Bismuth Subcitrate, Metronidazole, and Tetracycline

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Pylera: Bismuth subcitrate potassium 140 mg, metronidazole 125 mg, and tetracycline hydrochloride 125 mg

Pharmacology

Mechanism of Action

Bismuth: Has both antisecretory and antimicrobial action; may provide some anti-inflammatory action as well.

Metronidazole: After diffusing into the organism, interacts with DNA to cause a loss of helical DNA structure and strand breakage resulting in inhibition of protein synthesis and cell death in susceptible organisms.

Tetracycline: Inhibits bacterial protein synthesis by binding with the 30S and possibly the 50S ribosomal subunit(s) of susceptible bacteria; may also cause alterations in the cytoplasmic membrane.

Bismuth, metronidazole, and tetracycline individually have demonstrated in vitro activity against most susceptible strains of H. pylori isolated from patients with duodenal ulcers.

Pharmacokinetics/Pharmacodynamics

Absorption

Food reduced AUC by 6% (metronidazole), 34% (tetracycline), and 60% (bismuth)

Use: Labeled Indications

Duodenal ulcer associated with Helicobacter pylori infection: In combination with omeprazole for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori.

Contraindications

Hypersensitivity (eg, erythema rash, flushing, fever, urticaria) to bismuth, metronidazole, other nitroimidazole derivatives, tetracycline, or any component of the formulation; severe renal impairment; pregnancy; concomitant use with disulfiram (within the previous 2 weeks); concomitant use with methoxyflurane; concomitant use with alcohol or other products containing propylene glycol (during therapy and for ≥3 days after).

Dosage and Administration

Dosing: Adult

Duodenal ulcer associated with H. pylori infection: Oral: Three capsules (bismuth subcitrate 420 mg, metronidazole 375 mg, and tetracycline 375 mg) 4 times daily after meals and at bedtime (plus omeprazole 20 mg twice daily) for 10 days

Dosing: Geriatric

Refer to adult dosing.

Administration

Swallow capsules whole with 240 mL (8 oz) of water after meals and at bedtime. Administer concomitant omeprazole after morning meal and evening meal.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Alcohol (Ethyl): MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Alcohol (Ethyl). A disulfiram-like reaction may occur. Avoid combination

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

Antacids: May diminish the therapeutic effect of Bismuth Subcitrate. Management: Avoid administration of antacids within 30 minutes of bismuth subcitrate (tripotassium bismuth dicitrate) administration. Consider therapy modification

Atovaquone: Tetracycline (Systemic) may decrease the serum concentration of Atovaquone. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Tetracyclines. Consider therapy modification

Bismuth Subcitrate: May decrease the serum concentration of Tetracyclines. Management: Avoid administration of oral tetracyclines within 30 minutes of bismuth subcitrate administration. This is of questionable significance for at least some regimens intended to treat H. pylori infections. Consider therapy modification

Bismuth-Containing Compounds: May enhance the neurotoxic effect of Bismuth Subcitrate. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Busulfan: MetroNIDAZOLE (Systemic) may increase the serum concentration of Busulfan. Management: The toxic effects of busulfan may be greatly increased with concomitant use of metronidazole. This combination should probably be avoided when possible. If these agents must be used together, increased monitoring for busulfan toxicity is recommended. Consider therapy modification

Calcium Salts: May decrease the serum concentration of Tetracyclines. Management: If coadministration of oral calcium with oral tetracyclines can not be avoided, consider separating administration of each agent by several hours. Consider therapy modification

Carbocisteine: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Carbocisteine. Specifically, metronidazole may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Avoid combination

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Disulfiram: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). In particular, the risk for CNS toxicities such as psychosis may be increased. Avoid combination

Dronabinol: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Dronabinol. Specifically, metronidazole may produce severe intolerance to the alcohol contained in the dronabinol oral solution. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Fluorouracil Products: MetroNIDAZOLE (Systemic) may increase the serum concentration of Fluorouracil Products. Monitor therapy

Iron Preparations: Tetracyclines may decrease the absorption of Iron Preparations. Iron Preparations may decrease the serum concentration of Tetracyclines. Management: Avoid this combination if possible. Administer oral iron preparations at least 2 hours before, or 4 hours after, the dose of the oral tetracycline derivative. Monitor for decreased therapeutic effect of oral tetracycline derivatives. Exceptions: Ferric Carboxymaltose; Ferric Derisomaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Lanthanum: May decrease the serum concentration of Tetracyclines. Management: Administer oral tetracycline antibiotics at least two hours before or after lanthanum. Consider therapy modification

Lithium: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Lithium. MetroNIDAZOLE (Systemic) may increase the serum concentration of Lithium. Monitor therapy

Lopinavir: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Lopinavir. Specifically, the combination of metronidazole and lopinavir/ritonavir solution, which contains 42% alcohol, may result in a disulfiram-like reaction. MetroNIDAZOLE (Systemic) may enhance the arrhythmogenic effect of Lopinavir. Management: Avoid the concomitant use of lopinavir/ritonavir and metronidazole if possible. If these agents are used concomitantly, monitor for QTc prolongation/arrhythmia and if the lopinavir/ritonavir solution is used, development of a disulfiram-like reaction. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Magnesium Dimecrotate: May interact via an unknown mechanism with Tetracyclines. Monitor therapy

Magnesium Salts: May decrease the absorption of Tetracyclines. Only applicable to oral preparations of each agent. Consider therapy modification

Mebendazole: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Particularly the risk for Stevens-Johnson syndrome or toxic epidermal necrolysis may be increased. Avoid combination

Mecamylamine: Tetracyclines may enhance the neuromuscular-blocking effect of Mecamylamine. Avoid combination

Methoxyflurane: Tetracyclines may enhance the nephrotoxic effect of Methoxyflurane. Avoid combination

Mipomersen: Tetracyclines may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Tetracyclines. Management: If coadministration of a polyvalent cation-containing multivitamin with oral tetracyclines can not be avoided, separate administration of each agent by several hours. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Tetracyclines. Management: If coadministration of a polyvalent cation-containing multivitamin with oral tetracyclines can not be avoided, separate administration of each agent by several hours. Consider therapy modification

Mycophenolate: MetroNIDAZOLE (Systemic) may decrease the serum concentration of Mycophenolate. Specifically, metronidazole may decrease concentrations of the active metabolite of mycophenolate. Monitor therapy

Neuromuscular-Blocking Agents: Tetracyclines may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Penicillins: Tetracyclines may diminish the therapeutic effect of Penicillins. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Products Containing Propylene Glycol: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Products Containing Propylene Glycol. A disulfiram-like reaction may occur. Avoid combination

Quinapril: May decrease the serum concentration of Tetracyclines. Management: Separate doses of quinapril and oral tetracycline derivatives by at least 2 hours in order to reduce the risk of interaction. Monitor for reduced efficacy of the tetracycline if these products are used concomitantly. Consider therapy modification

QuiNINE: Tetracycline (Systemic) may increase the serum concentration of QuiNINE. Monitor therapy

Retinoic Acid Derivatives: Tetracyclines may enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Exceptions: Adapalene; Bexarotene (Topical); Tretinoin (Topical). Avoid combination

Ritonavir: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Specifically, the combination of ritonavir oral solution or ritonavir soft gelatin capsule, both of which contain alcohol, and metronidazole may result in a disulfiram-like reaction. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Strontium Ranelate: May decrease the serum concentration of Tetracyclines. Management: In order to minimize any potential impact of strontium ranelate on tetracycline antibiotic concentrations, it is recommended that strontium ranelate treatment be interrupted during tetracycline therapy. Avoid combination

Sucralfate: May decrease the absorption of Tetracyclines. Management: Administer most tetracycline derivatives at least 2 hours prior to sucralfate in order to minimize the impact of this interaction. Administer oral omadacycline 4 hours prior to sucralfate. Consider therapy modification

Sucroferric Oxyhydroxide: May decrease the serum concentration of Tetracyclines. Management: Administer oral/enteral doxycycline at least 1 hour before sucroferric oxyhydroxide. Specific dose separation guidelines for other tetracyclines are not presently available. No interaction is anticipated with parenteral administration of tetracyclines. Consider therapy modification

Tetracyclines: Bismuth Subcitrate may decrease the serum concentration of Tetracyclines. Management: Avoid administration of oral tetracyclines within 30 minutes of bismuth subcitrate administration. This is of questionable significance for at least some regimens intended to treat H. pylori infections. Exceptions: Eravacycline. Consider therapy modification

Tipranavir: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Tipranavir. A disulfiram-like reaction may occur due to the alcohol contained in tipranavir capsules. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vecuronium: MetroNIDAZOLE (Systemic) may enhance the neuromuscular-blocking effect of Vecuronium. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): MetroNIDAZOLE (Systemic) may increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased INR/bleeding. Consider therapy modification

Zinc Salts: May decrease the absorption of Tetracyclines. Only a concern when both products are administered orally. Management: Consider doxycycline as a noninteracting tetracycline derivative. Separate dose administration of oral tetracycline derivative and oral zinc salts by at least 2 hours to minimize interaction. Exceptions: Zinc Chloride. Consider therapy modification

Test Interactions

See individual agents.

Adverse Reactions

Also see individual agents. Adverse reactions are associated with concomitant administration of omeprazole.

>10%: Gastrointestinal: Abnormal stools (16%)

1% to 10%:

Central nervous system: Headache (5%), dizziness (3%)

Dermatologic: Maculopapular rash (1%)

Gastrointestinal: Nausea (8%), diarrhea (7%), abdominal pain (5%), dysgeusia (4%), dyspepsia (3%), constipation (1%), xerostomia (1%)

Genitourinary: Vaginitis (3%), urine abnormality (1%)

Hepatic: Increased serum ALT (1%), increased serum AST (1%)

Neuromuscular & skeletal: Weakness (3%)

Miscellaneous: Laboratory test abnormality (2%)

<1%, postmarketing, and/or case reports: Abdominal distention, anxiety, back pain, candidiasis, chest discomfort, chest pain, drowsiness, duodenal ulcer, eructation, fatigue, flatulence, gastritis, gastroenteritis, increased appetite, increased creatine phosphokinase, malaise, myalgia, skin rash, tachycardia, tongue discoloration (darkening), visual disturbance, vomiting, weight gain

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Bismuth may be neurotoxic with excessive doses. Aseptic meningitis (symptoms may occur within hours of a dose), encephalopathy (cerebellar toxicity with ataxia, dizziness, dysarthria, and/or CNS lesions), seizures, peripheral neuropathy (including extremity numbness and paresthesia) and optic neuropathy have been reported with metronidazole. CNS symptoms generally resolve within days to weeks following therapy discontinuation; monitor patients with CNS conditions closely and discontinue promptly if abnormal neurologic signs develop.
• Cutaneous reactions: Skin and subcutaneous disorders including Stevens-Johnson, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported; discontinue treatment at first sign of cutaneous reaction.
• Intracranial hypertension: Intracranial hypertension (IH), including pseudotumor cerebri has been reported with use of tetracyclines; women of childbearing age who are overweight or have a history of IH are at greater risk. IH typically resolves after discontinuation of treatment but the possibility for permanent visual loss exists; prompt ophthalmic evaluation is warranted if visual disturbances occur.
• Oral/gastrointestinal effects: Bismuth may cause temporary and harmless darkening of the tongue and/or black stools; generally reversible within several days after treatment is discontinued.
• Photosensitivity: Tetracycline may cause photosensitivity; avoid exposure to the sun or sun lamps; discontinue use at first evidence of skin erythema.
• Potential for carcinogenicity: [US Boxed Warning]: Metronidazole has been shown to be carcinogenic in mice and rats. It is unknown whether metronidazole is associated with carcinogenicity in humans.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Blood dyscrasias: Use metronidazole with caution in patients with or history of blood dyscrasias; mild leukopenia has occurred. Monitor CBC with differential at baseline and after treatment.
• Cockayne syndrome: Severe hepatotoxicity/acute hepatic failure (has been fatal) has been reported with systemic metronidazole in patients with Cockayne syndrome; onset is rapid after initiation of treatment. Use metronidazole only after risk vs benefit assessment and if there are no appropriate alternatives in patients with Cockayne syndrome. Obtain LFTs prior to treatment initiation, within the first 2 to 3 days of initiation, frequently during therapy, and after treatment is complete. Discontinue treatment if elevated LFTs occur and monitor until LFTs return to baseline.
• Hepatic impairment: Use with caution in patients with mild to moderate hepatic impairment due to potential metronidazole accumulation; use in patients with severe hepatic impairment may not be appropriate.
• H. pylori infection: If H. pylori is not eradicated in patients being treated with metronidazole in a regimen, it should be assumed that metronidazole-resistance has occurred and it should not be used again.
• Renal impairment: Tetracycline may be associated with increases in BUN secondary to antianabolic effects; use is contraindicated in patients with severe renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: May cause tissue hyperpigmentation, enamel hypoplasia, or permanent tooth discoloration; more common during long-term treatment, but has been observed following repeated short-term courses. Use of tetracyclines should be avoided during tooth development (children <8 years) unless other drugs are not likely to be effective or are contraindicated.

Other warnings/precautions:

• Appropriate use: Helicobacter pylori eradication: Short-term combination therapy (≤7 days) has been associated with a higher incidence of treatment failure. The American College of Gastroenterology recommends 10 to 14 days of therapy (triple or quadruple) for eradication of H. pylori (Chey 2017).

Monitoring Parameters

Monitor CBC with differential at baseline and after treatment (due to metronidazole); development of abnormal neurologic signs/symptoms. H. pylori eradication confirmation, when indicated (Chey, 2007).

Pregnancy

Pregnancy Considerations

This combination is contraindicated in women who are pregnant. Metronidazole and tetracycline both cross the human placenta and may have adverse effects to the fetus. See individual agents.

Patient Education

What is this drug used for?

• It is used to treat GI (gastrointestinal) ulcers caused by infection.

Frequently reported side effects of this drug

• Nausea
• Diarrhea
• Abdominal pain
• Tongue discoloration
• Stool discoloration

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Burning or numbness feeling
• Vision changes
• Change in balance
• Dizziness
• Passing out
• Headache
• Trouble sleeping
• Seizures
• Trouble speaking
• Confusion
• Depression
• Irritability
• Fatigue
• Muscle weakness
• Black, tarry, or bloody stools
• Vomiting blood
• Clostridioides difficile (C. diff)-associated diarrhea like abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Infection
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Aseptic meningitis like headache, fever, chills, severe nausea or vomiting, stiff neck, rash, sensitivity to lights, fatigue, or confusion
• Blindness
• Double vision
• Blurred vision
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.