}, or bariatric surgery^{† [off-label]}.

Bismuth subgallate not expected to be effective for reduction of odor from faulty personal hygiene^{† [off-label]}.

Dyspepsia (Upset Stomach)

Bismuth subsalicylate used as self-medication in children and adults for symptomatic relief of dyspepsia (e.g., upset stomach, nausea, heartburn, fullness, belching, gas) secondary to overindulgence in food and drink.

Effectiveness of bismuth salts in the treatment of nonulcer dyspepsia^† uncertain. Not recommended as first-line therapy because of potential risk of neurotoxicity with long-term use; may be useful as second-line agents.

Bismuth Salts Dosage and Administration

Administration

Oral Administration

Capsules

Bismuth subgallate: Administer orally up to 4 times daily with meals. Swallow capsule whole.

Bismuth subcitrate potassium in fixed combination with metronidazole and tetracycline hydrochloride (Pylera): Administer orally 4 times daily after meals and at bedtime; give omeprazole concomitantly as part of regimen. (See Fixed Combination Containing Bismuth Subcitrate Potassium, Metronidazole, and Tetracycline Hydrochloride [Pylera] under Dosage.) Swallow capsule whole. Administer with full glass (240 mL) of water, particularly with bedtime doses, to reduce risk of esophageal irritation and ulceration by tetracycline hydrochloride component. If a dose of Pylera is missed, take next dose at regularly scheduled time; do not double the dose. Contact clinician if >4 doses are missed.

Suspension

Bismuth subsalicylate: Shake suspension well prior to administration. Use dose cup provided by manufacturer for accurate dosing. For Diotame, twist off lid and dispense appropriate dose by squeezing tube.

Chewable Tablets

Bismuth subgallate: Administer orally up to 4 times daily with meals. Chew or swallow whole.

Bismuth subsalicylate: Chew or dissolve in mouth and swallow.

Bismuth subsalicylate (with metronidazole and tetracycline hydrochloride in Helidac Therapy kit): Administer each component orally 4 times daily with meals and at bedtime. Chew and swallow bismuth subsalicylate tablets. Administer tetracycline hydrochloride and metronidazole components with full glass (240 mL) of water, particularly with bedtime doses, to reduce risk of esophageal irritation and ulceration by tetracycline hydrochloride component. If a dose of Helidac Therapy is missed, take next dose at regularly scheduled time; do not double the dose. If >4 doses are missed, contact clinician.

Conventional Tablets

Bismuth subsalicylate (e.g., Pepto-Bismol Easy-to-Swallow Caplets): Swallow with water; do not chew.

Dosage

Available as bismuth subgallate, bismuth subcitrate potassium, and bismuth subsalicylate; dosages expressed in terms of the salts.

Bismuth subcitrate potassium available in fixed combination with metronidazole and tetracycline hydrochloride (Pylera); dosage of Pylera expressed as number of capsules.

Pediatric Patients

Acute Nonspecific Diarrhea and Travelers’ Diarrhea

Bismuth Subsalicylate

Oral

Children ≥12 years of age: 525 mg every 30–60 minutes or 1.05 g every hour as needed, not to exceed 4.2 g in a 24-hour period. Use until diarrhea stops, but not >2 days.

Children ≥12 years of age: Alternatively, administer 1.05 g every 30 minutes^† to every hour as needed, not to exceed 4.2 g in a 24-hour period.

Flatulence or Stool Odor

Bismuth Subgallate

Oral

Children ≥12 years of age: 200–400 mg up to 4 times daily.

Dyspepsia (Upset Stomach)

Bismuth Subsalicylate

Oral

Children ≥12 years of age: 525 mg every 30–60 minutes as needed, not to exceed 4.2 g in a 24-hour period. Do not use for >2 days.

Children ≥12 years of age: Alternatively, administer 1.05 g every 30–60 minutes^† as needed, not to exceed 4.2 g in a 24-hour period.

Adults

Acute Nonspecific Diarrhea and Travelers’ Diarrhea

Bismuth Subsalicylate

Oral

525 mg every 30–60 minutes or 1.05 g every hour as needed, not to exceed 4.2 g in a 24-hour period. Use until diarrhea stops, but not >2 days.

Alternatively, administer 1.05 g every 30 minutes^† to every hour as needed, not to exceed 4.2 g in a 24-hour period.

Prevention of Travelers’ Diarrhea†

Bismuth Subsalicylate

Oral

525 mg 4 times daily has been recommended.

Helicobacter pylori Infection and Duodenal Ulcer Disease

Bismuth Subsalicylate, Metronidazole, and Tetracycline Hydrochloride Regimen

Oral

525 mg of bismuth subsalicylate in conjunction with metronidazole (250 mg) and tetracycline hydrochloride (500 mg) 4 times daily for 10–14 days; give concomitantly with ranitidine (150 mg) twice daily or usual dosage of a proton-pump inhibitor once or twice daily.

Salvage therapy for persistent H. pylori infection: Administer for 7–14 days.

Bismuth Subsalicylate (with Metronidazole and Tetracycline Hydrochloride) in Helidac Therapy Kit

Oral

525 mg of bismuth subsalicylate in conjunction with metronidazole (250 mg) and tetracycline hydrochloride (500 mg) 4 times daily (at meals and at bedtime) for 14 days; give concomitantly with usual dosage of H₂-receptor antagonist.

Fixed Combination Containing Bismuth Subcitrate Potassium, Metronidazole, and Tetracycline Hydrochloride (Pylera)

Oral

3 capsules 4 times daily (after meals and at bedtime) for 10 days; give concomitantly with omeprazole 20 mg twice daily (after morning and evening meal) for 10 days.

Flatulence or Stool Odor

Bismuth Subgallate

Oral

200–400 mg up to 4 times daily.

Dyspepsia (Upset Stomach)

Bismuth Subsalicylate

Oral

525 mg every 30–60 minutes as needed, not to exceed 4.2 g in a 24-hour period. Do not use for >2 days.

Alternatively, administer 1.05 g every 30–60 minutes^† as needed, not to exceed 4.2 g in a 24-hour period.

Prescribing Limits

Pediatric Patients

Acute Nonspecific Diarrhea and Travelers’ Diarrhea

Bismuth Subsalicylate

Oral

Children ≥12 years of age: Maximum 4.2 g in a 24-hour period. Self-medication should not exceed 2 days.

Dyspepsia (Upset Stomach)

Bismuth Subsalicylate

Oral

Children ≥12 years of age: Maximum 4.2 g in a 24-hour period. Self-medication should not exceed 2 days.

Adults

Acute Nonspecific Diarrhea and Travelers’ Diarrhea

Bismuth Subsalicylate

Oral

Maximum 4.2 g in a 24-hour period. Self-medication should not exceed 2 days.

Dyspepsia (Upset Stomach)

Bismuth Subsalicylate

Oral

Maximum 4.2 g in a 24-hour period. Self-medication should not exceed 2 days.

Special Populations

No special population dosage recommendations at this time. (See Geriatric Use and also see Renal Impairment, under Cautions.)

Cautions for Bismuth Salts

Contraindications

• Helidac Therapy (kit containing bismuth subsalicylate, metronidazole, tetracycline hydrochloride) contraindicated in pregnant or nursing women, pediatric patients, patients with hepatic or renal impairment, patients with known allergy to aspirin or salicylates, and those with known hypersensitivity to any component of the kit.

• Pylera (fixed-combination capsule containing bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride) contraindicated in pregnant or nursing women, pediatric patients, patients with hepatic or renal impairment, and those with known hypersensitivity to any ingredient in the capsule.

Warnings/Precautions

Warnings

GI Disorders

Do not use bismuth subsalicylate (e.g., Maalox Total relief) for self-medication in patients with an ulcer, bleeding disorder, or bloody or black stools.

Reye’s Syndrome

Risk of Reye’s syndrome with bismuth subsalicylate in children or adolescents who have or are recovering from varicella or influenza-like symptoms. (See Pediatric Use under Cautions.)

Neurotoxicity

Neurotoxicity associated with excessive doses of bismuth salts reported rarely; reversible following discontinuance of drug.

Discoloration of Tongue and/or Stool

Possible transient and harmless darkening of tongue and/or black stool; do not confuse stool darkening with melena.

Lead Content

Bismuth mined from the ground, and commercially available Pepto-Bismol preparations, may contain small amounts of naturally occurring lead. Amounts of lead in Pepto-Bismol preparations are low compared with average daily lead exposure. Pepto-Bismol preparations not intended for chronic use.

Sensitivity Reactions

Hypersensitivity

Bismuth subsalicylate contains salicylate; do not use in patients allergic to salicylates (including aspirin).

General Precautions

Selection and Use of Anti-infectives in H. pylori Regimens

To reduce development of drug-resistant bacteria and maintain effectiveness of Helidac Therapy, Pylera, and other anti-infective agents, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Phenylketonuria

Diotame chewable tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to phenylalanine following oral administration.

Use of Fixed Combinations or Multiple-Drug Kits

When the fixed-combination preparation containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride (Pylera) or the kit containing bismuth subsalicylate, metronidazole, and tetracycline hydrochloride (Helidac Therapy) is used for the treatment of H. pylori infection and duodenal ulcer disease, the cautions, precautions, and contraindications associated with metronidazole and tetracycline hydrochloride must be considered in addition to those associated with bismuth subcitrate potassium or bismuth subsalicylate.

Medication Errors

Serious medication errors have been reported to FDA in which consumers used Maalox Total Relief (bismuth subsalicylate) when they intended to use traditional Maalox liquid antacid products containing aluminum hydroxide, magnesium hydroxide, and simethicone (e.g., Maalox Advanced Regular Strength, Maalox Advanced Maximum Strength). Because of the potential for serious adverse effects associated with accidental use of bismuth subsalicylate (which is chemically related to aspirin), the manufacturer of Maalox Total Relief initially agreed to change the trade name of the product to one that did not include “Maalox”; however, the manufacturer instead discontinued the bismuth subsalicylate preparation in the summer of 2010.

Specific Populations

Pregnancy

Bismuth subsalicylate: Category C (Category D in 3rd trimester).

Helidac Therapy, Pylera: Category D.

Helidac Therapy, Pylera: Effect on labor and delivery unknown.

Lactation

Bismuth subsalicylate: Use with caution.

Helidac Therapy, Pylera: Discontinue nursing or the drug.

Pediatric Use

Do not use bismuth subsalicylate in children or adolescents who have or are recovering from varicella or influenza-like symptoms. Changes in behavior accompanied by nausea and vomiting in children or adolescents taking the drug may be an early sign of Reye’s syndrome.

Safety and efficacy of the commercially available Helidac Therapy kit or the fixed-combination preparation Pylera in pediatric patients infected with H. pylori not established. Pylera or the Helidac Therapy kit should not be used in children <8 years of age. (See Contraindications under Cautions.)

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults to the commercially available Helidac Therapy kit or the fixed-combination preparation or Pylera for treatment of H. pylori infection and duodenal ulcer disease.

Consider age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Accumulation of bismuth salts may occur in patients with severe hepatic disease. The commercially available Helidac Therapy kit and the fixed-combination preparation Pylera are contraindicated in patients with hepatic impairment. (See Contraindications under Cautions and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Use bismuth subsalicylate with caution, if at all, in patients with renal impairment. The commercially available Helidac Therapy kit and the fixed-combination preparation Pylera are contraindicated in patients with renal impairment. (See Contraindications under Cautions.)

Common Adverse Effects

Bismuth: Transient and harmless darkening of the tongue and/or black stools, decreased peristalsis (with bismuth subgallate).

Helidac Therapy: Nausea, diarrhea, abdominal pain, melena, upper respiratory infection.

Pylera: Stool abnormality, diarrhea, dyspepsia, abdominal pain, nausea, headache, flu syndrome, taste perversion, asthenia, vaginitis, dizziness.

Drug Interactions

Specific Drugs and Laboratory Tests

Bismuth Salts Pharmacokinetics

Absorption

Bioavailability

Bismuth subsalicylate: Hydrolyzed in GI tract to bismuth and salicylic acid following oral administration.

Bismuth: <1% absorbed from GI tract into systemic circulation following oral administration of bismuth subsalicylate.

Salicylic acid: >80% absorbed following oral administration of bismuth subsalicylate chewable tablets.

Food

Food reduces systemic absorption of all three components of fixed-combination preparation containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride (Pylera); effect not considered clinically important. (See Administration under Dosage and Administration.)

Distribution

Extent

Bismuth: Distributed throughout body.

Plasma Protein Binding

Bismuth: >90%.

Salicylic acid: About 90%.

Elimination

Metabolism

Salicylic acid: Extensively metabolized.

Elimination Route

Bismuth: Excreted principally via urine and biliary routes.

Salicylic acid: About 10% excreted in urine as unchanged drug.

Half-life

Bismuth: Multiple disposition half-lives; intermediate and terminal half-lives of 5–11 and 21–72 days, respectively.

Metabolic clearance of salicylic acid is saturable.

Salicylic acid: Terminal half-life of 2–5 hours following a single oral 525-mg dose of bismuth subsalicylate.

Special Populations

Severe liver disease may be associated with accumulation of bismuth because of suggested biliary excretion of bismuth from the body.

Metabolic clearance of salicylic acid lower in women than in men.

Stability

Storage

Oral

Capsules

Bismuth subgallate: Protect from light.

Suspension

Bismuth subsalicylate: Tightly closed containers at 20–25°C. Avoid excessive heat (>40°C); protect from freezing.

Tablets

Bismuth subsalicylate: Avoid excessive heat (>40°C).

Chewable Tablets

Bismuth subgallate: Protect from light.

Bismuth subsalicylate: Dry place; avoid excessive heat (>40°C).

Bismuth Subcitrate Potassium Combinations

Fixed-combination preparation containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride (Pylera): 20–25°C.

Bismuth Subsalicylate Combinations

Kit containing bismuth subsalicylate, metronidazole, and tetracycline hydrochloride (Helidac Therapy): 20–25°C.

Actions and Spectrum

• Bismuth subsalicylate may protect gastric mucosa, bind to ulcer base and mucosa, bind bile acids, and decrease endogenous prostaglandin and bicarbonate secretion.

• Bismuth subsalicylate reduces number of bowel movements, aids in firming stool, normalizes fluid movement via antisecretory mechanisms, binds bacterial toxins, and exhibits antimicrobial activity in patients with diarrhea.

• Mechanism of antibacterial action of bismuth salts not fully elucidated.

• Bismuth salts may exert bactericidal action by complexing in bacterial wall and periplasmic space, inhibiting urease, catalase and lipase/phospholipase, ATP synthesis, and H. pylori adherence.

• Multiple-drug regimen of bismuth subsalicylate, metronidazole, and tetracycline hydrochloride and the fixed-combination preparation containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride (Pylera) active against most strains of H. pylori in vitro and in clinical infections.

• Bismuth subgallate may reduce number of odor-producing anaerobic intestinal microbes and/or directly interact with sulfur-containing compounds; reduces flatulence odor but not flatulence itself.

• Each 262.4-mg tablet of bismuth subsalicylate contains an amount of salicylate comparable to that in approximately 130 mg of aspirin.

Advice to Patients

• Importance of advising patients of the cautions, precautions, and contraindications associated with metronidazole and tetracycline hydrochloride when using Helidac Therapy or Pylera.

• Importance of informing patient that temporary and harmless darkening of the tongue and/or black stool may occur with bismuth salts, and that stool darkening should not be confused with blood in the stool.

• Do not use bismuth subsalicylate for self-medication in presence of peptic ulcers, bleeding disorders, bloody or black stool, known allergy to salicylates (including aspirin), or if taking other salicylates; consult clinician before use if diarrhea is accompanied by fever, mucus in stools, or if patient is on a sodium-restricted diet or currently taking drugs for anticoagulation, diabetes, gout, or arthritis.

• Importance of instructing patients to discontinue bismuth subsalicylate for self-medication and inform clinician if symptoms worsen, ringing in the ears or loss of hearing occurs, or if diarrhea or other symptoms do not improve after 2 days of therapy.

• Importance of advising patients not to use bismuth subsalicylate in children or adolescents who have or are recovering from chickenpox or flu-like symptoms. Importance of informing clinician if changes in behavior accompanied by nausea and vomiting occur while using bismuth subsalicylate, because these symptoms may be an early sign of Reye’s syndrome.

• Importance of adequate hydration (with clear fluids) to help prevent dehydration caused by diarrhea.

• Importance of informing patients with phenylketonuria that Diotame chewable tablets contain aspartame.

• Importance of instructing patients about correct administration of Helidac Therapy or Pylera capsules, including administration of each dose after meals and at bedtime and with a full glass of water (particularly at bedtime to reduce risk of esophageal irritation and ulceration), swallowing Pylera capsules whole, chewing and swallowing bismuth subsalicylate tablets, and about duration of therapy.

• Importance of informing patients that Helidac Therapy contains salicylates, and to contact a clinician if ringing in the ears occurs with concomitant aspirin therapy.

• Importance of advising patient that if a dose of Helidac Therapy or Pylera is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled. Importance of informing clinicians if >4 doses of Helidac Therapy or Pylera are missed.

• Importance of advising patients that antibacterials (including Helidac Therapy and Pylera) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).

• Importance of completing full course of therapy, even if feeling better after a few days.

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with Helidac Therapy or other anti-infective agents in the future.

• Advise patients that Helidac Therapy or the Pylera fixed combination may reduce the effectiveness of oral contraceptives and that alternative nonhormonal contraceptive measures should be used.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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