Metronidazole has been shown to be carcinogenic in mice and rats. It is unknown whether metronidazole is associated with carcinogenicity in humans.
Helicobacter pylori eradication: 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 to 14 days (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Severe impairment: Use is contraindicated.
Mild to moderate impairment (Child-Pugh class A or B): There are no dosage adjustments provided in the manufacturer's labeling; use with caution. See individual agents.
Severe impairment (Child-Pugh class C): Use may not be appropriate in severe impairment; accumulation of metronidazole may occur. See individual agents.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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
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); Cockayne syndrome.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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; 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; females 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.
• 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.
• 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.
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).
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
Generic: Bismuth subcitrate potassium 140 mg, metronidazole 125 mg, and tetracycline hydrochloride 125 mg
Yes
Capsules (Pylera Oral)
140-125-125 mg (120): $731.28
Disclaimer: The pricing data provide a representative AWP and/or AAWP price from a single manufacturer of the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for reimbursement or purchasing functions. Pricing data is updated monthly.
Oral: Swallow capsules whole with 240 mL (8 oz) of water after meals and at bedtime. Administer concomitant omeprazole after morning meal and evening meal.
Helicobacter pylori eradication: 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.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (contraindicated in pregnancy) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).
KIDs List: Tetracycline, when used in neonates, infants, and children <8 years of age, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list. In neonates, tetracycline should be used with caution due to risk of retardation of skeletal development and bone growth in premature neonates (strong recommendation; moderate quality of evidence); in infants and children <8 years of age, it should be used with caution due to risk of tooth discoloration and enamel hypoplasia (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Alcohol (Ethyl). A disulfiram-like reaction may occur. Risk X: Avoid combination
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: 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. Risk D: Consider therapy modification
Atovaquone: Tetracycline (Systemic) may decrease the serum concentration of Atovaquone. Risk C: Monitor therapy
Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Tetracyclines. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Bismuth-Containing Compounds: May enhance the neurotoxic effect of Bismuth Subcitrate. Risk X: Avoid combination
Busulfan: MetroNIDAZOLE (Systemic) may increase the serum concentration of Busulfan. Management: Avoid coadministration metronidazole and busulfan due to increased risks of busulfan toxicity. If coadministration is required, monitor busulfan concentrations closely and adjust the busulfan dose as needed. Risk D: Consider therapy modification
Calcium Salts: May decrease the serum concentration of Tetracyclines. Management: If coadministration of oral calcium with oral tetracyclines cannot be avoided, consider separating administration of each agent by several hours. Risk D: Consider therapy modification
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. Risk X: Avoid combination
Disulfiram: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). In particular, the risk for CNS toxicities such as psychosis may be increased. Risk X: 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. Risk X: Avoid combination
Fecal Microbiota (Live) (Oral): May diminish the therapeutic effect of Antibiotics. Risk X: Avoid combination
Fecal Microbiota (Live) (Rectal): Antibiotics may diminish the therapeutic effect of Fecal Microbiota (Live) (Rectal). Risk X: Avoid combination
Fluorouracil Products: MetroNIDAZOLE (Systemic) may increase the serum concentration of Fluorouracil Products. Risk C: Monitor therapy
Fosphenytoin: May decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Fosphenytoin. Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: 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. Risk D: Consider therapy modification
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Lanthanum: May decrease the serum concentration of Tetracyclines. Management: Administer oral tetracycline antibiotics at least 2 hours before or after lanthanum. Risk D: Consider therapy modification
Lithium: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Lithium. MetroNIDAZOLE (Systemic) may increase the serum concentration of Lithium. Risk C: 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. Risk D: Consider therapy modification
Magnesium Dimecrotate: May interact via an unknown mechanism with Tetracyclines. Risk C: Monitor therapy
Magnesium Salts: May decrease the absorption of Tetracyclines. Only applicable to oral preparations of each agent. Management: Avoid coadministration of oral magnesium salts and oral tetracyclines. If coadministration cannot be avoided, administer oral magnesium at least 2 hours before, or 4 hours after, oral tetracyclines. Monitor for decreased tetracycline therapeutic effects. Risk D: 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. Risk X: Avoid combination
Mecamylamine: Tetracyclines may enhance the neuromuscular-blocking effect of Mecamylamine. Risk X: Avoid combination
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Methoxyflurane: Tetracyclines may enhance the nephrotoxic effect of Methoxyflurane. Risk X: Avoid combination
Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Tetracyclines. Management: Avoid this combination if possible. If coadministration cannot be avoided, administer the polyvalent cation-containing multivitamin at least 2 hours before or 4 hours after the tetracycline derivative. Monitor for decreased tetracycline effects. Risk D: 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 cannot be avoided, administer the polyvalent cation-containing multivitamin either 2 hours before or 4 hours after the tetracycline product. Risk D: Consider therapy modification
Mycophenolate: Antibiotics may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be reduced. Risk C: Monitor therapy
Neuromuscular-Blocking Agents: Tetracyclines may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy
Penicillins: Tetracyclines may diminish the therapeutic effect of Penicillins. Risk C: Monitor therapy
PHENobarbital: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of PHENobarbital. A disulfiram-like reaction may occur if combined with phenobarbital dosage forms that contain propylene glycol or alcohol. PHENobarbital may decrease the serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor therapy
Phenytoin: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Phenytoin. A disulfiram-like reaction may occur if combined with phenytoin dosage forms that contain propylene glycol. Phenytoin may decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Phenytoin. Risk C: Monitor therapy
Polyethylene Glycol-Electrolyte Solution: May decrease the absorption of Tetracyclines. Management: Give oral tetracyclines at least 2 hours before or at least 6 hours after polyethylene glycol-electrolyte solutions that contain magnesium sulfate (Suflave brand). Other products without magnesium do not require dose separation. Risk D: Consider therapy modification
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Primidone: May decrease the serum concentration of MetroNIDAZOLE (Systemic). Risk C: 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. Risk X: Avoid combination
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Quinapril: May decrease the serum concentration of Tetracyclines. Risk C: Monitor therapy
QuiNINE: Tetracycline (Systemic) may increase the serum concentration of QuiNINE. Risk C: 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. Risk X: 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. Risk X: Avoid combination
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. Risk D: 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. Risk X: 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. Risk D: 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. Risk D: Consider therapy modification
Sulfonylureas: MetroNIDAZOLE (Systemic) may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
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. Risk D: 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. Risk C: Monitor therapy
TOLBUTamide: CYP2C9 Inhibitors (Weak) may increase the serum concentration of TOLBUTamide. Risk C: Monitor therapy
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Vecuronium: MetroNIDAZOLE (Systemic) may enhance the neuromuscular-blocking effect of Vecuronium. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: 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. Risk D: Consider therapy modification
Zinc Salts: May decrease the absorption of Tetracyclines. Only a concern when both products are administered orally. Management: Separate administration of oral tetracycline derivatives and oral zinc salts by at least 2 hours to minimize this interaction. Risk D: Consider therapy modification
This combination is contraindicated in pregnant patients. Metronidazole and tetracycline both cross the human placenta and may have adverse effects to the fetus. See individual monographs for additional information.
Metronidazole and tetracycline are excreted in breast milk in concentrations similar to the maternal plasma; it is not known if bismuth is excreted in breast milk. Because of the potential for serious adverse reactions in the nursing infant, the manufacturer recommends that breast-feeding be interrupted during therapy and for 2 days after the last dose. See individual agents.
Monitor CBC with differential at baseline and after treatment (due to metronidazole); development of abnormal neurologic signs/symptoms. H. pylori eradication confirmation, when indicated (ACG [Chey 2017]).
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.
Also see individual agents.
Absorption: Food reduced AUC by 6% (metronidazole), 34% (tetracycline), and 60% (bismuth)
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